MALTA2 is a Depleted Monolithic Active Pixel Sensor designed to meet the challenging requirements of future collider experiments, in particularly extreme radiation tolerance and high hit rate. The sensor is fabricated in a modified Tower 180 nm CMOS imaging technology to mitigate performance degradation caused by 100 MRad of Total Ionising Dose and greater than 10(15) 1 MeV neq/cm(2) of Non-Ionising Energy Loss. MALTA2 samples have been tested during the CERN SPS test beam campaign in 2023-2024, before and after irradiation at a fluence of 1 x 10(15) 1 MeV n(eq)/cm(2). The sensors were positioned at various inclinations relative to the beam, covering grazing angles from 0 to 60 degrees. This contribution presents measurements of detection efficiency and cluster size as functions of these angles, along with an estimation of the active depth of the depleted region based on the test beam results.

The MALTA monolithic active pixel detector is developed to address some of the challenges anticipated in future high-energy physics detectors. As part of its characterization, we conducted timing studies necessary to provide a figure of merit for this family of monolithic pixel detectors. MALTA has a metal layer in front-end electronics, and the conventional laser technique is not suitable for timing studies due to the reflection of the laser from the metallic surface. X-rays have been employed as a more effective alternative for penetration through these layers. The triggered X-ray set-up is designed to study timing measurements of monolithic detectors. The timing response of the X-ray set-up is characterized using an LGAD. The timing response of the MALTA and MALTA2 pixel detectors is studied, and the best response time of MALTA2 pixel detectors is measured at about 2.6 ns.

MALTA2 is a depleted monolithic active pixel sensor (DMAPS) developed in the Tower 180 nm CMOS imaging process. Monolithic CMOS sensors offer advantages over current hybrid imaging sensors both in terms of increased tracking performance due to lower material budget but also in terms of ease of integration and construction costs due to the monolithic design. Current research and development efforts are aimed towards radiation-hard designs up to 100 Mrad in Total Ionizing Dose and 3×1015 1 MeV neq/cm2 in Non-Ionizing Energy Loss. One important property of a sensor’s radiation hardness is the depletion depth at which efficient charge collection is achieved via drift movement. Grazing angle test-beam data was taken during the 2023 SPS CERN test beam with the MALTA telescope and Edge Transient Current Technique studies were performed at DESY in order to develop a quantitative study of the depletion depth for un-irradiated, epitaxial MALTA2 samples. The study is planned to be extended for irradiated and Czochralski MALTA2 samples.

The MALTA silicon pixel detector combines a depleted monolithic active pixel sensor (DMAPS) with a fully asynchronous front-end and readout. It features a high granularity pixel matrix with a 36.4 μm symmetric pixel pitch, low power consumption of <1μW/pixel and low material budget with detector thicknesses as little as 50 μm. It achieves a radiation hardness to 100MRad TID and more than 1×10E15 1 MeV neq/cm2 with a time resolution of <2 ns (Pernegger et al., 2023). In order to cover large sensitive areas efficiently with a minimum of power and data connections the development of modules, comprising of up to 4 MALTA detectors, is studied. This contribution presents the beam test performance of parallel and serial powered MALTA 4-chip modules in an effort to characterize the sensor's chip-to-chip data and power transmission and prepare the production of a first prototype of an ultra-light weight 4-chip module on a flexible circuit with next generation MALTA2 sensors.

The planned MALTA3 DMAPS designed in the standard TowerJazz 180 nm imaging process will implement the numerous process modifications, as well as front-end changes in order to boost the charge collection efficiency after the targeted fluence of 1 × 1015 1 MeV neq/cm2. The effectiveness of these changes have been demonstrated with recent measurements of the full size MALTA2 chip. With the original MALTA concept being fully asynchronous, a small-scale MiniMALTA demonstrator chip has been developed with the intention of bridging the gap between the asynchronous pixel matrix, and the synchronous DAQ. This readout architecture will serve as a baseline for MALTA3, with focus on improved timing performance. The synchronization memory has been upgraded to allow clock speeds of up to 1.28 GHz, with the goal of achieving a sub-nanosecond on-chip timing resolution. The subsequent digital readout chain has been modified and will be discussed in the context of the overall sensor architecture.

The MALTA family of Depleted Monolithic Active Pixel Sensor (DMAPS) produced in Tower 180 nm CMOS technology targets radiation hard applications for the HL-LHC and beyond. Several process modifications and front-end improvements have resulted in radiation hardness up to 2 × 10^15 1 MeV n_eq/cm^2 and time resolution below 2 ns, with uniform charge collection efficiency across the Pixel of size 36.4 × 36.4 μm^2 with a 3 μm^2 electrode size. The MALTA2 demonstrator produced in 2021 on high-resistivity epitaxial silicon and on Czochralski substrates implements a new cascoded front-end that reduces the RTS noise and has a higher gain. This contribution shows results from MALTA2 on timing resolution at the nanosecond level from the CERN SPS test-beam campaign of 2021.

Depleted Monolithic Active Pixel Sensor (DMAPS) sensors developed in the Tower Semiconductor 180 nm CMOS imaging process have been designed in the context of the ATLAS ITk upgrade Phase-II at the HL-LHC and for future collider experiments. The “MALTA-Czochralski (MALTA-Cz)” full size DMAPS sensor has been developed with the goal to demonstrate a radiation hard, thin CMOS sensor with high granularity, high hit-rate capability, fast response time and superior radiation tolerance. The design targets radiation hardness of > 10 15 (1 MeV) n eq /cm 2 and 100 Mrad TID. The sensor shall operate as tracking sensor with a spatial resolution of ≈ 10 μm and be able to cope with hit rates in excess of 100 MHz/cm 2 at the LHC bunch crossing frequency of 40 MHz. The 512 × 512 pixel sensor uses small collection electrodes (3.5 μm) to minimize capacitance. The small pixel size (36.4 × 36.4 μm 2 ) provides high spatial resolution. Its asynchronous readout architecture is designed for high hit-rates and fast time response in triggered and trigger-less detector applications. The readout architecture is designed to stream all hit data to the multi-channel output which allows an off-sensor trigger formation and the use of hit-time information for event tagging. The sensor manufacturing has been optimised through process adaptation and special implant designs to allow the manufacturing of small electrode DMAPS on thick high-resistivity p-type Czochralski substrate. The special processing ensures excellent charge collection and charge particle detection efficiency even after a high level of radiation. Furthermore the special implant design and use of a Czochralski substrate improves the sensor's time resolution. This paper presents a summary of sensor design optimisation through process and implant choices and TCAD simulation to model the signal response. Beam and laboratory test results on unirradiated and irradiated sensors have shown excellent detection efficiency after a dose of 2 × 10 15 1 MeV n eq /cm 2 . The time resolution of the sensor is measured to be σ = 2 ns.

MALTA is a depleted monolithic active pixel sensor (DMAPS) developed in the Tower Semiconductor 180-nm CMOS imaging process. Monolithic CMOS sensors offer advantages over current hybrid imaging sensors in terms of both increased tracking performance due to lower material budget and ease of integration and construction costs due to the integration of read-out and active sensor into one ASIC. Current research and development efforts are aimed toward radiation hard designs up to 100 Mrad in total ionizing dose (TID) and $1\,\, \times 10 ^{15}~1~\text {MeV}\text {n}_{\text {eq}}/\text {cm}^{2}$ in nonionizing energy loss (NIEL). The design of the MALTA sensors was specifically chosen to achieve radiation hardness up to these requirements and satisfy current and future collider constraints. The current MALTA pixel architecture uses small electrodes which provide less noise, higher signal voltage, and a better power-to-performance ratio. To counteract the loss of efficiency in pixel corners, modifications to the Tower process have been implemented. The MALTA sensors have been tested during the 2021 and 2022 SPS CERN Test Beam in the MALTA telescope. The telescope ran for the whole duration of the beam time and took data to characterize the novel MALTA2 variant and the performance of irradiated samples in terms of efficiency and cluster size. These campaigns show that MALTA is an interesting prospect for HL-LHC and beyond collider experiments, providing both very good tracking capabilities and radiation hardness in harsh radiation environments.

The MALTA CMOS monolithic silicon pixel sensors has been developed in the Tower 180 nm CMOS imaging process. It includes an asynchronous readout scheme and complies with the ATLAS inner tracker requirements for the HL-LHC. Several 4-chip MALTA modules have been built using Al wedge wire bonding to demonstrate the direct transfer of data from chip-to-chip and to read out the data of the entire module via one chip only. Novel technologies such as Anisotropic Conductive Films (ACF) and nanowires have been investigated to build a compact module. A lightweight flex with 17 μm trace spacing has been designed, allowing compact packaging with a direct attachment of the chip connection pads to the flex using these interconnection technologies. This contribution shows the current state of our work towards a flexible, low material, dense and reliable packaging and modularization of pixel detectors.

The MALTA pixel chip is a 2 cm x 2 cm large monolithic pixel detector developed in the Tower 180 nm imaging process. The chip contains four CMOS transceiver blocks at its sides which allow chip-to-chip data transfer. The power pads are located mainly at the side edges on the chip which allows for chip-to-chip power transmission. The MALTA chip has been used to study module assembly using different interconnection techniques to transmit data and power from chip to chip and to minimize the overall material budget. Several 2-chip and 4-chip modules have been assembled using standard wire bonding, ACF (Anisotropic Conductive Films) and laser reflow interconnection techniques. These proceedings will summarize the experience with the different interconnection techniques and performance tests of MALTA modules with 2 and 4 chips tested in a cosmic muon telescope. They will also show first results on the effect of serial power tests on chip performance as well as the impact of the different interconnection techniques and the results of mechanical tests. Finally, a conceptual study for a flex based ultra-light weight monolithic pixel module based on the MALTA chip with minimum interconnections is presented.

BACKGROUND:This randomized, open-label study evaluated the efficacy, safety and pharmacokinetics of darbepoetin alfa administered intravenously (i.v.) or subcutaneously (s.c.) in chemotherapy-induced anemia.PATIENTS AND METHODS:Patients received darbepoetin alfa i.v. (n=59) or s.c. (n=59) at a dose of 4.5 mug/kg once weekly for 6 weeks (correction phase) followed by 4.5 mug/kg once every 3 weeks for the remainder of the 18-week treatment period (maintenance phase).RESULTS:During the correction phase, the mean [95% confidence interval (CI)] change in hemoglobin (intention-to-treat) was 1.1 (0.6-1.5) g/dl in the i.v. group and 1.3 (0.9-1.7) g/dl in the s.c. group; using available data, the mean change was 1.4 (1-1.9) g/dl and 1.6 (1.2-2) g/dl, respectively. The percentage (95% CI) of patients maintaining hemoglobin (i.e. average decrease < or =0.5 g/dl) during the maintenance phase was similar between the i.v. (82%; 95% CI 66% to 92%) and s.c. (80%; 95% CI 66% to 90%) groups. Thirty-five per cent (95% CI 20% to 50%) of patients in the i.v. group and 32% of patients in the s.c. group (95% CI 18% to 45%) received red blood cell transfusions during week 5 to the end of the treatment period. Darbepoetin alfa was well tolerated in both groups. No significant difference (P=0.36) in weekly darbepoetin alfa serum concentrations was observed between groups.CONCLUSIONS:Darbepoetin alfa can be administered i.v. or s.c. at equal doses for the treatment of anemia in this setting.

Patient psychological distress is associated with many aspects of the bone marrow transplantation (BMT) process and has been linked with poor treatment outcomes. We assessed psychological distress in potential BMT candidates, and compared patient and nurse coordinator ratings of emotional distress at the time of initial BMT consultation. Fifty patients self-reported psychological distress using both the NCCN Distress Thermometer (DT) and the Hospital Anxiety and Depression Scale (HADS). Coordinators rated patient emotional distress using the DT and Coordinator Rating Scales that measure anxiety and depression. Fifty and 51% of patients self-reported clinically significant levels of emotional distress and anxiety, respectively, but only 20% self-reported clinically significant levels of depression. There was good correlation between ratings using the brief DT and the more comprehensive HADS. There was significant but only moderate agreement between patient and coordinator ratings of emotional distress and anxiety, with coordinators underestimating the number of patients with high levels of emotional distress. In addition, coordinator ratings of patient emotional distress primarily reflected anxiety, whereas anxiety and depression together only minimally accounted for patient self-reports of psychological distress. These findings suggest that: (1) the DT can be a useful screening device; (2) approximately half of patients at the time of initial consultation for BMT already experience significant levels of psychological distress; and (3) coordinators observe emotional distress primarily as anxiety, but patients experience psychological distress as something more than anxiety and depression.

Therapeutic resistance is a major obstacle in the treatment of acute myeloid leukemia (AML). Such resistance has been associated with rapid drug efflux mediated by the multidrug resistance gene 1 (MDR1; encoding P-glycoprotein) and more recently with expression of other novel proteins conferring multidrug resistance such as MRP1 (multidrug resistance-associated protein 1) and LRP (lung resistance protein). To determine the frequency and clinical significance of MDR1, MRP1, and LRP in younger AML patients, we developed multiparameter flow cytometric assays to quantify expression of these proteins in pretreatment leukemic blasts from 352 newly diagnosed AML patients (median age, 44 years) registered to a single clinical trial (SWOG 8600). Protein expression was further correlated with functional efflux by leukemic blasts [assessed using two substrates: Di(OC)(2) and Rhodamine 123] and with the ability of MDR-reversing agents to inhibit efflux in vitro. MDR1/P-glycoprotein expression, which was highly correlated with cyclosporine-inhibited efflux, was noted in only 35% of these younger AML patients, distinctly lower than the frequency of 71% we previously reported in AML in the elderly (Blood 89:3323, 1997). Interestingly, MDR1 expression and functional drug efflux increased with patient age, from a frequency of only 17% in patients less than 35 years old to 39% in patients aged 50 years (P =.010). In contrast, MRP1 was expressed in only 10% of cases and decreased with patient age (P =. 024). LRP was detected in 43% of cases and increased significantly with increasing white blood cell counts (P =.0015). LRP was also marginally associated with favorable cytogenetics (P =.012) and French-American-British (FAB) AML FAB subtypes (P =.013), being particularly frequent in M4/M5 cases. Only MDR1/P-glycoprotein expression and cyclosporine-inhibited efflux were significantly associated with complete remission (CR) rate (P(MDR1) =.012; P(efflux) =.039) and resistant disease (RD; P(MDR1) =.0007; P(efflux) =.0092). No such correlations were observed for MRP1 (P(CR) =.93; P(RD) =.55) or LRP (P(CR) =.50; P(RD) =.53). None of these parameters were associated with overall or relapse-free survival. Unexpectedly, a distinct and nonoverlapping phenotype was detected in 18% of these cases: cyclosporine-resistant efflux not associated with MDR1, MRP1, or LRP expression, implying the existence of other as yet undefined efflux mechanisms in AML. In summary, MDR1 is less frequent in younger AML patients, which may in part explain their better response to therapy. Neither MRP1 nor LRP are significant predictors of outcome in this patient group. Thus, inclusion of MDR1-modulators alone may benefit younger AML patients with MDR1(+) disease.

The Southwest Oncology Group analyzed outcome with cytotoxic chemotherapy for previously untreated acute myeloblastic leukemia (AML) from 1982 through 1986. Results with acute promyelocytic leukemia (APL) prompted comparison with patients from 1986 through 1991 and analysis of factors contributing to APL results. Patient and disease characteristics and treatment outcome were compared for all evaluable patients, with more detailed analysis of factors affecting APL treatment outcome. From 1982 through 1986, median survival and disease-free survival in 45 APL patients were 106 months and greater than 105 months, respectively, versus 6 and 14 months for 417 other AML patients. Such differences were not seen from 1986 through 1991. In the 141 APL patients from 1982 through 1991, after adjusting for significant patient and disease characteristics, higher daunomycin (DNR) doses during induction were significantly associated with higher complete remission rates (P < .0001), longer survival (P < .0001), and longer DFS (P < .0001). Cytosine arabinoside (Ara-C) induction dose, the inclusion of other chemotherapy agents in induction, postremission therapy (consolidation, maintenance, or bone marrow transplantation) other than DNR, APL subtype, and patient age did not appear to significantly affect outcome of APL, except for a significant detrimental effect of high-dose Ara-C in consolidation (P = .0042). Morphologic AML subtypes other than APL did not affect outcome. We conclude that high-dose DNR selectively increases survival in APL. This good survival is important for evaluation of combined all-trans retinoic acid (ATRA)/chemotherapy protocols and for planning future combinations of chemotherapy and ATRA. These results illustrate the need to individualize chemotherapy for subtypes of AML. Therapeutic response of APL is independent of age. Except for APL, morphologic subclassification of AML contributed little prognostic information.

Because WR-2721 reduces the toxicity of cisplatin and carboplatin in preclinical systems, we have treated 35 patients in a phase I study of WR-2721 and carboplatin. As the plasma half-life of WR-2721 is short relative to that of carboplatin, WR-2721 was administered in two divided doses. This schedule produced acceptable toxicity in 24 patients treated with carboplatin 400 mg/m2 and escalating doses of WR-2721. In the subsequent 11 patients, WR-2721 was fixed at 740 mg/m2/dose and the dose of carboplatin was escalated. With WR-2721, grade 3-4 thrombopenia (platelets <50 x 10(9)/l) was produced in 4/5 patients treated with carboplatin 625 mg/m2 and in 1/6 patients treated with carboplatin 500 mg/m2. Carboplatin pharmacokinetic parameters in 4 patients were similar to those reported for carboplatin alone. These results suggest that WR-2721 might increase the maximum tolerated dose of carboplatin from 400 to 500 mg/m2.

We have performed two Phase I trials of the combination of dipyridamole, 5-fluorouracil (5-FU), and folinic acid in patients with advanced refractory malignancy, based upon in vitro evidence that dipyridamole can modulate the cytotoxicity of 5-FU. In the first trial, patients were treated every 4 wk with dipyridamole (50 mg/m2) p.o. every 6 h on Days 0 to 6, beginning 24 h prior to the i.v. administration of folinic acid (200 mg/m2) and escalating doses of i.v. 5-FU on Days 1 to 5. The maximum tolerated daily dose of 5-FU that could be given with this combination was 375 mg/m2. Because dipyridamole is extensively bound to plasma proteins, it was hypothesized that the concentrations of free dipyridamole achieved with a dose of 50 mg/m2 were inadequate to modulate the cytotoxicity of 5-FU and folinic acid. Therefore, a second Phase I trial of escalating dose of p.o. dipyridamole was performed. Folinic acid (200 mg/m2) and 5-FU (375 mg/m2) were given i.v. on Days 1 to 5 every 4 wk, beginning 24 h after the start of therapy with dipyridamole; dipyridamole was administered p.o. on Days 0 to 6 at doses of 75, 100, 125, 150, 175, or 200 mg/m2/dose to successive cohorts of patients. Dose-limiting neutropenia, mucositis, and nausea were produced at a dose of 200 mg/m2/dose; the recommended dose of dipyridamole for use in Phase II studies is 175 mg/m2 p.o. every 6 h, or 700 mg/m2/day. At this dose, a mean peak plasma concentration of total dipyridamole of 16.32 mumol and a mean peak plasma concentration of free dipyridamole of 38.30 nmol were observed. Trough concentrations of free dipyridamole averaged 60% of the peak concentrations. Objective antitumor responses were seen in a number of tumor types; five of 13 patients with breast cancer treated with high-dose p.o. dipyridamole, 5-FU, and folinic acid responded. High-dose p.o. dipyridamole can produce plasma concentrations of free dipyridamole within the range shown to modulate the cytotoxicity of 5-FU and other agents. Phase II trials of this combination are justified.