Measurable residual disease (MRD) dynamics in multiple myeloma and the influence of clonal diversity analyzed by artificial intelligence.

Minimal residual disease (MRD) assessment is a known surrogate marker for survival in multiple myeloma (MM). Here, we present a single institution's experience assessing MRD by NGS of Ig genes and the long-term impact of depth of response as well as clonal diversity on the clinical outcome of a large population of MM patients; 482 MM patients at the University of California, San Francisco (UCSF) diagnosed from 2008 to 2020 were analyzed retrospectively. MRD assessment was performed by NGS. PFS curves were plotted by the Kaplan-Meier method. In the newly diagnosed group, 119 of 304, achieved MRD negativity at the level of 10-6 at least once. These patients had a prolonged PFS versus patients who were persistently MRD positive at different levels (p > 0.0001). In the relapsed disease group, 64 of 178 achieved MRD negativity at 10-6, and PFS was prolonged versus patients who remained MRD positive (p = 0.03). Three categories of MRD dynamics were defined by artificial intelligence: (A) patients with ≥3 consistently MRD negative samples, (B) patients with continuously declining but detectable clones, and (C) patients with either increasing or a stable number of clones. Groups A and B had a more prolonged PFS than group C (p < 10-7). Patients who were MRD positive and had not yet relapsed had a higher clonal diversity than those patients who were MRD positive and had relapsed. MRD dynamics can accurately predict disease evolution and drive clinical decision-making. Clonal Diversity could complement MRD assessment in the prediction of outcomes in MM.

Image quality of opportunistic breast examinations in photon-counting computed tomography: A phantom study.

PURPOSE: To compare the breast imaging performance of a clinical whole-body photon-counting CT (PCCT) to that of a dedicated breast CT (BCT) to determine the image quality of opportunistic breast examinations in clinical PCCT. MATERIALS AND METHODS: To quantify image quality for breast cancer applications, acquisitions of a breast phantom including representations of calcifications, fibers, and masses were performed using a clinical PCCT and a dedicated BCT. When imaging with the PCCT, the phantom was also combined with a thorax phantom to simulate realistic patient positioning, while only the breast phantom was imaged in the BCT. Images in BCT were acquired at 7.0 mGy (CTDI16cm) and using 2.6 mGy-25.0 mGy in the PCCT. Spatial resolution between the BCT and PCCT images was matched and data were reconstructed using the default methods of each system. The dose-normalized contrast-to-noise ratio (CNRD) of masses and the structural visibility of fibers and calcifications were evaluated as figures of merit for all reconstructions. RESULTS: CNRD between masses and background was 0.56 mGy-½, on average with BCT and varied between 0.39 mGy-½ to 1.46 mGy-½ with PCCT over all dose levels, phantom configurations, and reconstruction algorithms. Calcifications down to a size of 0.29 mm and fibers down to a size of 0.23 mm could be reliably identified in the images of both systems. CONCLUSIONS: Clinical PCCT provides an image quality superior to that obtained with BCT in terms of CNRD and allows for the identification of calcifications and fibers at comparable dose levels.

Overall survival and central nervous system activity of crizotinib in ROS1-rearranged lung cancer-final results of the EUCROSS trial.

BACKGROUND: In 2019, we reported the first efficacy and safety analysis of EUCROSS, a phase II trial investigating crizotinib in ROS1 fusion-positive lung cancer. At that time, overall survival (OS) was immature and the effect of crizotinib on intracranial disease control remained unclear. Here, we present the final analysis of OS, systemic and intracranial activity, and the impact of co-occurring aberrations. MATERIALS AND METHODS: EUCROSS was a prospective, single-arm, phase II trial. The primary endpoint was best overall response rate (ORR) using RECIST 1.1. Secondary and exploratory endpoints were progression-free survival (PFS), OS, and efficacy in pre-defined subgroups. RESULTS: Median OS of the intention-to-treat population (N = 34) was 54.8 months [95% confidence interval (CI) 20.3 months-not reached (NR); median follow-up 81.4 months] and median all-cause PFS of the response-evaluable population (N = 30) was 19.4 months (95% CI 10.1-32.2 months). Time on treatment was significantly correlated with OS (R = 0.82; P < 0.0001). Patients with co-occurring TP53 aberrations (28%) had a significantly shorter OS [hazard ratio (HR) 11; 95% CI 2.0-56.0; P = 0.006] and all-cause PFS (HR 4.2; 95% CI 1.2-15; P = 0.025). Patients with central nervous system (CNS) involvement at baseline (N = 6; 20%) had a numerically shorter median OS and all-cause PFS. Median intracranial PFS was 32.2 months (95% CI 23.7 months-NR) and the rate of isolated CNS progression was 24%. CONCLUSIONS: Our final analysis proves the efficacy of crizotinib in ROS1-positive lung cancer, but also highlights the devastating impact of TP53 mutations on survival and treatment efficacy. Additionally, our data show that CNS disease control is durable and the risk of CNS progression while on crizotinib treatment is low.

Impact of the hypoxic microenvironment on spermatogonial stem cells in culture.

The stem cell niche plays a crucial role in the decision to either self-renew or differentiate. Recent observations lead to the hypothesis that O2 supply by blood and local O2 tension could be key components of the testicular niche of spermatogonial stem cells (SSCs). In this study, we investigated the impact of different hypoxic conditions (3.5%, 1%, and 0.1% O2 tension) on murine and human SSCs in culture. We observed a deleterious effect of severe hypoxia (1% O2 and 0.1% O2) on the capacity of murine SSCs to form germ cell clusters when plated at low density. Severe effects on SSCs proliferation occur at an O2 tension ≤1% and hypoxia was shown to induce a slight differentiation bias under 1% and 0.1% O2 conditions. Exposure to hypoxia did not appear to change the mitochondrial mass and the potential of membrane of mitochondria in SSCs, but induced the generation of mitochondrial ROS at 3.5% and 1% O2. In 3.5% O2 conditions, the capacity of SSCs to form colonies was maintained at the level of 21% O2 at low cell density, but it was impossible to amplify and maintain stem cell number in high cell density culture. In addition, we observed that 3.5% hypoxia did not improve the maintenance and propagation of human SSCs. Finally, our data tend to show that the transcription factors HIF-1α and HIF-2α are not involved in the SSCs cell autonomous response to hypoxia.

Tendon-test del nervio tibial en el mal de Hansen. / Tendon-test of tibial nerve in Hansen's disease

De un total de 17 enfermos hansenianos examinados por tendon-test, se obtuvo respuesta claramente patologica en 9. En otros 4 no hubo respuesta alguna, y cabe suponer que ello se debe al serio estado patologico del nervio. El total de respuestas patologicas llegaria asi a 76,5% (13 enfermos). En otros dos pacientes la respuesta fue limitrofe, y se los clasifico junto con los dos pacientes que dieron respuesta normal, alcanzando asi el porcentaje a 23,5% (4 enfermos). A fin de verificar si los nervios tibiales son atacados al mismo tiempo que los ulnares y medianos, se recomienda practicar este metodo no traumatico en un numero superior de enfermos, y en otro ambiente socio-geografico