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.

IKZF1 expression is a prognostic marker in newly diagnosed standard-risk multiple myeloma treated with lenalidomide and intensive chemotherapy: a study of the German Myeloma Study Group (DSMM).

Lenalidomide is an immunomodulatory compound with high clinical activity in multiple myeloma. Lenalidomide binding to the Cereblon (CRBN) E3 ubiquitin ligase results in targeted ubiquitination and degradation of the lymphoid transcription factors Ikaros (IKZF1) and Aiolos (IKZF3) leading to growth inhibition of multiple myeloma cells. Recently, Basigin (BSG) was identified as another protein regulated by CRBN that is involved in the activity of lenalidomide. Here, we analyzed the prognostic value of IKZF1, IKZF3, CRBN and BSG mRNA expression levels in pretreatment plasma cells from 60 patients with newly diagnosed multiple myeloma uniformly treated with lenalidomide in combination with intensive chemotherapy within a clinical trial. We found that IKZF1 mRNA expression levels are significantly associated with progression-free survival (PFS). Patients in the lowest quartile (Q1) of IKZF1 expression had a superior PFS compared with patients in the remaining quartiles (Q2-Q4; 3-year PFS of 86 vs 51%, P=0.01). This translated into a significant better overall survival (100 vs 74%, P=0.03). Subgroup analysis revealed a significant impact of IKZF1, IKZF3 and BSG expression levels on PFS in cytogenetically defined standard-risk but not high-risk patients. Our data suggest a prognostic role of IKZF1, IKZF3 and BSG expression levels in lenalidomide-treated multiple myeloma.

Longitudinal analysis of 25 sequential sample-pairs using a custom multiple myeloma mutation sequencing panel (M(3)P).

Recent advances in genomic sequencing technologies now allow results from deep next-generation sequencing to be obtained within clinically meaningful timeframes, making this an attractive approach to better guide personalized treatment strategies. No multiple myeloma-specific gene panel has been established so far; we therefore designed a 47-gene-targeting gene panel, containing 39 genes known to be mutated in ≥3 % of multiple myeloma cases and eight genes in pathways therapeutically targeted in multiple myeloma (MM). We performed targeted sequencing on tumor/germline DNA of 25 MM patients in which we also had a sequential sample post treatment. Mutation analysis revealed KRAS as the most commonly mutated gene (36 % in each time point), followed by NRAS (20 and 16 %), TP53 (16 and 16 %), DIS3 (16 and 16 %), FAM46C (12 and 16 %), and SP140 (12 and 12 %). We successfully tracked clonal evolution and identified mutation acquisition and/or loss in FAM46C, FAT1, KRAS, NRAS, SPEN, PRDM1, NEB, and TP53 as well as two mutations in XBP1, a gene associated with bortezomib resistance. Thus, we present the first longitudinal analysis of a MM-specific targeted sequencing gene panel that can be used for individual tumor characterization and for tracking clonal evolution over time.

Vitamin D as a possible independent predictor of bone mineral density in Estonian adults: a cross-sectional population-based study.

BACKGROUND: Vitamin D insufficiency and deficiency are prevalent worldwide, with the highest prevalence in the northern countries due to the lack of ultraviolet exposure. The individual effect of vitamin D on bone mineral density (BMD) has been studied but the results are inconclusive. AIM: The aim of our study was to investigate the effect of vitamin D on BMD in a random population-based cohort of Estonian adults. METHODS: A cross-sectional population-based study. A total of 273 individuals free of diseases or states known to affect bone or vitamin D metabolism participated in the study. We measured BMD, vitamin D and parathyroid hormone concentrations (in winter and in summer). Several co-variables were included in the regression analysis, including age, smoking, alcohol consumption, body mass index, physical activity, fresh milk consumption, caffeinated beverage consumption, lean tissue mass and total body fat percentage, and in women the number of children and breastfeeding history. RESULTS: We show that summer vitamin D independently correlates with BMD in lumbar spine, trochanter and total body regions (P < 0.05 to 0.01). Subgroup analysis for women showed that summer vitamin D predicts independently lumbar spine (P < 0.05) and in men total body BMD (P < 0.01). Lean tissue mass and fat mass were additional contributors of the BMD (P < 0.001). CONCLUSION: In addition to body composition indices, vitamin D could be an independent contributor of BMD in several skeletal regions in men and women.

[Supportive therapy of urogenital tumors: diagnostic and therapy of common complications]. / Supportivtherapie bei Urogenitaltumoren : Diagnostik und Therapie häufiger Komplikationen.

Within the framework of systemic therapy with cytostatic agents and advanced stages of tumor diseases, therapy-induced and disease-related complications can severely impair the quality of life. This article gives a brief synopsis of the current literature on the diagnosis and therapy concerning anemia thrombotic events and tumor-related hypercalcemia as well as recommendations on treating therapy-associated neutropenia.

Repair of long-bone fractures in cats and small dogs with the Unilock mandible locking plate system.

OBJECTIVES: To retrospectively evaluate stabilisation of long-bone fractures in cats and small dogs using the Unilock system. METHODS: Medical histories and radiographs of consecutive patients with long-bone fractures stabilised with the Unilock system were reviewed. Cases with follow-up radiographs taken at least four weeks postoperatively were included. Signalment of the patient, fracture localisation and type, primary fracture repair or revision surgery, single or double plating, and complications for each patient were noted. Additionally, implant size, number of screws, number of cortices engaged with screws, and number of empty holes across the fracture were evaluated in fractures where a single plate had been applied. RESULTS: Eighteen humeral, 18 radial, 20 femoral, and 10 tibial fractures were treated. The Unilock system was used for primary repair in 44 fractures and for revision surgery in 22 fractures. Two plates were applied in 17 fractures, and a single plate was applied in 49 fractures. Follow-up radiographs were taken four to 109 weeks postoperatively. Complications were seen in 12 animals and 13 fractures (19.7%). Fixation failure occurred in seven fractures (10.6%). Cases with a single plate that suffered fixation failure had thinner screws in relation to bone diameter than cases with double plates, and more screws in a main fragment than those without fixation failure. CLINICAL SIGNIFICANCE: The Unilock system is a suitable implant for fracture fixation of long bones in cats and small dogs.

Body mass index determines sunbathing habits: implications on vitamin D levels.

Vitamin D is crucial for calcium and bone metabolism. Overweight people have been found to have lower levels of this vitamin. The aim of the paper was to test if sun exposure habits might differ according to weight and body fat per cent in a random population-based sample, and have an impact on vitamin D levels. The analysis of 367 persons showed that, among other established factors, differences in sunbathing also explain the lower vitamin D levels in overweight and elderly individuals.

Design and synthesis of N4,N9-disubstituted spermines for non-viral siRNA delivery--structure-activity relationship studies of siFection efficiency versus toxicity.

PURPOSE: To study the effect of sequentially changing the chain length, oxidation level, and charge distribution in N4,N9-diacyl and N4,N9-dialkyl spermines on siRNA formulation, and then to compare their lipoplex transfection efficiency in cell lines. METHODS: Eight N4,N9-diacyl polyamines: N4,N9-[didecanoyl, dilauroyl, dimyristoyl, dimyristoleoyl, dipalmitoyl, distearoyl, dioleoyl and diretinoyl]-1,12-diamino-4,9-diazadodecane were synthesized. Their abilities to bind to siRNA and form nanoparticles were studied using a RiboGreen intercalation assay and particle sizing. Two diamides were also reduced to afford tetraamines N4,N9-distearyl- and N4,N9-dioleyl-1,12-diamino-4,9-diazadodecane. Delivery of fluorescein-labelled Label IT RNAi Delivery Control was studied in FEK4 primary skin cells and in an immortalized cancer cell line (HtTA), and compared with TransIT-TKO. RESULTS: The design, synthesis, and structure-activity relationship studies of a series of N4,N9-disubstituted spermines as efficient vectors for non-viral siRNA delivery to primary skin and cancer cell lines is reported. These non-liposomal cationic lipids are promising siRNA carriers based on the naturally occurring polyamine spermine showing that C-18 is a better chain length as shorter chains are more toxic. CONCLUSIONS: N4,N9-Distearoyl spermine and N4,N9-dioleoyl spermine are efficient siRNA formulation and delivery vectors, even in the presence of serum, comparable to TransIT-TKO. However, four positive charges distributed as in spermine was significantly more toxic.

Ageing, soft-palate tone and sleep-related breathing disorders.

UNLABELLED: We compared the tissue tone of the soft palate in 10 young (18-29 years) and 15 middle-aged (30-70 years) apnoeics with 10 young and 10 middle-aged non-snorers and healthy volunteers of the same ages. The obstructive sleep apnoea syndrome (OSAS) was diagnosed by means of the self-reported questionnaire about the medical history of the subjects and polysomnography (PSG) with overnight pulse oximetry. Computerized endopharyngeal myotonometry (CEM) was used to measure the tissue tone of the soft palate. The CEM study is performed while the subjects are awake. CEM records and analyses the biomechanical properties of tissue in response to a brief mechanical impact. Tissue stiffness is expressed as a frequency and elasticity as a logarithmic decrement of damped oscillation. RESULTS: The values of the tissue stiffness (13.5, SD 2.5 Hz) and elasticity (1.2, SD 0.4) of the soft palate in young adults with OSAS reveal no important differences in comparison with the tissue stiffness (12.7, SD 2.4 Hz) and elasticity (0.9, SD 0.2) in non-snoring young adults. The difference in the value of the tissue stiffness of the soft palate is significant among middle-aged patients with OSAS (20.3, SD 4.7 Hz) and non-snoring middle-aged persons (13.9, SD 2.3 Hz). A non-significant difference was observed in the value of the tissue elasticity among middle-aged patients with OSAS (1.7, SD 0.8) and non-snoring middle-aged persons (1.6, SD 0.3). The tissue tone of the soft palate in young and middle-aged healthy subjects differs by elasticity but not by stiffness. CONCLUSIONS: We found that some biomechanical properties of the tissues of the soft palate may be changed by OSAS and some by age.

Computerized endopharyngeal myotonometry (CEM): a new method to evaluate the tissue tone of the soft palate in patients with obstructive sleep apnoea syndrome.

This study compared the tissue tone of the soft palate in nonsnoring subjects and patients with obstructive sleep apnoea syndrome (OSAS) during wakefulness. Here, tissue tone means the biomechanical property of the tissue which can be characterized by two main parameters: stiffness and elasticity. Tissue tone includes both structural and neural components. A new method to evaluate the tissue tone of the soft palate was used - computerized endopharyngeal myotonometry (CEM). This method records and analyses the response of the soft palate tissues to a brief mechanical impact. The method enabled us to evaluate the most important parameters of tissue tone: stiffness, which is expressed as a frequency; and elasticity, expressed as a logarithmic decrement of the damped oscillation. First, a self-reported questionnaire was completed about the medical history of the subjects. Subjects then underwent a physical examination of the oropharynx and polysomnography with overnight pulse oximetry. The results of the CEM method indicated that patients with OSAS show an increased stiffness of the soft palate tissues (20.3, SD 4.7 Hz) compared with nonsnoring subjects (12.2, SD 1.8 Hz). In patients with sleep apnoea, elasticity is not increased in a similar way to stiffness. Thus, the disproportion between tissue stiffness and elasticity of the soft palate is a measure of the pathological changes in patients with sleep apnoea.

Spectrophotometric determination of ketoprofen in pharmaceutical preparations by means of charge transfer complex formation.

A spectrophotometric determination of ketoprofen based upon oxime formation followed by charge transfer complexation with o-chloranil has been developed. Different variables affecting the complexation process have been studied. Beer's law is obeyed in the concentration range 10-80 microg/ml. The method has been successfully applied to the determination of ketoprofen in pure form and in pharmaceutical dosage forms in the presence of its impurities.

[Morphofunctional characteristics of wound inflicted by an ultrasonic destroyer]. / Morfofunktsional'naia kharakteristika rany, nanesennoi ul'trazvukovym destruktorom.

A surgical model of EstoRex ultrasound destroyer operating at a frequency of 60 KHz, power of 6 W, and vibration amplitude at the tip of the tool of 15 microns was used to make incisions on rat liver. 5 to 7 s or 24 hr after surgery the specimens of the wound wall were fixed and further processed for electron microscopy and histochemical visualization of glucose-6-phosphatase at the ultrastructural level. In a separate series 2 mm-thick strips of the tissue were excised from the liver, processed by the destroyer for 45 s, and then exposed to a digestion treatment with mixture of trypsin and chymotrypsin for 24 hr at 37 degrees C or in solution of cathepsin L for 60 hr at 25 degrees C. The results showed that ultrasound caused not only thermal but also nonthermal ultrastructural and histochemical alterations, due probably to cavitation and viscous stresses. The ultrasound wound did not contain any proteolytically resistant material. Since ultrasound-processed tissue turned out to be highly susceptible to proteolytic digestion we suggest that the ultrasound destroyer, unlike Nd:YAG laser surgical instrument, would be a promising surgical tool with respect to wound cleaning and healing.

Experimental results of second-harmonic generation from a polyurethane waveguide on a silver grating coupler.

Second-harmonic generation by excitation of guided modes and the surface plasmon in a polyurethane-coated silver grating coupler is presented. In order to study the spectral dependence of the second-harmonic efficiency, two different pump wavelengths are used, 1064 and 1319 nm. For the longer-wavelength pump we observe a large enhancement of the second-harmonic efficiency as the incident angle is scanned through an electromagnetic resonance, whereas for the shorter-wavelength pump the second-harmonic wavelength falls within the absorption band of the polymer, and we observe unexpected minima instead of maxima.

[Electron histochemical characteristics of laser necrosis]. / Elektronno-gistokhimicheskaia kharakteristika lazernogo nekroza.

Linear or dot-shaped lesions were inflicted on rat liver with Nd:YAG laser, and fine structural alterations of hepatocytes were studied in the specimens processed for an endoplasmic reticulum (ER) marker glucose-6-phosphatase (GP). 5-7 s after irradiation a severe cell damage and GP inhibition occurred near the lesions, with less injured cells located laterally. 24 hr later the zone of the necrosis increased markedly. An autolytic decomposition in the newly formed necrotic area was much more pronounced as compared to the area of the initial necrosis. Phagocytic resorption of the intensively irradiated tissue was retarded this explaining some clinical observations on the long-term healing after Nd:YAG laser surgery. Based on our observations the so-called contact regimen of the irradiation is recommended due to the small size of the initial necrosis produced with this method. The various patterns of cell injuries including some changes in ER and enzyme GP as its marker are described in detail.

The development of a posterior tooth composite system, in-vitro investigation.

Adaptation and marginal seal of conventional MOD composite restorations was investigated in vitro with the scanning electron microscope and a dye penetration test. An optimal adaptation i.e. with over 90% "perfect margin" was achieved in conventional MOD cavity preparations without using the enamel-etch technique. After applying a composite sealer the proximal boxes were filled with a condensable composite to the level of the occlusal floor. Only after the proximal portions had hardened was the occlusal portion of the restoration completed. The proximal margin of an MOD composite restoration made in this manner is, in comparison to amalgam, about four times better adapted, however, because of the conventional cavity form with sharp line angles there is some percolation. With the presently available composite materials a clinically acceptable posterior resoration comosite system can be constructed: For the initial proximal portion a sufficiently radiopaque, condensable, not necessarily wear resistant composite would be used, and for the occlusal portion a proven wear-resistant, not necessarily radiopaque composite. On the basis of experiments measuring roughness it could be shown in test samples and in MOD composite restoration, in vitro and in vivo, that ultrafine diamond burs were well suited for the finishing of conventional and microfill composites. For the finishing of MOD microfill composites burs with fine and ultrafine diamond particles and specially developed forms are necessary.