Real-world analysis of teclistamab in 123 RRMM patients from Germany.

Teclistamab, a B-cell maturation antigen (BCMA) × CD3 directed bispecific antibody, has shown high response rates and durable remissions in the MAJESTEC-1 trial in patients with relapsed and refractory multiple myeloma (RRMM). We retrospectively assessed efficacy and tolerability in 123 patients treated at 18 different German centers to determine whether outcome is comparable in the real-world setting. Most patients had triple-class (93%) or penta-drug (60%) refractory disease, 37% of patients had received BCMA-directed pretreatment including idecabtagene vicleucel (ide-cel) CAR-T cell therapy (21/123, 17.1%). With a follow-up of 5.5 months, we observed an overall response rate (ORR) of 59.3% and a median progression-free survival (PFS) of 8.7 months. In subgroup analyses, we found significantly lower ORR and median PFS in patients with extramedullary disease (37%/2.1 months), and/or an ISS of 3 (37%/1.3 months), and ide-cel pretreated patients (33%/1.8 months). Nonetheless, the duration of response in ide-cel pretreated patients was comparable to that of anti-BCMA naive patients. Infections and grade ≥3 cytopenias were the most frequent adverse events. In summary, we found that teclistamab exhibited a comparable efficacy and safety profile in the real-world setting as in the pivotal trial.

FGF2 overrides key pro-fibrotic features of bone marrow stromal cells isolated from Modic type 1 change patients.

Extensive extracellular matrix production and increased cell-matrix adhesion by bone marrow stromal cells (BMSCs) are hallmarks of fibrotic alterations in the vertebral bone marrow known as Modic type 1 changes (MC1). MC1 are associated with non-specific chronic low-back pain. To identify treatment targets for MC1, in vitro studies using patient BMSCs are important to reveal pathological mechanisms. For the culture of BMSCs, fibroblast growth factor 2 (FGF2) is widely used. However, FGF2 has been shown to suppress matrix synthesis in various stromal cell populations. The aim of the present study was to investigate whether FGF2 affected the in vitro study of the fibrotic pathomechanisms of MC1-derived BMSCs. Transcriptomic changes and changes in cell-matrix adhesion of MC1-derived BMSCs were compared to intra-patient control BMSCs in response to FGF2. RNA sequencing and quantitative real-time polymerase chain reaction revealed that pro-fibrotic genes and pathways were not detectable in MC1-derived BMSCs when cultured in the presence of FGF2. In addition, significantly increased cell-matrix adhesion of MC1-derived BMSCs was abolished in the presence of FGF2. In conclusion, the data demonstrated that FGF2 overrides key pro-fibrotic features of MC1 BMSCs in vitro. Usage of FGF2-supplemented media in studies of fibrotic mechanisms should be critically evaluated as it could override normally dominant biological and biophysical cues.

Pro-fibrotic phenotype of bone marrow stromal cells in Modic type 1 changes.

Modic type 1 changes (MC1) are painful vertebral bone marrow lesions frequently found in patients suffering from chronic low-back pain. Marrow fibrosis is a hallmark of MC1. Bone marrow stromal cells (BMSCs) are key players in other fibrotic bone marrow pathologies, yet their role in MC1 is unknown. The present study aimed to characterise MC1 BMSCs and hypothesised a pro-fibrotic role of BMSCs in MC1. BMSCs were isolated from patients undergoing lumbar spinal fusion from MC1 and adjacent control vertebrae. Frequency of colony-forming unit fibroblast (CFU-F), expression of stem cell surface markers, differentiation capacity, transcriptome, matrix adhesion, cell contractility as well as expression of pro-collagen type I alpha 1, α-smooth muscle actin, integrins and focal adhesion kinase (FAK) were compared. More CFU-F and increased expression of C-X-C-motif-chemokine 12 were found in MC1 BMSCs, possibly indicating overrepresentation of a perisinusoidal BMSC population. RNA sequencing analysis showed enrichment in extracellular matrix proteins and fibrosis-related signalling genes. Increases in pro-collagen type I alpha 1 expression, cell adhesion, cell contractility and phosphorylation of FAK provided further evidence for their pro-fibrotic phenotype. Moreover, a leptin receptor high expressing (LEPRhigh) BMSC population was identified that differentiated under transforming growth factor beta 1 stimulation into myofibroblasts in MC1 but not in control BMSCs. In conclusion, pro-fibrotic changes in MC1 BMSCs and a LEPRhigh MC1 BMSC subpopulation susceptible to myofibroblast differentiation were found. Fibrosis is a hallmark of MC1 and a potential therapeutic target. A causal link between the pro-fibrotic phenotype and clinical characteristics needs to be demonstrated.

Cost-effectiveness of conservative versus surgical treatment strategies of lumbar spinal stenosis in the Swiss setting: analysis of the prospective multicenter Lumbar Stenosis Outcome Study (LSOS).

PURPOSE: To evaluate the cost-effectiveness of conservative versus surgical treatment strategies for lumbar spinal stenosis (LSS). METHODS: Patients prospectively enrolled in the multicenter Lumbar Stenosis Outcome Study (LSOS) with a minimum follow-up of 12 months were included. Quality adjusted life years (QALY) were calculated based on EQ-5D data. Cost data were retrieved retrospectively. Cost-effectiveness was calculated via decision tree analysis. RESULTS: A total of 434 patients were included, treated surgically (n = 170) or conservatively (n = 264) for LSS. The majority of surgically treated patients underwent decompression (n = 141, 82.9%), and 17.1% (n = 29) additionally underwent fusion. A reoperation was required in 13 (7.6%) surgically treated patients. In 27 (10.2%) conservatively treated patients, a single infiltration was successful, with no further infiltration or surgery within the follow-up. However, 46 patients (17.4%) required multiple infiltrations, and in 191 (72.4%) initially conservatively treated patients a subsequent surgery was needed. The area under the curve was 0.776 QALY in the surgical arm (0.776 and 0.790, decompression or additional fusion, respectively), compared to 0.778 in the conservative arm. Treatment costs were estimated at CHF 12,958 and 13,637 (USD 13,465 and 14,169) in surgically and initially conservatively treated patients, respectively [base-case incremental cost-effectiveness ratio (ICER): CHF 392,145, USD 407,831], per QALY gained. Probabilistic sensitivity analysis identified surgery as the preferred strategy in 67.1%. CONCLUSIONS: Both the surgical and the conservative treatment approach resulted in a comparable health-related quality of life within the first year after study inclusion. Due to slightly higher costs, mostly because the majority of initially conservatively treated patients underwent multiple infiltrations or a subsequent surgery, decompressive surgery was identified as the most cost-effective approach for LSS in this setting.

The acromiohumeral distance and the subacromial clearance are correlated to the glenoid version.

BACKGROUND: The acromiohumeral distance (ACHD) is a radiographic parameter for evaluating the presence of a rotator cuff rupture. Previous investigations have demonstrated that several factors may influence the magnitude of the acromiohumeral distance, but glenoid version has not yet been considered. HYPOTHESIS: Our hypothesis was that there is a direct correlation between glenoid version and acromiohumeral distance as well as subacromial clearance. METHODS: Four right glenohumeral joints from adult fresh cadavers were anatomically dissected to the level of the rotator cuff. After fixation to a board and positioning of the humeral head in neutral position, an osteotomy of the glenoid neck was carried out and the version was altered in steps of 5°. The ACHD as well as the subacromial clearance (SAC) were measured for every degree of glenoid version. RESULTS: The ACHD increased with increased anteversion and consistently decreased with increased retroversion of the glenoid. The SAC also depended on glenoid version. Neutral version was associated with a minimal clearance under the anterior third of the acromion, retroversion transferred the minimal SAC posteriorly and anteversion transferred minimal SAC under the coracoacromial ligament. CONCLUSION: Our results indicate that glenoid version correlates directly with the magnitude of ACHD and SAC. Therefore, variations of glenoid version can lead to false interpretations of cuff integrity. TYPE OF STUDY: Biomechanical investigation. LEVEL OF EVIDENCE: Not possible to define.

[Case report of granulomatous necrotizing sialadenitis. Rarity of first manifestation in submandibular gland]. / Fallbericht einer granulomatös-nekrotisierenden Sialadenitis. Rarität einer Erstmanifestation in der Glandula submandibularis.

This article presents the case of a 43-year-old male patient with recurrent painful swelling of the right submandibular gland. Submandibulectomy was performed. Histological investigations showed an intense granulomatous inflammation with severe destruction of the parenchyma. The inflammatory infiltrate consisted of abscesses with neutrophilic and eosinophilic granulocytes and ill-defined granulomas with multinucleated giant cells. Some of the blood vessels showed evidence of vasculitis. After further clinical and serological investigations with highly elevated levels of cytoplasmic antineutrophil cytoplasmic antibodies (c-ANCA) and antiproteinase-3 antibodies, a rare limited disease of granulomatous polyangiitis (Wegener granulomatosis) was finally diagnosed. Such a manifestation of the disease is exceedingly rare; therefore, only single case reports have so far been described. The certain establishment of the diagnosis seems to be challenging because of the lack of involvement of the respiratory tract and the kidneys. In this case a histological assessment and clinical findings are mandatory for the correct diagnosis.

Subcutaneous injection of liquid and foamed polidocanol: extravasation is not responsible for skin necrosis during reticular and spider vein sclerotherapy.

BACKGROUND: Cutaneous necrosis is one of the most annoying complications of reticular and spider vein sclerotherapy. The precise incidence of the complication is not known, although various sources reported incidence between 0.2% and 1.2%. Among a few mechanisms proposed to explain it, extravasation of the sclerosant into the perivascular tissue has been cited as the major cause. OBJECTIVES: The aim of the experimental study in rats was to examine the potential of various concentrations and volumes of polidocanol in both liquid and foam forms to cause cutaneous necrosis after superficial subcutaneous injection. METHODS: Twenty-four female Sprague Dawley rats were injected subcutaneously different concentrations (0.5%, 1%, 2% and 3%) of polidocanol as well as different preparations of polidocanol (liquid vs. foam) and volumes (0.1-0.5 mL). The animals were sacrificed 10 days after injections and biopsy specimens were obtained. RESULTS: Cutaneous necrosis was not seen at volumes <0.5 mL regardless of the concentration or form of polidocanol injected. Foam preparation was shown to be less potent in inducing necrosis with a minimal strength being 2% in comparison with the liquid form where 1% was sufficient to produce overt cutaneous necrosis. CONCLUSIONS: This experimental study shows that extravasation of polidocal in usual circumstances of sclerotherapy of spider and reticular veins cannot be a significant cause of cutaneous necrosis rarely observed in this setting. It is particularly true for the foamed polidocanol where 1% strength seems safe if injected extravascularly in volumes up to 0.5 mL.

Hemorrhagic complications after systemic thrombolysis in acute stroke patients with abnormal baseline coagulation.

BACKGROUND AND PURPOSE: As patients with abnormal baseline coagulation were excluded from the large randomized trials, the safety of intravenous thrombolysis after ischaemic stroke in this patient population remains controversial. METHODS: We assessed the risk of symptomatic intracerebral hemorrhage (SICH) after systemic thrombolysis in patients with elevated baseline international normalized ratios (INRs) (≥1.3) or activated partial thromboplastin times (aPTT) (>37 s) using a prospectively recorded database from 2006 to 2010. An intracerebral hemorrhage leading to a deterioration of ≥4 points on the National Institutes of Health Stroke scale (NIHSS) was classified as symptomatic. RESULTS: Amongst 688 patients (mean age, 72 years; median NIHSS, 11, median onset-to-treatment time, 135 min), 36 patients (5%) had an abnormal baseline coagulation. Twenty-nine of these patients had taken oral anticoagulants leading to elevated baseline INRs (median INR: 1.5; IQR 1.4-1.9), whereas seven patients had elevated aPTTs because of heparin therapy (n = 2), a coagulation disorder (n = 2), or for unknown reasons (n = 3). The rate of SICH did not differ significantly between patients with abnormal and normal baseline coagulation (4.4% vs. 0%; P = 0.6). Moreover, the in-hospital mortality was not significantly different between both treatment groups (8.3% in patients with abnormal baseline coagulation vs. 8.7% in patients with normal baseline coagulation, P = 1.0). CONCLUSIONS: The risk of SICH following intravenous thrombolysis after ischaemic stroke does not appear to be increased in patients with abnormal baseline coagulation.

Imaging performance of the hybrid pixel detectors XPAD3-S.

Hybrid pixel detectors, originally developed for tracking particles in high-energy physics experiments, have recently been used in material sciences and macromolecular crystallography. Their capability to count single photons and to apply a threshold on the photon energy suggests that they could be optimal digital x-ray detectors in low energy beams such as for small animal computed tomography (CT). To investigate this issue, we have studied the imaging performance of photon counting hybrid pixel detectors based on the XPAD3-S chip. Two detectors are considered, connected either to a Si or to a CdTe sensor, the latter being of interest for its higher efficiency. Both a standard 'International Electrotechnical Commission' (IEC) mammography beam and a beam used for mouse CT results published in the literature are employed. The detector stability, linearity and noise are investigated as a function of the dose for several imaging exposures ( approximately 0.1-400 microGy). The perfect linearity of both detectors is confirmed, but an increase in internal noise for counting statistics higher than approximately 5000 photons has been found, corresponding to exposures above approximately 110 microGy and approximately 50 microGy for the Si and CdTe sensors, respectively. The noise power spectrum (NPS), the modulation transfer function (MTF) and the detective quantum efficiency (DQE) are then measured for two energy threshold configurations (5 keV and 18 keV) and three doses ( approximately 3, 30 and 300 microGy), in order to obtain a complete estimation of the detector performances. In general, the CdTe sensor shows a clear superiority with a maximal DQE(0) of approximately 1, thanks to its high efficiency ( approximately 100%). The DQE of the Si sensor is more dependent on the radiation quality, due to the energy dependence of its efficiency its maximum is approximately 0.4 with respect to the softer radiation. Finally, we compare the XPAD3-S DQE with published curves of other digital devices in a similar radiation condition. The XPAD3-S/CdTe detector appears to be the best with the highest DQE at low frequency, although some improvements are expected to reduce the increase of noise with the counts statistics and to guarantee a better stability of the detector response.

[Effects of Maitland's manual mobilization on the thoracic spine]. / Auswirkungen einer manuellen Mobilisation nach Maitland auf die Brustwirbelsäule.

The goal of manual therapy is to decrease pain and to increase function of the spine and peripheral joints. The method introduced by Maitland is widely used in manual medicine. However, no objective changes in the mobility of the thoracic spine after performing manual mobilization have been published in the literature. The aim of this study is to reveal possible changes in the segmental mobility of the thoracic spine after posterior-anterior manipulations without thrust in comparison with a control group. In addition, significant changes within the treatment group were examined. Thirty-six volunteers were randomized into an intervention (16) and a control group (20). The intervention group was treated two times a week for three weeks. The control group received no treatment. The mobility was objectively measured by using Medimouse. No significant difference in the mobility of the thoracic spine could be shown within the intervention group and in comparison with the control group.

A new selective estrogen receptor modulator HMR-3339 fully corrects bone alterations induced by ovariectomy in adult rats.

The selective estrogen receptor modulator (SERM) raloxifene has been shown to reduce the risk of vertebral fracture, but without significant effect on nonvertebral fractures. However, there is a need for SERMs capable of improving mechanical competence and reducing the risk of fractures at multiple skeletal sites, with minimal side effects. We investigated the effects of a new steroidal SERM, HMR-3339, compared to raloxifene, on bone strength and its determinants (BMD, microarchitecture, dimensions) at various skeletal sites (lumbar spine, tibia, and femur) of adult ovariectomized rats in both prevention and intervention protocols. In a prevention study, HMR-3339 and raloxifene treatments fully prevented alterations of bone strength. In an intervention protocol, where treatment was started 8 weeks after ovariectomy, HMR-3339 fully restored mechanical properties by influencing both areal BMD and outer diameter. This effect was observed at skeletal sites formed of cancellous and cortical bone or of cortical bone only. In contrast, raloxifene positively influenced structures containing mainly cancellous bone. In HMR-3339-treated rats, IGF-I plasma levels were higher than in ovariectomized controls; this was not observed with raloxifene. In conclusion, these results indicate that HMR-3339 increased not only bone mineral mass, but also restored bone mechanical strength at multiple sites in adult osteoporotic rats. In contrast to raloxifene, HMR-3339 also influenced skeletal sites predominantly formed of cortical bone.

Arsenic exposure in the wine growing industry in ten French departments.

OBJECTIVES: This study investigated exposure to arsenic, a carcinogenic fungicide used in wine growing. METHODS: The first phase compared urinary arsenic excretion of controls and workers exposed at the end of application. The second phase measured the increase in urinary arsenic excretion during the first day of use. RESULTS: A significant increase in urinary arsenic excretion was observed in arsenic applicators during the first phase. Urinary arsenic concentrations exceeded the American Conference of Governmental Industrial Hygienists (ACGIH) exposure index in one-third of the workers. The second phase showed a significant increase in urinary arsenic excretion by the first day of application. A closed tractor cabin provided a protective effect, but the efficacy of individual protection equipment was not demonstrated. CONCLUSION: This study showed the difficulties of achieving the effective protection of arsenic applicators and has led to the banning of the use of arsenic in French vineyards.

Ca2+ mobilization in saphenous vein smooth muscle cells derived from patients with primary varicosity.

BACKGROUND: Human primary varicosity is associated with 'weakness' of the vein wall. We investigated whether the reduced responsiveness of varicose veins to physiological vasoconstrictors might result from impaired Ca2+ mobilization in venous smooth muscle. MATERIALS AND METHODS: The hypothesis was tested in cells derived from phenotypically different vein segments that were obtained from the inguinal saphenous vein (tissue with incompetent valves), the distal portion of the long saphenous vein just above the medial ankle (clinically healthy tissue), and from a tributary to the long saphenous vein just below the knee (incompetent and overtly varicose tissue). Saphenous vein from patients undergoing cardiac surgery served as control. Cytosolic free Ca2+ levels ([Ca2+]i) were determined with the fura-2 method in cultured medial smooth muscle cells of third to sixth passage (21-23 measurements per tissue derived from five controls and seven patients). RESULTS: Angiotensin II (10 nmol L-1 to 10 mumol L-1) induced a significantly (P < 0.05) smaller rise in [Ca(2+)1i response in cells derived from incompetent or varicose segments (approximatley 70 nmol L-1) than in cells derived from clinically healthy vein (approximately 130 nmol L-1) or controls (approximately 170 nmol L-1). Likewise, the effect of endothelin-1 (100 nmol L-1) on [Ca2+]i was considerably less in cells derived from segments with incompetent valves or from varicose vessel segments than in cells derived from control patients (P < 0.05). In organ baths, endothelium-denuded strips of varicose vessels contracted significantly less in response to these agonists than clinically healthy segments from the same patient. CONCLUSIONS: The reduced contractility of diseased human varicose veins in response to angiotensin II and endothelin-1 involves impaired Ca2+ mobilization.

Bronchopulmonary disposition of the ketolide telithromycin (HMR 3647).

Telithromycin (HMR 3647) is the first member of a new family of antimicrobials, the ketolides, developed specifically for the treatment of community-acquired respiratory tract infections. Telithromycin has proven in vitro activity against both common and atypical respiratory tract pathogens. The penetration of telithromycin into bronchopulmonary tissues and subsequent elimination from these sites were evaluated in four groups (groups A, B, C, and D) of six healthy male subjects who received telithromycin at 800 mg once daily for 5 days. Subjects in groups A, B, C, and D underwent fiberoptic bronchoscopy and bronchoalveolar lavage 2, 8, 24, and 48 h after receipt of the last dose, respectively. The concentration of telithromycin in the alveolar macrophages, epithelial lining fluid (ELF), and plasma was determined by the agar diffusion method with Bacillus subtilis ATCC 6633 as the test organism. The concentration of telithromycin in alveolar macrophages markedly exceeded that in plasma, reaching up to 146 times the concentration in plasma 8 h after dosing (median concentration, 81 mg/liter). Telithromycin was retained in alveolar macrophages 24 h after dosing (median concentration, 23 mg/liter), and it was still quantifiable 48 h after dosing (median concentration, 2.15 mg/liter). Telithromycin median concentrations in ELF also markedly exceeded concentrations in plasma (median concentration in ELF, 3.7 mg/liter 8 h after dosing). Telithromycin achieves high and sustained concentrations in ELF and in alveolar macrophages, while it maintains adequate levels in plasma, providing an ideal pharmacokinetic profile for effective treatment of community-acquired respiratory tract infections caused by either common or atypical, including intracellular, respiratory tract pathogens.

Diagnostic yield of bronchoalveolar lavage following renal transplantation.

Organ transplant recipients are at high risk of infectious pulmonary complications. In this retrospective study, the diagnostic yield of bronchoalveolar lavage (BAL) was evaluated in renal transplant recipients. The results were analysed in special regard to the clinical presentation of pulmonary infections and the possible impact of new immunosuppressive agents. Over a 5-year period 91 BAL were performed in 71 renal transplant recipients. Microorganisms were isolated from 69% of BAL (63/91): bacteria 32%; cytomegalovirus (CMV) 27%; Pneumocystis carinii (PC) 22%; other viruses 9% (HSV; EBV, RSV, adenovirus, HHV8); Aspergillus fumigatus 1%. Total cell counts and neutrophil counts in BAL were significantly elevated in bacterial infection, whereas BAL positive for PC showed eosinophilia (P<0.05). There was no association between clinical symptoms and the radiological pattern of infiltrates and the type of infection. Immunosuppression containing tacrolimus or mycophenolate mofetil was associated with a significantly higher percentage of PC and CMV infections compared to cyclosporin-based immunosuppression (65% vs. 30%, P<0.005). A considerable number of PC and CMV infections occurred beyond 6 months after transplantation. In conclusion, BAL has a high diagnostic yield in renal transplant recipients. Infection with CMV and PC should also be considered beyond 6 months after transplantation, and prophylaxis for opportunistic infections should be given if the immunosuppression is intensified.

A new cause of renal thrombotic microangiopathy: yttrium 90-DOTATOC internal radiotherapy.

The chelator somatostatin analogue dota-D-phe(1)-tyr(3)-octreotide (DOTATOC), which is stably labeled with the beta-emitting radioisotope yttrium 90 ((90)Y), is used as internal radiotherapy for the treatment of patients with advanced neuroendocrine tumors. We report 5 patients who developed chronic renal failure, caused in 3 patients by biopsy-proven thrombotic microangiopathy (TMA). Twenty-nine patients (14 men, 15 women) with normal renal function before therapy were treated with divided intravenous doses of (90)Y-DOTATOC approximately 6 weeks apart (mean normalized cumulative dose, 165.4 +/- 36.4 mCi/m(2)). Twenty-two of 29 patients were administered a normalized cumulative dose of 200 mCi/m(2) without side effects. Among the 7 patients (6 women, 1 man) administered a normalized cumulative dose greater than 200 mCi/m(2), 5 patients (4 women, 1 man) developed renal failure. Increasing serum creatinine levels were observed within 3 months after the last (90)Y-DOTATOC injection. The evolution was rapidly progressive in 3 patients, resulting in end-stage renal failure within 6 months. The remaining 2 patients developed chronic renal insufficiency (mean serum creatinine level, 300 micromol/L an average 16 months after the end of treatment). Renal biopsies performed in 3 patients showed typical signs of TMA involving glomeruli, arterioles, and small arteries. Patients treated with high-dose (90)Y-DOTATOC internal radiotherapy (cumulative dose > 200 mCi/m(2)) are at high risk to develop severe renal failure caused by TMA lesions. The histopathologic lesions are identical to those found after external radiotherapy, which suggests a causal relationship between (90)Y-DOTATOC and renal TMA.