LRPAP1 autoantibodies in mantle cell lymphoma are associated with superior outcome.

Low-density lipoprotein (LDL) receptor-related protein-associated protein 1 (LRPAP1) had been identified by B-cell receptor (BCR) expression cloning and subsequent protein array screening as a frequent and proliferation-inducing autoantigen of mantle cell lymphoma (MCL). Of interest, high-titered and light chain-restricted LRPAP1 autoantibodies were detected in 8 of 28 patients with MCL. In the present study, LRPAP1 autoantibodies in sera of patients treated within the Younger and Elderly trials of the European MCL Network were analyzed regarding frequency, association with disease characteristics, and prognostic impact. LRPAP1 autoantibodies were detected in 41 (13%) of 312 evaluable patients with MCL. These LRPAP1 autoantibodies belonged predominantly to the immunoglobulin G (IgG) class and were clonally light chain restricted (27 with κ light chains, 14 patients with λ light chains). Titers ranged between 1:400 and 1:3200. The presence of LRPAP1 autoantibodies was not significantly associated with any baseline clinical characteristic, however, it was associated with a superior 5-year probability for failure-free survival (FFS) of 70% (95% confidence interval [CI], 57% to 87%) vs 51% (95% CI, 44% to 58%), P = .0052; and for overall survival (OS) of 93% (95% CI, 85% to 100%) vs 68% (95% CI, 62% to 74%), P = .0142. LRPAP1-seropositive patients had a Mantle Cell Lymphoma International Prognostic Index-adjusted hazard ratio for FFS of 0.48 (95% CI 0.27-0.83, P = .0083) and for OS of 0.47 (95% CI 0.24-0.94, P = .032). LRPAP1 autoantibodies were frequently detected in a large cohort of MCL patients treated within prospective multicenter clinical trials. Our results suggest better outcomes for LRPAP1-autoantibody seropositive patients.

B-cell receptor reactivity against Rothia mucilaginosa in nodular lymphocyte-predominant Hodgkin lymphoma.

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a Hodgkin lymphoma expressing functional B-cell receptors (BCR). Recently, we described a dual stimulation model of IgD+ lymphocyte-predominant cells by Moraxella catarrhalis antigen RpoC and its superantigen MID/hag, associated with extralong CDR3 and HLA-DRB1*04 or HLADRB1* 07 haplotype. The aim of the present study was to extend the antigen screening to further bacteria and viruses. The fragment antibody-binding (Fab) regions of seven new and 15 previously reported cases were analyzed. The reactivity of non-Moraxella spp.-reactive Fab regions against lysates of Rothia mucilaginosa was observed in 5/22 (22.7%) cases. Galactofuranosyl transferase (Gltf) and 2,3-butanediol dehydrogenase (Bdh) of R. mucilaginosa were identified by comparative silver- and immuno-staining in two-dimensional gels, with subsequent mass spectrometry and validation by western blots and enzyme-linked immunosorbent assay. Both R. mucilaginosa Gltf and Bdh induced BCR pathway activation and proliferation in vitro. Apoptosis was induced by recombinant Gltf/ETA'-immunotoxin conjugates in DEV cells expressing recombinant R. mucilaginosa-reactive BCR. Reactivity against M. catarrhalis RpoC was confirmed in 3/7 newly expressed BCR (total 10/22 reactive to Moraxella spp.), resulting in 15/22 (68.2%) cases with BCR reactivity against defined bacterial antigens. These findings strengthen the hypothesis of bacterial trigger contributing to subsets of NLPHL.

A novel model of locking plate and locking spongious screw: a biomechanical in vitro comparison study with classical locking plate.

BACKGROUND: Locking plates are commonly used for the fixation of comminuted, periprosthetic and osteoporotic bone fractures. These plates are secured to the bone with screws, creating a stable connection with fixed angle between the plate and the screws. In this biomechanical in vitro study, our aim is to evaluate and compare the novel locking plate-locking spongious screw model with FDA approved classical locking plate. METHODS: Sawbone PCF-15 osteoporotic bone model was utilized to simulate osteoporotic bone conditions. Two screws were used to attach both the classical locking plate and the novel locking plate-locking spongious screw model to these bone models. The attachment strength of the screws to the bone blocks was measured by pull-out tests. RESULTS: Novel locking plate-locking spongious screw model exhibited an 84.38% stronger attachment to the osteoporotic bone model compared to the current locking plate model. CONCLUSIONS: In conclusion, one of the important problems in the locking plates which is the high Pull-out risk of the locking spongious screws can been resolved with our proposed new model and has a chance of having a better purchase especially in osteoporotic bones.

Demonstrating the relationship of ultrasonographic parameters with disease activity and pain in lateral epicondylitis.

To evaluate the relationship of ultrasonographic evaluation parameters with pain, muscle strength and disease severity in lateral epicondylitis (LE). 64 people were included in present retrospective, cross-sectional study. Activity and rest pain was questioned with Visual Analog Scale (VAS). Also, Patient Rated Tennis Elbow Evaluation (PRTEE) and the maximum grip strength were evaluated. Hypoechoic region, neovascularity, cortical irregularity, enthesopathy and peritendinous fluid or bursitis were evaluated by ultrasonography. 48 of the patients were female and 16 were male. Mean age was 48.53 ±â€…6.12, body mass index was 27.70 ±â€…4.75. 55 (85.9%) hypoechoic region, 31 (48.4%) neovascularity, 21 (32.8%) cortical irregularity, 19 (29,7%) enthesopathy, and 18 (28.1%) peritendinous fluid or bursitis were detected by ultrasonography. When the ultrasonographic findings and clinical findings of the patients were compared, no significant difference was found between the hypoechoic region, cortical irregularity, enthesopathy and clinical findings (P > .05), while the extension grip strength was found to be significantly lower in patients with neovascularity (P = .045). In addition, patients with peritendinous fluid or bursitis, were found to be significantly lower in both flexion (P = .033) and extension (P = .023) grip strength, while PRTEE function (P = .021) subgroup and total (P = .038) scores were significantly higher. Hypoechoic region, cortical irregularities and enthesopathy were not evaluated to be associated with disease severity, pain and muscle strength. Neovascularity was found to be associated only with extension grip strength. Peritendinous fluid or bursitis was found to be associated with both flexion and extension grip strength and disease activity, but not associated with pain.

Results of arthroscopic treatment for anteroinferior shoulder instability using a single anterior working portal using birdbeak.

BACKGROUND: The shoulder joint is the joint with the most dislocations in all joints. The arthroscopic surgery method is considered the gold standard because it creates less soft tissue damage, shorter hospitalization and surgery time, and less restriction of movement after surgery in shoulder instability. Anterior single portal technique has become popular recently. In this study, it was aimed to evaluate the results of the anterior single portal repair technique using "birdbeak". We try to evaluate if this technique is a reliable technique and has the same or more advantages of two portal arthroscopic surgery and make the surgery easier for surgeons. METHODS: In the total of 40 patients who underwent arthroscopic surgery for traumatic recurrent anterior shoulder dislocation between January 2017 and February 2020, this study included 19 patients with the surgical technique of arthroscopic isolated anterior labrum tear repair using a birdbeak from the anterior single working portal. Clinical results were evaluated with the Simple Shoulder Test (SST), Rowe Score for Instability (RWS) and Oxford Shoulder Instability Score (OSIS) tests before and after surgery. The relationship between the time to surgery after the first dislocation and clinical outcomes was also examined in the study. Kolmogorov-Smirnov and Shapiro-Wilk tests were used to control the assumption of normality. In addition, Pearson correlation and Spearman correlation analyzes were used to test the relationship between the variables. RESULTS: The mean follow-up period of the 19 patients included in this study was 33.1 months. The mean time to surgery after the first dislocation was 18.4 months. The mean preoperative number of dislocations was 5.3. The mean number of anchors used in the repair was 2.1. No recurrent dislocations were observed after surgery. A significant difference was observed between preoperative and postoperative SST, RWS and OSIS scores (respectively, p = 0.000 < 0.001, p = 0.000 < 0.001, p = 0.000 < 0.001). There was no statistically significant relationship between the time elapsed after the first dislocation and the postoperative SST, RWS, OSIS scores (respectively, p = 0.43 > 0.05, p = 0.39 > 0.05, p = 0.31 > 0.05). CONCLUSION: It has been observed that the repair technique applied using the "birdbeak" from the anterior single working portal is a successful treatment, and further studies are required due to the limited literature.

The effect of comorbid factors and amputation level on mortality in geriatric patients with diabetic foot.

OBJECTIVES: The aim of this study was to evaluate the factors that influenced one-year and five-year mortality and to compare major and minor amputations in diabetic patients with comorbidities. PATIENTS AND METHODS: Between February 2008 and November 2014, a total of 201 type 2 diabetic foot patients (147 males, 54 females; median age: 65.99 years; range, 50 to 92 years) who underwent amputation were retrospectively analyzed. The patients were divided into two groups according to their initial amputation level: Group 1 (n=100), minor amputation group, which included the distal region of the ankle joint and Group 2 (n=101), major amputation group, which included trans-tibial amputation, trans-femoral amputation and hip disarticulation. Clinical data including patients' demographic features, re-amputation degree, length of hospitalization, hyperbaric oxygen therapy, comorbidities, blood parameters, and survival rates were recorded. RESULTS: The regression analysis of one-year mortality found that the presence of cerebrovascular disease increased death by 2.463 times (p=0.002). Minor amputation increased mortality by 2.284 (p=0.006), and each unit increase in patient age increased mortality by 1.05 (p=0.008). Chronic renal failure increased death by 3.164 times (p<0.001) in the five-year mortality regression analysis. CONCLUSION: Minor amputations have an effect on one-year mortality, as do cerebrovascular disease and age. On the other hand, chronic renal failure has a negative impact on five-year mortality. Minor amputations may have a detrimental effect on mortality due to the ongoing progression of diabetic foot disease and the involvement of comorbidities. Comorbidities associated with amputations of the diabetic foot have a significant impact on mortality.

Ars2-containing bispecific, Fab- and IgG1-format BAR-bodies to target DLBCL cells.

Despite recent advances in the therapy of diffuse large B-cell lymphoma, not otherwise specified (DLBCL), around 30% of patients develop refractory disease or relapse after first-line treatment. Recently, Ars2 was reported as the auto-antigenic target of the B-cell receptor (BCR) in approximately 25% of activated B-cell DLBCL cases. Ars2 could be used to specifically target B cells expressing Ars2-reactive BCRs. However, the optimal therapeutic format to integrate Ars2 into has yet to be determined. To mimic therapeutic antibody formats, Ars2-containing bispecific and IgG1-like constructs (BCR antigens for reverse [BAR]-bodies) were developed. Two bispecific BAR-bodies connecting single-chain antibodies against CD16 or CD3 to the BCR-binding epitope of Ars2 were constructed. Both constructs showed strong binding to U2932 cells and induced effector cell-dependent and selective cytotoxicity against U2932 cells of up to 44% at concentrations of 20 µg/ml. Additionally, IgG1-format Ars2 BAR-bodies were constructed by replacing the variable heavy- and light-chain regions of a full-length antibody with the Ars2 epitope. IgG1-format Ars2 BAR-bodies also bound selectively to U2932 and OCI-Ly3 cells and induced selective cytotoxicity of up to 60% at 10 µg/ml. In conclusion, Ars2-containing bispecific and IgG1-format BAR-bodies both are new therapeutic formats to target DLBCL cells.

Biomarker guided treatment in oncogene-driven advanced non-small cell lung cancer in older adults: A Young International Society of Geriatric Oncology report.

Lung cancer remains the leading cause of cancer-related deaths worldwide, with most patients diagnosed at an advanced age. The treatment of non-small cell lung cancer (NSCLC) has been revolutionized with the introduction of molecular guided therapy. Despites the challenges when considering treatment of older adults, they are still systematically underrepresented in registrational trials. This review aims to summarize the existing evidence on treatment of older patients with lung cancer with a targetable driver mutation or alteration (EGFR, ALK, ROS, BRAFV600E, MET, RET, KRASG12C and NTRK), and consider the evidence from a geriatric oncology perspective. Early generation EGFR-tyrosine kinase inhibitors (TKIs). TKIs are fairly well-studied in older adults and have been shown to be safe and efficient. However, older adult-specific data regarding the standard-of-care first-line agent osimertinib are lacking. Erlotinib, dacomitinib, and afatinib may be more toxic than other EGFR-TKIs. Next generation ALK-TKIs are preferred over crizotinib due to increased efficacy, as demonstrated in phase III trials. Alectinib seems to be safer than crizotinib, while brigatinib is associated with increased toxicity. Lorlatinib overcomes most resistance mutations, but data regarding this agent have only recently emerged. Regarding ROS1-fusion positive NSCLC, crizotinib is an option in older adults, while entrectinib is similarly effective but shows increased neurotoxicity. In BRAFV600E-mutant NSCLC, the combination darbafenib/tramectinib is effective, but no safety data for older adults exist. MET alterations can be targeted with capmatinib and tepotinib, and registrational trials included primarily older patients, due to the association of this alteration with advanced age. For RET-rearranged-NSCLC selpercatinib and pralsetinib are approved, and no differences in safety or efficacy between older and younger patients were shown. KRASG12C mutations, which are more frequent in older adults, became recently druggable with sotorasib, and advanced age does not seem to affect safety or efficacy. In NTRK-fusion positive tumors, larotrectinib and entrectinib have tumor agnostic approval, however, not enough data on older patients are available. Based on currently available data, molecularly-guided therapy for most alterations is safe and efficacious in older adults with oncogene-driven advanced NSCLC. However, for many TKIs, older adult-specific data are lacking, and should be subject of future prospective evaluations.

Adaptive humoral immune response and cellular immune status in cancer patients and patients under immunosuppression vaccinated against SARS-CoV-2.

BACKGROUND: Patients with cancer and autoimmune diseases are at higher risk of severe COVID-19. They may not develop protective immune responses following vaccination. We investigated patients' cellular and humoral immune response after two COVID-19 vaccine doses. RESEARCH DESIGN AND METHODS: Subjects were stratified into subgroups according to therapy and grade of immunosuppression at time of vaccination. RESULTS: Antibody titers were compared to healthy controls. 32/122 (26%) did not develop detectable antibody titers. Of these, 22 (66.6%) had active therapy. Patients showed significant lower antibody titers compared to controls (median 790 vs. 3923 AU/mL, p = 0.026). Patients with active therapy had significant lower antibody titers compared to those without (median 302 vs. 3952 U/L P < 0.001). B-cell count was lower in the group without antibody titers (median 29.97 vs. 152.8; p = 0.002). 100% of patients under anti-CD20 therapy had no detectable antibody titer, followed by anti-TNF (66%), BTK inhibitors (50%), ruxolitinib (35.5%), TKI (14.2%), and lenalidomide (12.5%). Anti-CD20 therapy, ruxolitinib, BTK inhibitors, and anti-CD38 therapy presented significant lower antibody titers compared to controls. CONCLUSIONS: Patients undergoing therapy for cancer or autoimmune diseases are at higher risk of insufficient humoral immune response following COVID-19 vaccination. Furthermore, alterations in the B-cell compartment correlate with lower antibody titers.

Autoantibodies against SUMO1-DHX35 in long-COVID.

Long COVID is a collection of symptoms as a late sequelae of SARS-CoV-2 infection. It often includes mental symptoms such as cognitive symptoms, persisting loss of smell and taste, in addition to exertional dyspnea. A role of various autoantibodies (autoAbs) has been postulated in long-COVID and is being further investigated. With the goal of identifying potentially unknown autoAbs, we screened plasma of patients with long COVID on in-house post-translationally modified protein macroarrays including citrullinated, SUMOylated and acetylated membranes. SUMO1ylated isoform DEAD/H (Asp-Glu-Ala-Asp/His) box helicase 35 (SUMO1-DHX35) was identified as only candidate antigen. In adult patients with long COVID, IgG autoAbs against SUMO1-DHX35 of IgG class were found in seven of 71 (9.8%) plasma samples, of IgM and IgG class in one of 69 (1.4%) samples, not in 200 healthy adult controls, not in 442 healthy children, and 146 children after SARS-CoV-2 infection. All autoAb-positive seven patients were female. AutoAb titers ranged between 200 to up to 400 By point mutagenesis and expression of FLAG-tagged mutants of DHX35 in HEK293 cells, and subsequent SUMOylation of purified constructs, lysine 53 was identified as a unique, never yet identified, SUMOylation site. The autoAbs had no reactivity against the non-SUMO1ylated mutant (K53R) of DHX35. To summarize, autoAbs against SUMO1-DHX35 were identified in adult female patients with long-COVID. Further studies are needed to verify the frequency of occurrence. The function of DHX35 has not yet been determined and there is no available information in relation to disease implication. The molecular mechanism causing the SUMOylation, the potential functional consequences of this post-translational modification on DHX35, and a potential pathogenicity of the autoAbs against SUMO1-DHX35 in COVID-19 and other possible contexts remain to be elucidated.

B-cell receptors of EBV-negative Burkitt lymphoma bind modified isoforms of autoantigens.

Burkitt lymphoma (BL) represents the most aggressive B-cell-lymphoma. Beside the hallmark of IG-MYC-translocation, surface B-cell receptor (BCR) is expressed, and mutations in the BCR pathway are frequent. Coincidental infections in endemic BL, and specific extra-nodal sites suggest antigenic triggers. To explore this hypothesis, BCRs of BL cell lines and cases were screened for reactivities against a panel of bacterial lysates, lysates of Plasmodium falciparum, a custom-made virome array and against self-antigens, including post-translationally modified antigens. An atypically modified, SUMOylated isoform of Bystin, that is, SUMO1-BYSL was identified as the antigen of the BCR of cell line CA46. SUMO1-BYSL was exclusively expressed in CA46 cells with K139 as site of the SUMOylation. Secondly, an atypically acetylated isoform of HSP40 was identified as the antigen of the BCR of cell line BL41. K104 and K179 were the sites of immunogenic acetylation, and the acetylated HSP40 isoform was solely present in BL41 cells. Functionally, addition of SUMO1-BYSL and acetylated HSP40 induced BCR pathway activation in CA46 and BL41 cells, respectively. Accordingly, SUMO1-BYSL-ETA' immunotoxin, produced by a two-step intein-based conjugation, led to the specific killing of CA46 cells. Autoantibodies directed against SUMO1-BYSL were found in 3 of 14 (21.4%), and autoantibodies against acetylated HSP40 in 1/14(7.1%) patients with sporadic Burkitt-lymphoma. No reactivities against antigens of the infectious agent spectrum could be observed. These results indicate a pathogenic role of autoreactivity evoked by immunogenic post-translational modifications in a subgroup of sporadic BL including two EBV-negative BL cell lines.

[Internal jugular vein thrombosis following functional and selective neck dissections]. / Fonksiyonel ve selektif boyun diseksiyonu sonrasi internal juguler ven trombozu.

OBJECTIVES: Internal jugular vein (IJV) thrombosis is a rare complication of functional and selective neck dissections. It increases morbidity and may seldom be fatal. We investigated the frequency of IJV thrombosis and its relationship with the dissection technique. PATIENTS AND METHODS: We evaluated 52 functional and selective neck dissections performed in 34 male patients (mean age 57 years; range 34 to 76 years) with head and neck cancer. Dissections were mainly performed by sharp dissection (n=27) or cautery (n=25). The patients were examined by Doppler ultrasonography with respect to IJV flow and thrombosis preoperatively, and at two weeks and at 3 to 6 months postoperatively. RESULTS: In the early postoperative period, thrombosis was observed in 7.4% (n=2) of the necks treated with sharp dissection and in 4% (n=1) of the necks treated with cautery. There was no statistically significant difference between the two groups with respect to IJV thrombosis. Late Doppler examinations showed complete recanalization of all thrombosed IJVs. CONCLUSION: Our data suggest that sharp dissection or cautery techniques performed in functional neck dissections do not differ with respect to the frequency of postoperative IJV thrombosis.

Arthroscopic Management and Treatment of Synovial Chondromatosis and Talus Osteochondral Defect in the Ankle Joint. A Case Study.

Synovial chondromatosis has an unknown aetiology and is a benign lesion especially seen in joints like the knee and hip. However, it is extremely rare in the ankle joint. A review of the literature shows that ankle joint chondromatosis is usually treated by arthrotomy. However, excision of loose bodies by arthroscopy in the ankle joint is not common. Arthroscopic surgery provides a wide visualisation area for excision of loose bodies, allowing for synovectomy and microfracture. Our patient was a 60-year-old female who presented to our clinic with primary osteochondromatosis and osteochondral defect. Our patient underwent arthroscopic excision of loose bodies, microfracture and synovectomy. Arthroscopic management can be successful in selected patients with synovial osteochondromatosis localized to the ankle joint.