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Abstract Clinical bleeding events are reported here from 773 patients with B‐cell malignancies receiving pirtobrutinib monotherapy from the phase 1/2 BRUIN study (ClinicalTrials.gov identifier: NCT03740529), either in the presence or absence of antithrombotic therapy (antithrombotic exposed [AT‐E], n = 216; antithrombotic nonexposed [AT‐NE], n = 557). Among the AT‐E cohort, 51.9% received platelet aggregation inhibitors, 36.6% received direct factor Xa inhibitors, 18.5% received heparins, 5.6% received salicylic acid for indications other than platelet aggregation inhibition, and 2.3% received thrombolytics. Warfarin was not permitted. Any‐grade bleeding/bruising events occurred in 97 patients (44.9%; 95% confidence interval [CI], 38.3–51.5) in the AT‐E cohort and 181 patients (32.5%; 95% CI, 28.6–36.4) in the AT‐NE cohort. Most bleeding/bruising events in both cohorts began within the first 6 months of treatment (AT‐E: 65.4%; AT‐NE: 72.5%). Contusion was the most common bleeding/bruising event in both cohorts (AT‐E: 22.7%; AT‐NE: 18.1%). Grade ≥3 bleeding/bruising events were reported in six patients (2.8%) in the AT‐E cohort and 11 patients (2.0%) in the AT‐NE cohort. Bleeding/bruising events requiring or prolonging hospitalization were reported in 2.3% and 1.6% of patients in the AT‐E and AT‐NE cohorts, respectively. No bleeding/bruising events led to pirtobrutinib dose reduction or permanent discontinuation in the AT‐E cohort, and one patient (0.2%) in the AT‐NE cohort experienced an event requiring dose reduction. These data support the safety of pirtobrutinib in patients requiring antithrombotic therapies.

Bruton tyrosine kinase inhibitors (BTKi) have transformed the treatment of B-cell malignancies, but intolerance has often led to their discontinuation. The phase 1/2 BRUIN study evaluated pirtobrutinib, a highly selective non-covalent (reversible) BTKi, in patients with R/R B-cell malignancies (NCT03740529). Pirtobrutinib was investigated in 127 patients with intolerance to at least one prior BTKi therapy in the absence of progressive disease. The most common adverse event (AE) leading to BTKi discontinuation was cardiac disorders (n=40, 31.5%), specifically atrial fibrillation (n=30, 23.6%). The median follow-up was 17.4 months and the median time on pirtobrutinib was 15.3 months. The most common reasons for pirtobrutinib discontinuation were progressive disease (26.8%), AE (10.2%), or death (5.5%). The most frequent treatment-emergent AEs were fatigue (39.4%) and neutropenia (37.0%). Among patients who discontinued a prior BTKi for a cardiac issue, 75% had no recurrence of their cardiac AE. No patient discontinued pirtobrutinib for the same AE that led to discontinuation of the prior BTKi. In 78 CLL/SLL and 21 MCL patients intolerant to prior BTKi, ORR to pirtobrutinib was 76.9% and 81.0%, respectively. Median PFS for CLL/SLL was 28.4 months and was not estimable for MCL. These results suggest that pirtobrutinib was safe, well-tolerated, and an efficacious option in patients with prior BTKi-intolerance.

This multicenter, open-label, phase 1b study (ACE-LY-106) assessed the safety and efficacy of acalabrutinib, bendamustine, and rituximab (ABR) in treatment-naive (TN) and relapsed or refractory (R/R) mantle cell lymphoma (MCL). Patients received acalabrutinib from cycle 1 until disease progression or treatment discontinuation, bendamustine on days 1 and 2 of each cycle for up to 6 cycles, and rituximab on day 1 of each cycle for 6 cycles, continuing every other cycle from cycle 8 for 12 additional doses (TN cohort). Eighteen patients enrolled in the TN and 20 in the R/R cohort. Median duration of exposure to acalabrutinib was 34.0 and 14.6 months in the TN and R/R cohorts, respectively. No new safety risks were identified, and most adverse events (AEs) were grades 1 or 2. Thirteen patients from the TN cohort (72.2%) and 17 patients from the R/R cohort (85.0%) reported grade 3–4 AEs, most commonly neutropenia (TN: 38.9%, R/R: 50.0%). AEs leading to death were pneumonitis (n=1, TN cohort), COVID-19, and cerebrospinal meningitis (n=1 each, R/R cohort). Overall response was 94.4% and 85.0% in the TN and R/R cohorts, respectively; complete response rates were 77.8% and 70.0%, respectively. After a median follow-up of 47.6 months, median progression-free survival (PFS) and overall survival (OS) were not reached in the TN cohort. After a median follow-up of 20.4 months, median PFS was 28.6 months and OS was not reached in the R/R cohort. Results indicate that ABR was safe and efficacious, supporting further study in patients with TN MCL. ClinicalTrials.gov identifier: NCT02717624

Abstract In this global phase 2 study in patients with relapsed/refractory follicular lymphoma (FL), zandelisib was administered on intermittent dosing to mitigate immune‐related adverse events and infections that have been reported with oral PI3Kδ inhibitors administered daily continuously. Eligible patients with measurable disease and progression after at least two prior therapies were administered zandelisib until disease progression or intolerability. The primary efficacy endpoint was objective response rate (ORR) and the key secondary efficacy endpoint was duration of response (DOR). We report on 121 patients with FL administered zandelisib on intermittent dosing after 8 weeks of daily dosing for tumor debulking. The median number of prior therapies was 3 (range, 2–8) and 45% of patients had refractory disease. The ORR was 73% (95% confidence interval [CI], 63.9–80.4), the complete response (CR) rate was 38% (95% CI, 29.3–47.3), and the median DOR was 16.4 months (95% CI, 9.5–not reached). With a median follow‐up of 14.3 months (range, 1–30.5), the median progression‐free survival was 11.6 months (95% CI, 8.3–not reached). Twenty‐one patients (17%) discontinued therapy due to an adverse event. Grade 3–4 class‐related toxicities included 6% diarrhea, 5% lung infections, 3% colitis (confirmed by biopsy or imaging), 3% rash, 2% AST elevation, and 1% non‐infectious pneumonitis. Zandelisib achieved a high rate of durable responses in heavily pretreated patients with relapsed/refractory FL. The intermittent dosing resulted in a relatively low incidence of severe class‐related toxicities, which supports the evaluation of zandelisib as a single agent and in combination with indolent B‐cell malignancies.

The dynamic development of measurement and recording techniques has been changing the way one conceives material strength. In this study, two different methods of evaluating the strength of fabrics are compared. The first is the typical and commonly used technique based on the use of a testing machine. The second method uses the so-called “fast camera” to monitor the entire process of the destruction of a fabric sample and analyse the behaviour of the fabric during the experiment. Both methods provide interesting data and present a very specific way of experimentally evaluating the strength of fabrics.

Tafasitamab, an anti-CD19 immunotherapy, is used with lenalidomide for patients with autologous stem cell transplant-ineligible relapsed/refractory diffuse large B-cell lymphoma based on the results of the phase II L-MIND study (NCT02399085). We report the final 5-year analysis of this study. Eighty patients ≥18 years who had received one to three prior systemic therapies, and had Eastern Cooperative Oncology Group performance status 0-2 received up to 12 cycles of co-administered tafasitamab and lenalidomide, followed by tafasitamab monotherapy until disease progression or unacceptable toxicity. The primary endpoint was the best objective response rate. Secondary endpoints included duration of response, progression-free survival, overall survival, and safety. Exploratory analyses evaluated efficacy endpoints by prior lines of therapy. At data cutoff on November 14, 2022, the objective response rate was 57.5%, with a complete response rate of 41.3% (n=33), which was consistent with prior analyses. With a median follow-up of 44.0 months, the median duration of response was not reached. The median progression-free survival was 11.6 months (95% confidence interval [95% CI]: 5.7-45.7) with a median follow-up of 45.6 months. The median overall survival was 33.5 months (95% CI: 18.3-not reached) with a median follow-up of 65.6 months. Patients who had received one prior line of therapy (n=40) showed a higher objective response rate (67.5%; 52.5% complete responses) compared to patients who had received two or more prior lines of therapy (n=40; 47.5%; 30% complete responses), but the median duration of response was not reached in either subgroup. Other exploratory analyses revealed consistent long-term efficacy results across subgroups. Adverse events were consistent with those described in previous reports, were manageable, and their frequency decreased during tafasitamab monotherapy, with no new safety concerns. This final 5-year analysis of L-MIND demonstrates that the immunotherapy combination of tafasitamab and lenalidomide is well tolerated and has long-term clinical benefit with durable responses.

Summary: Background: Parsaclisib is a potent and highly selective PI3Kδ inhibitor that has shown clinical benefit in patients with relapsed/refractory (R/R) B-cell malignancies. In this phase 2 study (CITADEL-205; NCT03235544, EudraCT 2017-003148-19), the efficacy and safety of parsaclisib was evaluated in patients with R/R mantle cell lymphoma (MCL). Methods: Patients ≥18 years old with pathologically confirmed R/R MCL and prior treatment with 1–3 systemic therapies, with (cohort 1) or without (cohort 2) previous Bruton kinase inhibitor (BTKi) treatment, received oral parsaclisib 20 mg once-daily (QD) for 8 weeks, then either parsaclisib 20 mg once-weekly (weekly dosing group [WG]) or parsaclisib 2.5 mg QD (daily dosing group [DG]). The primary endpoint was objective response rate (ORR). Findings: At the primary analysis data cutoff on January 15, 2021, 53 patients in cohort 1 (BTKi-experienced) (WG, n = 12; DG: n = 41) and 108 patients in cohort 2 (BTKi-naive) (WG, n = 31; DG: n = 77) had received parsaclisib monotherapy. The BTKi-experienced cohort was closed after an interim analysis demonstrated limited clinical benefit. In the BTKi-naive cohort, the ORR (95% CI) for DG (dosing selected for further study) was 70.1% (58.6%–80.0%), with a complete response rate (95% CI) of 15.6% (8.3%–25.6%) and a median duration of response (95% CI) of 12.1 (9.0–not evaluable) months. Treatment-emergent adverse events (TEAEs) occurred among 90.7% (98/108) of all treated patients in the BTKi-naive cohort. Grade ≥3 TEAEs occurred among 62.0% (67/108) of patients, including diarrhoea (13.9%, 15/108) and neutropenia (8.3%, 9/108). Parsaclisib interruption, reduction, or discontinuation due to TEAEs occurred among 47.2% (51/108), 8.3% (9/108), and 25.0% (27/108) of patients, respectively. Fatal TEAEs were experienced by six patients and determined to be treatment-related in one patient. Interpretation: Parsaclisib, a potent, highly selective, PI3Kδ inhibitor demonstrated meaningful clinical benefits and a manageable safety profile (25.0% discontinuation rate, low incidences of individually reported grade ≥3 or serious adverse events) in R/R MCL patients with no prior BTKi therapy. Limited clinical benefit was observed with parsaclisib monotherapy in patients who had previously received BTKi treatment. Future development of PI3K inhibitors for NHL will require further investigation of dose optimisation to improve safety and long-term survival. Funding: Incyte Corporation.

At present peristaltic pumps are widely used in many branches of industry and national economy. Simplicity of construction, processability and possibility of pumping liquids with big quantity of solid particles are the main advantages while using peristaltic pumps. Therefore development of methods of rational choice of parameters at designing of peristaltic pumps is the actual problem. To develop universal mathematical models of dynamic processes in peristaltic pumps for definition of rational technical parameters. In dynamic processes we propose to use differential equations of motion in the Lagrange form, where the angle of rotation of the pump rotor is taken as a universal coordinate. Mathematical model of dynamic processes in peristaltic pump with hydraulic drive has been created on the base of differential equation. The function of resistance forces caused by gravity forces of mixture particles in the hose reel has been determined. On the basis of the non-linear model of the resistance forces to the flow of the fluid Bingham method of constructing the dependence of the pressure drop on the angular velocity of the rotor to determine the resistance forces to the flow of the fluid has been proposed. The result of dynamic processes simulation is the determination of interrelationship of technological parameters of the device functioning: the velocity of the medium and pump performance is increasing at reducing the length of the diverting hose and reducing the height of its rise; a significant influence on the average speed has plastic viscosity of the environment; a significant change in the yield strength has an insignificant impact on the speed.

Background: Patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) have limited treatment options. Ceralasertib, a selective ataxia telangiectasia and Rad-3-related protein (ATR) inhibitor, demonstrated synergistic preclinical activity with a Bruton tyrosine kinase (BTK) inhibitor in TP53 - and ATM -defective CLL cells. Acalabrutinib is a selective BTK inhibitor approved for treatment of CLL. Objectives: To evaluate ceralasertib ± acalabrutinib in R/R CLL. Design: Nonrandomized, open-label phase I/II study. Methods: In arm A, patients received ceralasertib monotherapy 160 mg twice daily (BID) continuously (cohort 1) or 2 weeks on/2 weeks off (cohort 2). In arm B, patients received acalabrutinib 100 mg BID continuously (cycle 1), followed by combination treatment with ceralasertib 160 mg BID 1 week on/3 weeks off from cycle 2. Co-primary objectives were safety and pharmacokinetics. Efficacy was a secondary objective. Results: Eleven patients were treated [arm A, n = 8 (cohort 1, n = 5; cohort 2, n = 3); arm B, n = 3 (acalabrutinib plus ceralasertib, n = 2; acalabrutinib only, n = 1)]. Median duration of exposure was 3.5 and 7.2 months for ceralasertib in arms A and B, respectively, and 15.9 months for acalabrutinib in arm B. Most common grade ⩾3 treatment-emergent adverse events (TEAEs) in arm A were anemia (75%) and thrombocytopenia (63%), with four dose-limiting toxicities (DLTs) of grade 4 thrombocytopenia. No grade ⩾3 TEAEs or DLTs occurred in arm B. Ceralasertib plasma concentrations were similar when administered as monotherapy or in combination. At median follow-up of 15.1 months in arm A, no responses were observed, median progression-free survival (PFS) was 3.8 months, and median overall survival (OS) was 16.9 months. At median follow-up of 17.2 months in arm B, overall response rate was 100%, and median PFS and OS were not reached. Conclusion: Ceralasertib alone showed limited clinical benefit. Acalabrutinib plus ceralasertib was tolerable with preliminary activity in patients with R/R CLL, though findings are inconclusive due to small sample size. Registration: NCT03328273

Acalabrutinib is a Bruton tyrosine kinase inhibitor approved for patients with chronic lymphocytic leukemia (CLL). ASCEND is the pivotal phase 3 study of acalabrutinib versus investigator’s choice of idelalisib plus rituximab (IdR) or bendamustine plus rituximab (BR) in patients with relapsed/refractory (R/R) CLL. In the primary ASCEND analysis (median 16.1-month follow-up), acalabrutinib showed superior efficacy with an acceptable tolerability profile versus IdR/BR; here, we report final ~4 year follow-up results. Patients with R/R CLL received oral acalabrutinib 100 mg twice daily until progression or unacceptable toxicity, or investigator’s choice of IdR or BR. A total of 310 patients (acalabrutinib, n = 155; IdR, n = 119; BR, n = 36) were enrolled. At median follow-up of 46.5 months (acalabrutinib) and 45.3 months (IdR/BR), acalabrutinib significantly prolonged investigator-assessed progression-free survival (PFS) versus IdR/BR (median, not reached [NR] vs 16.8 months; P < 0.001); 42-month PFS rates were 62% (acalabrutinib) versus 19% (IdR/BR). Median overall survival (OS) was NR (both arms); 42-month OS rates were 78% (acalabrutinib) versus 65% (IdR/BR). Adverse events led to drug discontinuation in 23%, 67%, and 17% of patients in the acalabrutinib, IdR, and BR arms, respectively. Events of clinical interest (acalabrutinib vs IdR/BR) included all-grade atrial fibrillation/flutter (8% vs 3%), all-grade hypertension (8% vs 5%), all-grade major hemorrhage (3% vs 3%), grade ≥3 infections (29% vs 29%), and second primary malignancies excluding nonmelanoma skin cancer (7% vs 2%). At ~4 years follow-up, acalabrutinib maintained favorable efficacy versus standard-of-care regimens and a consistent tolerability profile in patients with R/R CLL.

Abstract Ibrutinib plus venetoclax, given with an ibrutinib lead-in, has shown encouraging clinical activity in early phase studies in mantle cell lymphoma (MCL). The ongoing phase 3 SYMPATICO study evaluates the safety and efficacy of concurrently administered, once-daily, all-oral ibrutinib plus venetoclax in patients with relapsed/refractory MCL. A safety run-in (SRI) cohort was conducted to inform whether an ibrutinib lead-in should be implemented for the randomized portion. Patients received concurrent ibrutinib 560 mg continuously plus venetoclax in a 5-week ramp-up to venetoclax 400 mg for up to 2 years. The primary endpoint was occurrence of tumor lysis syndrome (TLS) and dose-limiting toxicities (DLTs). The SRI cohort enrolled 21 patients; six and 15 were in low- or increased-risk categories for TLS, respectively. During the 5-week venetoclax ramp-up, three patients had DLTs, and one patient at increased risk for TLS had a laboratory TLS; no additional TLS events occurred during follow-up. With a median follow-up of 31 months, the overall response rate was 81% (17/21); 62% (13/21) of patients had a complete response. SRI data informed that the randomized portion should proceed with concurrent ibrutinib plus venetoclax, with no ibrutinib lead-in. Ibrutinib plus venetoclax demonstrated promising efficacy; no new safety signals were observed. Trial registration: ClinicalTrials.gov, NCT03112174. Registered 13 April 2017, https://clinicaltrials.gov/ct2/show/NCT03112174 .

Submarine, as a technical object, has many systems necessary for operation. In addition to weapon systems, there are many systems necessary for the ships safe operation under the water. One of such systems is the submarine steering system. Article presents the principle of operation and the concept of modification of the stern rudders of the project 207(Kobben class) submarine. Based on measurement, resistance force characteristics were determined. A calculation model was proposed using CFD (Computational Fluid Dynamics) and CAE (Computer Aided Engineering) techniques to determine resistance force characteristics during design stage. Then measured resistance force characteristics were used to verify the calculation model. Using the proposed method, resistance force characteristics for an existing submarine were determined, and then its modification was proposed. Simulation results for the modified rudder design allowed determining the reduction of ship resistance force for the new solution. Lower resistance force means lower demand for electrical power in the engine room, which consequently affects operational safety by increasing maneuverability and improving the immersion curve. The proposed modification allows to reduce power consumption by about 8 kW and reduced the resistance force by 2%, which increases the ship’s autonomy.

Studying roughness parameters and the topography of stiffening ribs in composite sandwich structures is important for understanding these materials’ surface quality and mechanical properties. The roughness parameters describe the micro-geometry of the surface, including the average height deviation, roughness depth, and waviness. The topography of the surface refers to the spatial arrangement and distribution of features such as bumps, ridges, and valleys. The study investigated the roughness parameters under three scenarios based on two SPIF process parameters: tool rotational speed(N) and feed rate (f). The vertical step was held constant at 0.4 mm across all scenarios. In scenario A, the process parameters were set at f = 300 mm/min and n = 300 rpm; in scenario B, f = 1500 mm/min and n = 3000 rpm; and in scenario C, f = 1500 mm/min and n = 300 rpm. The experimental research topography analyses revealed that the surface roughness of the stiffened ribs was highly dependent on the SPIF process parameters. The highest feed rate and tool rotational speed produced the smoothest surface texture with the lowest maximum height (Sz) value. In contrast, the lowest feed rate and tool rotational speed resulted in a rougher surface texture with a higher maximum height (Sz) value. Furthermore, the contour plots generated from the topography analyses provided a good visual representation of the surface texture and roughness, allowing for a more comprehensive analysis of the SPIF process parameters. This study emphasizes optimizing the SPIF process parameters to achieve the desired surface quality and texture of stiffened ribs formed in Litecor® panel sheets.

Abstract Background In a phase 3 randomized, double-blind, placebo-controlled trial, treatment with idelalisib, a phosphoinositol-3 kinase δ inhibitor, + bendamustine/rituximab improved progression-free survival (PFS) and overall survival (OS) in adult patients with relapsed/refractory chronic lymphocytic leukemia (R/R CLL). Here we report the results of health-related quality of life (HRQL) analyses from this study. Methods From June 15, 2012 to August 21, 2014, 416 patients with R/R CLL were enrolled; 207 patients were randomized to the idelalisib arm and 209 to the placebo arm. In the 416 patients randomized to receive bendamustine/rituximab and either oral idelalisib 150 mg twice-daily or placebo, HRQL was assessed at baseline and throughout the blinded part of the study using the Functional Assessment of Cancer Therapy–Leukemia (FACT-Leu) and EuroQoL Five-Dimension (EQ-5D) visual analogue scale (VAS) questionnaires. The assessments were performed at scheduled patient visits; every 4 weeks for the first 6 months from the initiation of treatment, then every 8 weeks for the next 6 months, and every 12 weeks thereafter until end of study. Least-squares mean changes from baseline were estimated using a mixed-effects model by including treatment, time, and treatment-by-time interaction, and stratification factors as fixed effects. Time to first symptom improvement was assessed by Kaplan-Meier analysis. Results In mixed-effects model analysis, idelalisib + bendamustine/rituximab treatment led to clinically meaningful improvements from baseline in leukemia-associated symptoms. Moreover, per Kaplan-Meier analysis, the proportion of patients with symptom improvement was higher and time to improvement was shorter among patients in the idelalisib-containing arm compared with those who did not receive idelalisib. The physical and social/family FACT-Leu subscale scores, along with the self-rated health assessed by EQ-VAS, showed improvement with idelalisib over placebo, but the difference did not reach statistical significance. The functional and emotional FACT-Leu subscale scores remained similar to placebo. Conclusions Addition of idelalisib to bendamustine/rituximab, apart from improving PFS and OS, had a neutral to beneficial impact on HRQL in patients with R/R CLL, particularly by reducing leukemia-specific disease symptoms. Trial registration Clinicaltrials.gov NCT01569295. Registered April 3, 2012.

Cardiovascular (CV) toxicities of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib may limit use of this effective therapy in patients with chronic lymphocytic leukemia (CLL). Acalabrutinib is a second-generation BTK inhibitor with greater BTK selectivity. This analysis characterizes pooled CV adverse events (AE) data in patients with CLL who received acalabrutinib monotherapy in clinical trials (clinicaltrials gov. Identifier: NCT02029443, NCT02475681, NCT02970318 and NCT02337829). Acalabrutinib was given orally at total daily doses of 100–400 mg, later switched to 100 mg twice daily, and continued until disease progression or toxicity. Data from 762 patients (median age: 67 years [range, 32–89]; median follow-up: 25.9 months [range, 0–58.5]) were analyzed. Cardiac AE of any grade were reported in 129 patients (17%; grade ≥3, n=37 [5%]) and led to treatment discontinuation in seven patients (1%). The most common any-grade cardiac AE were atrial fibrillation/flutter (5%), palpitations (3%), and tachycardia (2%). Overall, 91% of patients with cardiac AE had CV risk factors before acalabrutinib treatment. Among 38 patients with atrial fibrillation/flutter events, seven (18%) had prior history of arrhythmia or atrial fibrillation/flutter. Hypertension AE were reported in 67 patients (9%), 43 (64%) of whom had a preexisting history of hypertension; no patients discontinued treatment due to hypertension. No sudden cardiac deaths were reported. Overall, these data demonstrate a low incidence of new-onset cardiac AE with acalabrutinib in patients with CLL. Findings from the head-to-head, randomized trial of ibrutinib and acalabrutinib in patients with highrisk CLL (clinicaltrials gov. Identifier: NCT02477696) prospectively assess differences in CV toxicity between the two agents.

Not available.

We analyzed potential biomarkers of response to ibrutinib plus nivolumab in biopsies from patients with diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and Richter's transformation (RT) from the LYM1002 phase I/IIa study, using programmed death ligand 1 (PD-L1) immunohistochemistry, whole exome sequencing (WES), and gene expression profiling (GEP). In DLBCL, PD-L1 elevation was more frequent in responders versus nonresponders (5/8 [62.5%] vs. 3/16 [18.8%]; p = 0.065; complete response 37.5% vs. 0%; p = 0.028). Overall response rates for patients with WES and GEP data, respectively, were: DLBCL (38.5% and 29.6%); FL (46.2% and 43.5%); RT (76.5% and 81.3%). In DLBCL, WES analyses demonstrated that mutations in RNF213 (40.0% vs. 6.2%; p = 0.055), KLHL14 (30.0% vs. 0%; p = 0.046), and LRP1B (30.0% vs. 6.2%; p = 0.264) were more frequent in responders. No responders had mutations in EBF1, ADAMTS20, AKAP9, TP53, MYD88, or TNFRSF14, while the frequency of these mutations in nonresponders ranged from 12.5% to 18.8%. In FL and RT, genes with different mutation frequencies in responders versus nonresponders were: BCL2 (75.0% vs. 28.6%; p = 0.047) and ROS1 (0% vs. 50.0%; p = 0.044), respectively. Per GEP, the most upregulated genes in responders were LEF1 and BTLA (overall), and CRTAM (germinal center B-cell–like DLBCL). Enriched pathways were related to immune activation in responders and resistance-associated proliferation/replication in nonresponders. This preliminary work may help to generate hypotheses regarding genetically defined subsets of DLBCL, FL, and RT patients most likely to benefit from ibrutinib plus nivolumab.

The aim of this study is to determine the influence of the amount of magnesium in Al-Mg alloys and strain rate on the grain refinement and mechanical properties of the material as determined in a dynamic tensile test. Hydrostatic extrusion was used to process the material. This method is not commonly used to impose severe plastic deformation of Al-Mg alloys. The article presents the results of static and dynamic strength tests on aluminium alloys subjected to plastic deformation in the hydrostatic extrusion process. Technically pure aluminium Al99.5 and three aluminium alloys with different magnesium content, Al-1Mg, Al-3Mg and Al-7.5Mg, were used in the tests. The samples were subjected to static tests using the uniaxial tensile test machine and dynamic tests using a rotary hammer. Compared to pure aluminium, increasing the magnesium content in Al-based alloys strengthened them in hydrostatic extrusion (logarithmic strain ε = 0.86) and caused an increase in the static ultimate tensile stress Rm, relative strain εr and the value of the yield stress. For strengthened aluminium alloys, an increase in the strain rate from 750 to 1750 s−1 caused an increase in the dynamic ultimate tensile stress from 1.2 to 1.9 times in relation to the static ultimate tensile stress. The increase in magnesium content results in the formation of a larger strengthening phase, influences a different state of stress during dynamic loading and leads to a change in the orientation of the fracture surface. It was also found that an increase in magnesium content is associated with an increased number of voids, which is also directly proportional to the strain rate in the dynamic rotary hammer test.

This paper presents the results of research on adhesive joints durability properties of ship austenitic steel done with the use of the latest adhesives – glues: a composite one from Belzona company, described as 1111 and 1212 as well as a Hysol 9466 adhesive, produced by Hysol. The 1.4301 (304) and 1.3964 (2xx) steels used for shipbuilding were single-lap adhesive joint, with varying degree of edges’ chamfering and offsetting (with a deflection). This type of alternative connections will provide protection and temporary structure’s protection in case of emergency cracking (due to corrosion or an impact) of the examined steel or welded joints of the ship’s construction and hull’s sheathings. The adhesive joints of the tested steel were made in laboratory conditions (according to the technological card) as well as outside the laboratory, hereinafter called as the emergency ones with the use of Belzon 1212. Adhesive joints of 304 and 2xx steel using Hysol 9466 adhesive made in laboratory conditions showed better durability properties than the ones made with the use of Belzona 1111 composite. However, in case of emergency connections the bonding strength as well as the bonding time (hardening) are important factors. The use of the special Belzona 1212 (for wet surfaces) gives a relatively good durability of approx. 20MPa with a much shorter (up to 20 minutes) hardening time and does not require such an accurate surface preparation as the adhesive joints made with the use of Hysol 9466.

Paper presents the results of the studies of wear, corrosion and cavitation resistances of the S355J2 low alloy medium carbon steel subjected to surface modification by friction-mechanical treatment, as tested in sea water simulated solution. To evaluate the effect of the surface treatment, the comparative studies of the corrosive properties of the steel before and after treatment have been considered. The treatment due to a severe plastic deformation enable forming nanocrystalline structure of steel with grain sizes in the range 20–50 nm and the favorable internal stress state within the treated layer. The research indicated as well that the applied surface treatment improved the steel resistance to the wear and erosion-corrosion but decreased the resistance to general corrosion and stress corrosion. The surface treated steel revealed the lower diffusivity and the lower transport of hydrogen into the material core. Hydrogen collecting within the surface layer did not proceed to the deeper layer of structural metal, and thus prevented it from the hydrogen cracking.

The main objectives of this symposium were to review the value of biosimilars in sustainable treatment for haematologic malignancies and to recognise the developmental differences between biosimilars and their reference products. The meeting also aimed to evaluate the data on monoclonal antibodies for the treatment of haematologic malignancies and the role of biosimilars to address gaps in healthcare. Dr Cornes highlighted recent innovations in cancer treatment and presented biosimilars as economic tools that can address the financial issues that hamper progress. Prof Vulto discussed the need for healthcare professionals to be well informed about the principles of biosimilarity and aware of current and emerging therapies. Prof Jurczak presented the case for rituximab (and its biosimilars) as the standard of care for first-line B cell non-Hodgkin’s lymphoma (NHL) and its potential as maintenance treatment for indolent NHL (iNHL).

The article presents the results of the analysis of the interactions between the single point incremental forming (SPIF) process parameters and the main roughness parameters of stiffened ribs fabricated in Alclad aluminium alloy panels. EN AW-7075-T6 and EN AW-2024-T3 Alclad aluminium alloy sheets were used as the research material. Panels with longitudinal ribs were produced with different values of incremental vertical step size and tool rotational speed. Alclad is formed of high-purity aluminium surface layers metallurgically bonded to aluminium alloy core material. The quality of the surface roughness and unbroken Alclad are key problems in SPIF of Alclad sheets destined for aerospace applications. The interactions between the SPIF process parameters and the main roughness parameters of the stiffened ribs were determined. The influence of forming parameters on average roughness Sa and the 10-point peak–valley surface roughness Sz was determined using artificial neural networks. The greater the value of the incremental vertical step size, the more prominent the ridges found in the inner surface of stiffened ribs, especially in the case of both Alclad aluminium alloy sheets. The predictive models of ANNs for the Sa and the Sz were characterised by performance measures with R2 values lying between 0.657 and 0.979. A different character of change in surface roughness was found for sheets covered with and not covered with a soft layer of technically pure aluminium. In the case of Alclad sheets, increasing the value of the incremental vertical step size increases the value of the surface roughness parameters Sa and Sz. In the case of the sheets not covered by Alclad, reduction of the tool rotational speed increases the Sz parameter and decreases the Sa parameter. An obvious increase in the Sz parameter was observed with an increase in the incremental vertical step size.

The earlier obtained organosilicon derivatives of rapeseed oil were used for the production of coatings protecting steel surface against corrosion. Vegetable oils have been hitherto used for temporary protection of metals against corrosion, while thanks to the synthesis of appropriate organosilicon derivatives, it is now possible to create durable protective coatings. Due to the presence of alkoxysilyl groups and the use of the sol-gel process, the coatings obtained were bonded to the steel surface. The effectiveness of the coatings was checked by electrochemical methods and steel surface analysis.

Primary cutaneous follicle center lymphoma is an Indolent Cutaneous B-cell Lymphoma responsible for almost 11% of primary cutaneous hematopoietic skin neoplasm. Although PCFCL has excellent prognosis of more than 95% 5 year survival rate it might be a challenge for a clinician because of diagnostic difficulties and a need to proceed complete differential diagnosis with systemic follicle center lymphoma. We present a case of a 55-year-old male patient with small, bug bite alike, erythematous, gradually extending lesion on the parietal area of the head. There were no other sign of disease on the skin and no other sides spreading of disease which was confirmed in CT imaging and no other systemic symptoms. After the diagnosis was made course of radical skin lesions 30 Gy radiotherapy were administered. In the follow-up examination skin lesion resolved completely and patient achieved complete remission of the disease.

The present manuscript aims to determine the effect of various deformation levels during low-temperature thermo-mechanical treatment (LTTT) on the microstructure and fatigue strength of Zr-microalloyed Al-Zn-Mg alloy. The fatigue strength of the alloy was studied in high-cycle bending-torsion tests. The determination of the influence of plastic deformation level during LTTT on the microstructure was based on transmission electron microscopy (TEM) observations. The analysis of fracture after the fatigue tests was performed based on fractographic images using scanning electron microscopy (SEM). It was found that the major factor affecting the microstructure of the alloy, and determining the nature of fatigue fracture, is the strain level applied during LTTT.

The paper presents results of the investigations on the effect of low-temperature thermomechanical treatment (LTTT) on the microstructure of AlZn6Mg0.8Zr alloy (7000 series) and its mechanical properties as well as electrochemical and stress corrosion resistance. For comparison of the LTTT effect, the alloy was subjected to conventional precipitation hardening. Comparative studies were conducted in the fields of metallographic examinations and static tensile tests. It was found that mechanical properties after the LTTT were better in comparison to after conventional heat treatment (CHT). The tested alloy after low-temperature thermomechanical treatment with increasing plastic deformation shows decreased electrochemical corrosion resistance during potentiodynamic tests. The alloy after low-temperature thermomechanical treatment with deformation degree in the range of 10 to 30% is characterized by a high resistance to stress corrosion specified by the level of PSCC indices.