Sensitizing protective tumor microenvironments to antibody-mediated therapy.

Therapy-resistant microenvironments represent a major barrier toward effective elimination of disseminated malignancies. Here, we show that select microenvironments can underlie resistance to antibody-based therapy. Using a humanized model of treatment refractory B cell leukemia, we find that infiltration of leukemia cells into the bone marrow rewires the tumor microenvironment to inhibit engulfment of antibody-targeted tumor cells. Resistance to macrophage-mediated killing can be overcome by combination regimens involving therapeutic antibodies and chemotherapy. Specifically, the nitrogen mustard cyclophosphamide induces an acute secretory activating phenotype (ASAP), releasing CCL4, IL8, VEGF, and TNFα from treated tumor cells. These factors induce macrophage infiltration and phagocytic activity in the bone marrow. Thus, the acute induction of stress-related cytokines can effectively target cancer cells for removal by the innate immune system. This synergistic chemoimmunotherapeutic regimen represents a potent strategy for using conventional anticancer agents to alter the tumor microenvironment and promote the efficacy of targeted therapeutics.

BCL-2-family protein tBID can act as a BAX-like effector of apoptosis.

During apoptosis, the BCL-2-family protein tBID promotes mitochondrial permeabilization by activating BAX and BAK and by blocking anti-apoptotic BCL-2 members. Here, we report that tBID can also mediate mitochondrial permeabilization by itself, resulting in release of cytochrome c and mitochondrial DNA, caspase activation and apoptosis even in absence of BAX and BAK. This previously unrecognized activity of tBID depends on helix 6, homologous to the pore-forming regions of BAX and BAK, and can be blocked by pro-survival BCL-2 proteins. Importantly, tBID-mediated mitochondrial permeabilization independent of BAX and BAK is physiologically relevant for SMAC release in the immune response against Shigella infection. Furthermore, it can be exploited to kill leukaemia cells with acquired venetoclax resistance due to lack of active BAX and BAK. Our findings define tBID as an effector of mitochondrial permeabilization in apoptosis and provide a new paradigm for BCL-2 proteins, with implications for anti-bacterial immunity and cancer therapy.

Different transmembrane domains determine the specificity and efficiency of the cleavage activity of the γ-secretase subunit presenilin.

The γ-secretase complex catalyzes the intramembrane cleavage of C99, a carboxy-terminal fragment of the amyloid precursor protein. Two paralogs of its catalytic subunit presenilin (PS1 and PS2) are expressed which are autocatalytically cleaved into an N-terminal and a C-terminal fragment during maturation of γ-secretase. In this study, we compared the efficiency and specificity of C99 cleavage by PS1- and PS2-containing γ-secretases. Mass spectrometric analysis of cleavage products obtained in cell-free and cell-based assays revealed that the previously described lower amyloid-ß (Aß)38 generation by PS2 is accompanied by a reciprocal increase in Aß37 production. We further found PS1 and PS2 to show different preferences in the choice of the initial cleavage site of C99. However, the differences in Aß38 and Aß37 generation appear to mainly result from altered subsequent stepwise cleavage of Aß peptides. Apart from these differences in cleavage specificity, we confirmed a lower efficiency of initial C99 cleavage by PS2 using a detergent-solubilized γ-secretase system. By investigating chimeric PS1/2 molecules, we show that the membrane-embedded, nonconserved residues of the N-terminal fragment mainly account for the differential cleavage efficiency and specificity of both presenilins. At the level of individual transmembrane domains (TMDs), TMD3 was identified as a major modulator of initial cleavage site specificity. The efficiency of endoproteolysis strongly depends on nonconserved TMD6 residues at the interface to TMD2, i.e., at a putative gate of substrate entry. Taken together, our results highlight the role of individual presenilin TMDs in the cleavage of C99 and the generation of Aß peptides.

Post-transplant-cyclophosphamide and short-term Everolimus as graft-versus-host-prophylaxis in patients with relapsed/refractory lymphoma and myeloma-Final results of the phase II OCTET-EVER trial.

BACKGROUND: Conditioning regimens and the choice of immunosuppression have substantial impact on immune reconstitution after allogeneic hematopoietic stem cell transplantation (aHSCT). The pivotal mechanism to maintain remission is the induction of the graft-versus-tumor effect. Relapse as well as graft versus host disease remain common. Classic immunosuppressive strategies implementing calcineurin inhibitors (CNI) have significant toxicities, hamper the immune recovery, and reduce the anti-cancer immune response. METHODS: We designed a phase II clinical trial for patients with relapsed and refractory lymphoid malignancies undergoing aHSCT using a CNI-free approach consisting of post-transplant cyclophosphamide (PTCy) and short-term Everolimus after reduced-intensity conditioning and matched peripheral blood stem cell transplantation. The results of the 19 planned patients are presented. Primary endpoint is the cumulative incidence and severity of acute GvHD. RESULTS: Overall incidence of acute GvHD was 53% with no grade III or IV. Cumulative incidence of NRM at 1, 2, and 4 years was 11%, 11%, and 16%, respectively, with a median follow-up of 43 months. Cumulative incidence of relapse was 32%, 32%, and 42% at 1, 2, and 4 years after transplant, respectively. Four out of six early relapses were multiple myeloma patients. Overall survival was 79%, 74%, and 62% at 1, 2, and 4 years. GvHD-relapse-free-survival was 47% after 3 years. CONCLUSIONS: Using PTCy and short-term Everolimus is safe with low rates of aGvHD and no severe aGvHD or cGvHD translating into a low rate of non-relapse mortality. Our results in this difficult to treat patient population are encouraging and warrant further studies.

Disequilibrium reaction pathways and the twin-mediated growth of tabular forsterite during contact metamorphism of quartz-bearing dolomite.

The forsterite zone of the Ubehebe Peak contact aureole, Death Valley, USA consists of an outer zone of tabular/jack-straw olivine and an inner zone of subequant polyhedral olivine. Subequant polyhedral forsterite crystals close to the intrusion are small and tabular forsterite crystals farther away are larger. To investigate the formation of the two morphologies, forsterite growth experiments were conducted in cold seal pressure vessels in the CaO-MgO-SiO2-CO2-H2O system. Forsterite precipitation follows a disequilibrium reaction pathway made of three reactions: [1] tabular forsterite growth from quartz and dolomite, [2] forsterite growth from tremolite dissolution, and [3] subequant polyhedral forsterite growth from tabular forsterite dissolution. Initially, quartz reacts with dolomite to simultaneously form twinned tabular forsterite and tremolite. As quartz reacts away, forsterite precipitation continues at a slower rate through tremolite dissolution. A second generation of forsterite then precipitates on top of some tabular forsterite but has different habit and tracht. Once all the tremolite reacts away, subequant polyhedral forsterite precipitation continues at an even slower rate through dissolution of tabular forsterite. The tabular morphology of jack-straw olivine is a consequence of twin-mediated unidirectional growth; the abundance of twins being due to rapid nucleation and growth at initially high reaction affinities. Twin junctions are preferential nucleation centers for steps, so faceted growth is enhanced on {100}. This phenomenon is the twin plane re-entrant effect. Subequant polyhedral forsterite in the Ubehebe Peak inner contact aureole recrystallized and ripened from tabular forsterite. In the outer contact aureole, conditions were not conducive to recrystallization and ripening so well-developed tabular forsterite persists.

Statistical shape models that predict native glenoid width based on glenoid height are inaccurate in their current form: a cross-sectional study.

BACKGROUND: The extent of measurement errors of statistical shape models that predict native glenoid width based on glenoid height to subsequently determine the amount of anterior glenoid bone loss is unclear. Therefore, the aim of this study was to (1) create a statistical shape model based on glenoid height and width measured on 3-dimensional computed tomography (3D-CT) and determine the accuracy through measurement errors and (2) determine measurement errors of existing 3D-CT statistical shape models. MATERIALS AND METHODS: A retrospective cross-sectional study included all consecutive patients who underwent CT imaging before undergoing primary surgical treatment of traumatic anterior shoulder dislocation between 2007 and 2022 at the Tohoku University Hospital and affiliated hospitals. Patients were included when instability was unilateral and CT scans of both the injured and contralateral uninjured shoulder were available. 3D segmentations were created and glenoid height and width of the injured and contralateral uninjured side (gold standard) were measured. Accuracy was determined through measurement errors, which were defined as a percentage error deviation from native glenoid width (contralateral uninjured glenoid), calculated as follows: measurement error = [(estimated glenoid width with a statistical shape model - native glenoid width) / native glenoid width] × 100%. A linear regression analysis was performed to create a statistical shape model based on glenoid height according to the formula: native glenoid width = a × glenoid height + b. RESULTS: The diagnosis and procedure codes identified 105 patients, of which 69 (66%) were eligible for inclusion. Glenoid height demonstrated a very strong correlation (r = 0.80) with native glenoid width. The linear regression formula based on this cohort was as follows: native glenoid width = 0.75 × glenoid height - 0.61, and it demonstrated an absolute average measurement error of 5% ± 4%. The formulas by Giles et al, Chen et al and Rayes et al demonstrated absolute average measurement errors of 10% ± 7%, 6% ± 5%, and 9% ± 6%, respectively. CONCLUSION: Statistical shape models that estimate native glenoid width based on glenoid height demonstrate unacceptable measurement errors, despite a high correlation. Therefore, great caution is advised when using these models to determine glenoid bone loss percentage. To minimize errors caused by morphologic differences, preference goes to methods that use the contralateral side as reference.

MARCKS affects cell motility and response to BTK inhibitors in CLL.

Bruton tyrosine kinase (BTK) inhibitors are highly active drugs for the treatment of chronic lymphocytic leukemia (CLL). To understand the response to BTK inhibitors on a molecular level, we performed (phospho)proteomic analyses under ibrutinib treatment. We identified 3466 proteins and 9184 phosphopeptides (representing 2854 proteins) in CLL cells exhibiting a physiological ratio of phosphorylated serines (pS), threonines (pT), and tyrosines (pY) (pS:pT:pY). Expression of 83 proteins differed between unmutated immunoglobulin heavy-chain variable region (IGHV) CLL (UM-CLL) and mutated IGHV CLL (M-CLL). Strikingly, UM-CLL cells showed higher basal phosphorylation levels than M-CLL samples. Effects of ibrutinib on protein phosphorylation levels were stronger in UM-CLL, especially on phosphorylated tyrosines. The differentially regulated phosphopeptides and proteins clustered in pathways regulating cell migration, motility, cytoskeleton composition, and survival. One protein, myristoylated alanine-rich C-kinase substrate (MARCKS), showed striking differences in expression and phosphorylation level in UM-CLL vs M-CLL. MARCKS sequesters phosphatidylinositol-4,5-bisphosphate, thereby affecting central signaling pathways and clustering of the B-cell receptor (BCR). Genetically induced loss of MARCKS significantly increased AKT signaling and migratory capacity. CD40L stimulation increased expression of MARCKS. BCR stimulation induced phosphorylation of MARCKS, which was reduced by BTK inhibitors. In line with our in vitro findings, low MARCKS expression is associated with significantly higher treatment-induced leukocytosis and more pronounced decrease of nodal disease in patients with CLL treated with acalabrutinib.

Active Akt signaling triggers CLL toward Richter transformation via overactivation of Notch1.

Richter's transformation (RT) is an aggressive lymphoma that occurs upon progression from chronic lymphocytic leukemia (CLL). Transformation has been associated with genetic aberrations in the CLL phase involving TP53, CDKN2A, MYC, and NOTCH1; however, a significant proportion of RT cases lack CLL phase-associated events. Here, we report that high levels of AKT phosphorylation occur both in high-risk CLL patients harboring TP53 and NOTCH1 mutations as well as in patients with RT. Genetic overactivation of Akt in the murine Eµ-TCL1 CLL mouse model resulted in CLL transformation to RT with significantly reduced survival and an aggressive lymphoma phenotype. In the absence of recurrent mutations, we identified a profile of genomic aberrations intermediate between CLL and diffuse large B-cell lymphoma. Multiomics assessment by phosphoproteomic/proteomic and single-cell transcriptomic profiles of this Akt-induced murine RT revealed an S100 protein-defined subcluster of highly aggressive lymphoma cells that developed from CLL cells, through activation of Notch via Notch ligand expressed by T cells. Constitutively active Notch1 similarly induced RT of murine CLL. We identify Akt activation as an initiator of CLL transformation toward aggressive lymphoma by inducing Notch signaling between RT cells and microenvironmental T cells.

Identifying crustal contributions in the Patagonian Chon Aike Silicic Large Igneous Province.

The volcanic rocks of the Chon Aike Silicic Large Igneous Province (CASP) are recognized as magmas dominantly produced by crustal anatexis. Investigating the zircon of the CASP provides an opportunity to gain further insight into geochemical and isotopic differences of the potential magmatic sources (i.e., crust versus mantle), to identify crustal reservoirs that contributed to the felsic magmas during anatexis, and to quantify the contributions of the respective sources. We present a combined zircon oxygen and hafnium isotope and trace element dataset for 16 volcanic units of the two youngest volcanic phases in Patagonia, dated here with LA-ICP-MS U-Pb geochronology at ca. 148-153 Ma (El Quemado Complex, EQC) and ca. 159 Ma (western Chon Aike Formation, WCA). The EQC zircon have 18O-enriched values (δ18O from 7 to 9.5‰) with correspondingly negative initial εHf values (- 2.0 to - 8.0). The WCA zircon have δ18O values between 6 and 7‰ and εHf values ranging between - 4.0 and + 1.5. Binary δ18O-εHf mixing models require an average of 70 and 60% melt derived from partial melting of isotopically distinct metasedimentary basements for the EQC and WCA, respectively. Zircon trace element compositions are consistent with anatexis of sedimentary protoliths derived from LIL-depleted upper continental crustal sources. The overlap between a high heat flux environment (i.e., widespread extension and lithospheric thinning) during supercontinental breakup and a fertile metasedimentary crust was key in producing voluminous felsic volcanism via anatexis following the injection and emplacement of basaltic magmas into the lower crust. Supplementary Information: The online version contains supplementary material available at 10.1007/s00410-023-02065-1.

Cerebral oxygenation immediately after birth and long-term outcome in preterm neonates-a retrospective analysis.

BACKGROUND: Prematurity is associated with increased risk for morbidity and mortality. Aim of this study was to evaluate whether cerebral oxygenation during fetal-to-neonatal transition period was associated with long-term outcome in very preterm neonates. METHODS: Preterm neonates ≤ 32 weeks of gestation and/or ≤ 1500 g with measurements of cerebral regional oxygen saturation (crSO2) and cerebral fractional tissue oxygen extraction (cFTOE) within the first 15 min after birth were analysed retrospectively. Arterial oxygen saturation (SpO2) and heart rate (HR) were measured with pulse oximetry. Long-term outcome was assessed at two years using "Bayley Scales of Infant Development" (BSID-II/III). Included preterm neonates were stratified into two groups: adverse outcome group (BSID-III ≤ 70 or testing not possible due to severe cognitive impairment or mortality) or favorable outcome group (BSID-III > 70). As the association between gestational age and long-term outcome is well known, correction for gestational age might disguise the potential association between crSO2 and neurodevelopmental impairment. Therefore, due to an explorative approach the two groups were compared without correction for gestational age. RESULTS: Forty-two preterm neonates were included: adverse outcome group n = 13; favorable outcome group n = 29. Median(IQR) gestational age and birth weight were 24.8 weeks (24.2-29.8) and 760 g (670-1054) in adverse outcome group and 30.6 weeks (28.1-32.0) (p = 0.009*) and 1250 g (972-1390) (p = 0.001*) in the favorable outcome group, respectively. crSO2 was lower (significant in 10 out of 14 min) and cFTOE higher in adverse outcome group. There were no difference in SpO2, HR and fraction of inspired oxygen (FiO2), except for FiO2 in minute 11, with higher FiO2 in the adverse outcome group. CONCLUSION: Preterm neonates with adverse outcome had beside lower gestational age also a lower crSO2 during immediate fetal-to-neonatal transition when compared to preterm neonates with age appropriate outcome. Lower gestational age in the adverse outcome group would suggest beside lower crSO2 also lower SpO2 and HR in this group, which were however similar in both groups.

Cardiac output and regional-cerebral-oxygen-saturation in preterm neonates during immediate postnatal transition: An observational study.

AIM: To examine potential correlations between cardiac output (CO) with cerebral-regional-oxygen-saturation (crSO2 ) and cerebral-fractional-tissue-oxygen-extraction (cFTOE) during immediate foetal-to-neonatal transition in term and preterm neonates with and without respiratory support. METHODS: Post hoc analyses of secondary outcome parameters of prospective observational studies were performed. We included neonates with cerebral near-infrared-spectroscopy (NIRS) monitoring and an oscillometric blood pressure measurement at minute 15 after birth. Heart rate (HR) and arterial oxygen saturation (SpO2 ) were monitored. CO was calculated with Liljestrand and Zander formula and correlated with crSO2 and cFTOE. RESULTS: Seventy-nine preterm neonates and 207 term neonates with NIRS measurements and calculated CO were included. In 59 preterm neonates (mean gestational age (GA): 29.4 ± 3.7 weeks) with respiratory support, CO correlated significantly positively with crSO2 and significantly negatively with cFTOE. In 20 preterm neonates (GA 34.9 ± 1.3 weeks) without respiratory support and in 207 term neonates with and without respiratory support, CO correlated neither with crSO2 nor with cFTOE. CONCLUSION: In compromised preterm neonates with lower gestational age and in need of respiratory support, CO was associated with crSO2 and cFTOE, whereas in stable preterm neonates with higher gestational age as well as in term neonates with and without respiratory support, no associations were observed.

Surgical Intervention Following a First Traumatic Anterior Shoulder Dislocation Is Worthy of Consideration.

Up to 60% of patients experience recurrence after a first traumatic anterior shoulder dislocation (FTASD), which is often defined as having experienced either dislocation or subluxation. Thus surgical intervention after FTASD is worthy of consideration and is guided by the number of patients who need to receive surgical intervention to prevent 1 redislocation (i.e., number needed to treat), (subjective) health benefit, complication risk, and costs. Operative intervention through arthroscopic stabilization can be successful in reducing recurrence risk in FTASD, as has been shown in multiple randomized controlled trials. Nevertheless, there is a large "gray area" for the indication of arthroscopic stabilization, and it is therefore heavily debated which patients should receive operative treatment. Previous trials showed widely varying redislocation rates in both the intervention and control group, meta-analysis shows 2% to 19% after operative and 20% to 75% after nonoperative treatment, and redislocation rates may not correlate with patient-reported outcomes. The literature is quite heterogeneous, and a major confounder is time to follow-up. Furthermore, there is insufficient standardization of reporting of outcomes and no consensus on definition of risk factors. As a result, surgery is a reasonable intervention for FTASD patients, but in which patients it best prevents redislocation requires additional refinement.

Wide Range in Complication Rates Following Elbow Arthroscopy in Adult and Pediatric Patients: A Systematic Review.

PURPOSE: To perform a systematic review of complications associated with elbow arthroscopy in adults and children. METHODS: A literature search was performed in the PubMed, EMBASE, and Cochrane databases. Studies reporting complications or reoperations after elbow arthroscopy with at least 5 patients were included. Based on the Nelson classification, the severity of complications was categorized as minor or major. Risk of bias was assessed using the Cochrane risk-of-bias tool for randomized clinical trials, and nonrandomized trials were assessed using the Methodological Items for Non-randomized Studies (MINORS) tool. RESULT: A total of 114 articles were included with 18,892 arthroscopies (16,815 patients). A low risk of bias was seen for the randomized studies and a fair quality for the nonrandomized studies. Complication rates ranged from 0% to 71% (median 3%; 95% confidence interval [CI], 2.8%-3.3%), and reoperation rates from 0% to 59% (median 2%; 95% CI, 1.8%-2.2%). A total of 906 complications were observed, with transient nerve palsies (31%) as the most frequent complication. According to Nelson classification, 735 (81%) complications were minor and 171 (19%) major. Forty-nine studies reported complications in adults and 10 studies in children, showing a complication rate ranging from 0% to 27% (median 0%; 95% CI, 0%-0.4%) and 0% to 57% (median 1%; 95% CI, 0.4%-3.5%), respectively. A total of 125 complications were observed in adults, with transient nerve palsies (23%) as the most frequent complication, and 33 in children, with loose bodies after surgery (45%) as the most frequent complication. CONCLUSIONS: Predominantly low-level evidence studies demonstrate varying complication rates (median 3%, range 0%-71%) and reoperation rates (median 2%, range 0%-59%) after elbow arthroscopy. Higher complication rates are observed after more complex surgery. The incidence and type of complications can aid surgeons in patient counseling and refining surgical techniques to further reduce the complication rates. LEVEL OF EVIDENCE: Level IV; systematic review of Level I-IV studies.

High resorption rates following glenoid augmentation procedures do not seem to lead to higher recurrence rates or worse clinical outcomes: a systematic review and meta-analysis.

PURPOSE: Bone augmentation techniques show a relatively high complication rate, which might be due to graft non-union and resorption. It is unclear which augmentation techniques demonstrate the highest amount of non-union and resorption and whether this leads to worse clinical or functional outcomes. Therefore, the aim of this review was (i) to compare non-union and resorption rates between surgical approaches, procedures, graft types, donor sites and fixation methods regarding clinical and functional outcomes and (ii) determine whether high non-union or resorption rates lead to less favorable clinical or functional outcomes. METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses statements were followed. PubMed, EMBASE (Ovid) and Cochrane Library were searched on December 15th 2021 for studies examining bone graft non-union or resorption using radiograph or CT following glenoid augmentation to treat anterior shoulder dislocation. RESULTS: The search resulted in 103 inclusions, comprising 5,128 glenoid augmentations. When comparing pooled proportions of bony union, graft fracture rate, hardware failure rate, recurrence rate, return to sports and Rowe score, most results were similar between approaches, procedures, graft types, donor sites and fixation methods. High resorption rates were seen for allograft augmentation (74.3; 95% CI: 39.8-92.7) compared to autograft augmentation (15.5; 95% CI 10.1-23.2), but this was not associated with higher recurrence rates or worse clinical outcomes. Meta-analyses (8 studies; 494 patients) demonstrated no difference in incomplete and complete non-union rates between arthroscopic and open procedures; however, both analyses showed substantial heterogeneity. Higher partial resorption rates were observed on CT (48.0; 95% CI 43.3-52.7) compared to radiograph (14.1; 95% CI 10.9-18.1). Three studies comprising 267 shoulders demonstrated a higher rate of non-union and recurrence in smokers, whereas one study comprising 38 shoulders did not. CONCLUSION: Non-union and resorption rates were similar among procedures, grafts and fixation methods. Higher resorption rates were observed in allografts, but this was not associated with higher recurrence rates or worse clinical outcomes. Pooling data demonstrated substantial heterogeneity and definitions varied among studies, warranting more standardized measuring. LEVEL OF EVIDENCE: IV.

"Nearly off-track lesions" or a short distance from the medial edge of the Hill-Sachs lesion to the medial edge of the glenoid track does not seem to be accurate in predicting recurrence after an arthroscopic Bankart repair in a military population: a case-control study.

BACKGROUND: On-track lesions with a short distance from the medial edge of the Hill-Sachs lesion to the medial edge of the glenoid track (nearly off-track) may predispose recurrence after arthroscopic Bankart repair (ABR) in the general population. The aim of this study was to determine if a shorter distance between the medial edge of the Hill-Sachs lesion and the medial edge of the glenoid track could accurately predict recurrence after an ABR in a high-demand military population. It was hypothesized that a shorter distance would not accurately predict recurrence. MATERIALS AND METHODS: A retrospective monocenter case-control study was performed at the Dutch Central Military Hospital. Patients with an on-track Hill-Sachs lesion who underwent a primary ABR between 2014 and 2019 with a minimal follow-up of 2 years and a preoperative magnetic resonance imaging (MRI) assessment received a questionnaire. The primary outcome was recurrence, defined as a complete dislocation or subluxation. Glenoid bone loss was assessed using a linear-based method on MRI. The distance from the medial edge of the Hill-Sachs lesion to the medial edge of the glenoid track was defined as the distance to dislocation (DTD). A receiver operating characteristic curve was created to determine the predictive value of the DTD for recurrence. Logistic regression was used to determine preoperative risk factors that predispose recurrence. Covariates were selected based on univariable analysis and included gender, body mass index, age at surgery and first dislocation, laterality, smoking habits, overhead shoulder activity during work, preoperative dislocations, sports type and level, bony or labral lesions on MRI, and DTD. RESULTS: In total, 80 patients with an average follow-up of 4.8 ± 1.9 years completed the questionnaire and were included in the analyses. Seventeen patients (21%) experienced recurrence at the final follow-up. No difference in DTD was observed among patients who experienced recurrence (9 ± 4 mm) compared with patients who did not (9 ± 5 mm; P = .81). The receiver operating characteristic curve demonstrated no predictive power of DTD for recurrence (area under the curve = 0.49). Smoking at the time of surgery (odds ratio: 3.9; confidence interval: 1.2-12.7; P = .02) and overhead shoulder movement during work (odds ratio: 9.3; confidence interval: 1.1-78.0; P = .04) were associated with recurrence according to the logistic regression analysis. CONCLUSION: A shorter DTD demonstrated no accuracy in predicting recurrence in a military population. Smoking at the time of surgery and overhead shoulder activity during work were associated with recurrence; however, these analyses were underpowered to draw valid conclusions.

Prognostic factors associated with failure to return to sport following primary arthroscopic Bankart repair: a retrospective multicenter study.

BACKGROUND: Even though many studies have been published regarding return-to-sport (RTS) rates following arthroscopic Bankart repair (ABR), evidence regarding prognostic factors for which patients do not RTS is limited. The aim of this study was to identify prognostic factors that are associated with failure to RTS and failure to return to preinjury level of sport (RTPS) following primary ABR. The hypothesis was that prognostic factors for failure to RTS and failure to RTPS would be similar to those predisposing recurrence. METHODS: A multicenter, retrospective case-control study including 6 Dutch hospitals was performed. Consecutive patients who underwent primary ABR between 2014 and 2019 were invited to participate and received a questionnaire. Sports participation was assessed before symptom onset, at 6 months postoperatively, and at final follow-up. Failure to RTS was defined as no return to any sport, and failure to RTPS was defined as no return to the same level (or a higher level) of sport. Prognostic factors for failure to RTS or failure to RTPS were identified using logistic regression. Covariates for the regression analysis were selected based on univariate analyses. RESULTS: This study included 318 patients with a mean follow-up period of 4.2 years (standard deviation, 1.8 years). Of these 318 patients, 26 (8.2%) did not RTS and 100 (31%) did not RTPS. Logistic regression analysis demonstrated that glenoid bone loss (odds ratio [OR], 1.09; 95% confidence interval [CI], 1.04-1.15; P = .001) and overhead use of the shoulder during work (OR, 3.77; 95% CI, 1.45-9.85; P = .007) were prognostic factors for failure to RTS. In addition, it showed that preoperative professional sports level (OR, 2.94; 95% CI, 1.07-8.05; P = .04) and preoperative body mass index (OR, 1.11; 95% CI, 1.01-1.21; P = .04) were prognostic factors for failure to RTPS. Repair of a bony Bankart lesion (OR, 0.35; 95% CI, 0.15-0.81; P = .02) and the presence of an anterior labral periosteal sleeve avulsion (ALPSA) (OR, 0.44; 95% CI, 0.20-0.97; P = .04) were identified as factors that facilitated RTPS. CONCLUSION: This study identified glenoid bone loss and overhead use of the shoulder during work to be associated with failure to RTS. Moreover, preoperative sports level and preoperative body mass index were found to be associated with failure to RTPS. In contrast, a bony Bankart lesion and an anterior labral periosteal sleeve avulsion (ALPSA) lesion facilitated RTPS. Future prospective studies are needed to confirm these factors and determine which part of the effect can be attributed to (failure of) surgical treatment or changes in behavior.

Substrate recruitment by γ-secretase.

γ-Secretase is a membrane-embedded protease complex that is crucial for many physiological processes throughout life. Due to its pivotal role in the etiology of Alzheimer's disease (AD), in particular the familial forms of the disease, the enzyme is one of the most studied intramembrane proteases and an important drug target. By cleaving a C-terminal fragment of the ß-amyloid precursor protein (APP), γ-secretase generates several amyloid ß-peptide (Aß) species including longer, neurotoxic forms such as Aß42 that are a widely believed to trigger AD. Besides APP, γ-secretase cleaves numerous other substrates including most prominently Notch1, whose cleavage by γ-secretase is essential for cell differentiation and affected in certain types of cancer. In this review, we will describe the exciting progress made in our understanding of how the γ-secretase complex recognizes and recruits its substrates to its catalytic subunit presenilin for their intramembrane proteolytic cleavage. This complicated process is not well understood and only recently insights from biochemical studies and structural biology are beginning to reveal this secret of γ-secretase.

Vinorelbine in bladder-preserving multimodality treatment for muscle-invasive bladder cancer-a valid option for cisplatin-unfit patients?

PURPOSE: Treatment of muscle-invasive bladder cancer (MIBC) remains challenging, especially for elderly and/or comorbid patients. Patients who are unfit for or refuse surgery should receive bladder-preserving multimodality treatment (BPMT), consisting of transurethral resection of the bladder tumor (TURB) followed by combined chemoradiotherapy (CRT). We aimed to investigate the effectiveness of vinorelbine, a chemotherapeutic agent not routinely used for MIBC, in patients referred to CRT who are unfit for standard chemotherapy and would thus rely solely on radiotherapy (RT). METHODS: We retrospectively analyzed 52 consecutive patients with MIBC who received standard CRT with cisplatin (n = 14), CRT with vinorelbine (n = 26), or RT alone (n = 12). Primary endpoints were median overall survival (OS) and median cancer-specific survival (CSS). Secondary endpoints were median local control (LC), median distant control (DC), and OS, CSS, LC, and DC after 1, 2, and 3 years, respectively. RESULTS: Median OS and CSS were significantly higher for patients who received vinorelbine as compared to RT alone (OS 8 vs. 22 months, p = 0.003; CSS 11 months vs. not reached, p = 0.001). Median LC and DC did not differ significantly between groups. Vinorelbine was well tolerated with no reported side effects >grade II. CONCLUSION: Our results suggest that CRT with vinorelbine is well tolerated and superior to RT alone in terms of OS and CSS. Therefore, this treatment regime might constitute a new treatment option for patients with MIBC who are unfit for or refuse surgery or standard chemotherapy. This study encourages a randomized controlled trial to compare this new regime to current standard therapies.

Geometric analysis of pedicle subtraction osteotomy (PSO) for Kyphosis correction: anterior lengthening may occur at the osteotomized body as well as at the discs above and below.

OBJECTIVE: To validate the authors kyphosis correction formula for pedicle subtraction osteotomy (PSO) cases. Additionally, to use the formula to evaluate the safety of PSO by determining if there is anterior lengthening. METHODS: Twenty-two patients with primarily kyphosis corrected by PSO and with clear landmarks on preoperative and postoperative x-rays were selected. Several anatomical lines and angle measurements were utilized as depicted previously in the Vertebral Column Resection formula (see below). Two approximations were calculated: the geometric approximation (G) = (tanG°*2 + 1)*15° and the rough approximation (R) which is about the same amount of actual shortening (x), if parallel length (y) ≥ 40; twice of x, if y < 40. For each patient, the change of segmental kyphosis angle (K°) was measured and compared with G° and R°, and the correlation between each value was analyzed. RESULTS: The absolute Mean ± SE for K - G and K - R was 2.33° ± 0.34 and 6.09° ± 0.58, respectively. K - G is < 3° (p = 0.03). K - R is < 8° (p = 0.001). In other words, K was close to G and R and thus can be predicted by these approximations. Average posterior shortening, anterior shortening, and kyphosis correction at each level were 20.8 ± 2.0 mm, - 3.64 ± 1.5 mm (which equates to anterior lengthening), and 31.05° ± 2.0, respectively. Anterior lengthening occurred in 13 cases (in 4 cases, both at the body as well as at the disc above and below.) The correlation between posterior and anterior shortening was 0.03 (p = 0.88). There were 3 cage insertion cases: 1 had anterior lengthening, while 2 had anterior shortening even with the cage. CONCLUSION: This study validated the geometric and rough approximations originally used in PVCR patients, for PSO patients. Additionally, this study found that anterior lengthening may occur in PSOs usually at the discs, but occasionally at the osteotomized body.

Recurrence in traumatic anterior shoulder dislocations increases the prevalence of Hill-Sachs and Bankart lesions: a systematic review and meta-analysis.

PURPOSE: The extent of shoulder instability and the indication for surgery may be determined by the prevalence or size of associated lesions. However, a varying prevalence is reported and the actual values are therefore unclear. In addition, it is unclear whether these lesions are present after the first dislocation and whether or not these lesions increase in size after recurrence. The aim of this systematic review was (1) to determine the prevalence of lesions associated with traumatic anterior shoulder dislocations, (2) to determine if the prevalence is higher following recurrent dislocations compared to first-time dislocations and (3) to determine if the prevalence is higher following complete dislocations compared to subluxations. METHODS: PubMed, EMBASE, Cochrane and Web of Science were searched. Studies examining shoulders after traumatic anterior dislocations during arthroscopy or with MRI/MRA or CT published after 1999 were included. A total of 22 studies (1920 shoulders) were included. RESULTS: The proportion of Hill-Sachs and Bankart lesions was higher in recurrent dislocations (85%; 66%) compared to first-time dislocations (71%; 59%) and this was statistically significant (P < 0.01; P = 0.05). No significant difference between recurrent and first-time dislocations was observed for SLAP lesions, rotator-cuff tears, bony Bankart lesions, HAGL lesions and ALPSA lesions. The proportion of Hill-Sachs lesions was significantly higher in complete dislocations (82%) compared to subluxations (54%; P < 0.01). CONCLUSION: Higher proportions of Hill-Sachs and Bankart were observed in recurrent dislocations compared to first-time dislocations. No difference was observed for bony Bankart, HAGL, SLAP, rotator-cuff tear and ALPSA. Especially when a Hill-Sachs or Bankart is present after first-time dislocation, early surgical stabilization may need to be considered as other lesions may not be expected after recurrence and to limit lesion growth. However, results should be interpreted with caution due to substantial heterogeneity and large variance. LEVEL OF EVIDENCE: IV.