Analysis and therapeutic targeting of the IL-1R pathway in anaplastic large cell lymphoma.

Anaplastic large cell lymphoma (ALCL), a subgroup of mature T-cell neoplasms with an aggressive clinical course, is characterized by elevated expression of CD30 and anaplastic cytology. To achieve a comprehensive understanding of the molecular characteristics of ALCL pathology and to identify therapeutic vulnerabilities, we applied genome-wide CRISPR library screenings to both anaplastic lymphoma kinase positive (ALK+) and primary cutaneous (pC) ALK- ALCLs and identified an unexpected role of the interleukin-1R (IL-1R) inflammatory pathway in supporting the viability of pC ALK- ALCL. Importantly, this pathway is activated by IL-1α in an autocrine manner, which is essential for the induction and maintenance of protumorigenic inflammatory responses in pC-ALCL cell lines and primary cases. Hyperactivation of the IL-1R pathway is promoted by the A20 loss-of-function mutation in the pC-ALCL lines we analyze and is regulated by the nonproteolytic protein ubiquitination network. Furthermore, the IL-1R pathway promotes JAK-STAT3 signaling activation in ALCLs lacking STAT3 gain-of-function mutation or ALK translocation and enhances the sensitivity of JAK inhibitors in these tumors in vitro and in vivo. Finally, the JAK2/IRAK1 dual inhibitor, pacritinib, exhibited strong activities against pC ALK- ALCL, where the IL-1R pathway is hyperactivated in the cell line and xenograft mouse model. Thus, our studies revealed critical insights into the essential roles of the IL-1R pathway in pC-ALCL and provided opportunities for developing novel therapeutic strategies.

Characterization of Bodily Pain and Use of Both Prescription and Non-Prescription Opioids in Tenants of Precarious Housing.

BACKGROUND: opioid use, which includes both prescribed and non-prescribed drugs, is relatively common amongst marginalized populations. Past research has shown that among those who use non-prescribed or diverted opioids recreationally, many were first exposed to the drug as prescribed pain medication. Objective: to better understand the relationship between pain and opioid use in tenants of precarious housing. Methods: in the present study, 440 individuals from a cohort living in homeless or precariously housed conditions in a neighborhood with high rates of poverty and drug use were interviewed for their bodily pain and opioid use. We examined the relationship between bodily pain levels, assessed using the Maudsley Addiction Profile questionnaire, and prescribed, non-prescribed and combined self-reported opioid use in the prior 28 days assessed using the Timeline Followback and Doctor-Prescribed Medication Timeline Followback questionnaires. Results: Analysis of the results indicated that sex (female), age (younger) and early exposure to opioids (≤ age 18) predicted current opioid use, but there was no association between current bodily pain levels and opioid use. Conclusions: these unexpected findings indicate the complex nature of the relationship between pain and opioid use in this population.

1q jumping translocation as a biomarker in myeloid malignancy: frequently mutated genes associated with bad prognosis and low survival.

1q jumping translocation (JT) is rare and its molecular profiles in myeloid malignancies are not well-known. This study evaluated gene mutations in 1q-JT cohorts (0.38%) from hematological malignant specimens that underwent genetic analysis at the Johns Hopkins Hospital (n = 11,908) and the MD Anderson Cancer Center. 1q-JT had frequent mutations in eleven genes, most of which are associated with worse prognosis. BCOR mutations significantly co-occurred with others. Patients tended to have mutations in DNA-repair, spliceosome, and epigenetic modification pathways, though genes utilized within each of these pathways were not randomly distributed. Multi-, albeit overlapping, pathway interruptions tended to manifest in mutations of two gene sets. One gene set consisted of SF3B1 (spliceosome) and TET2 (epigenetic modification), while the other consisted of STAG2 (DNA repair), SRSF2, U2AF (spliceosome), ASXL1, KMT2D (epigenetic modification), BCOR, and GATA2 (transcription factors). An "intermediate" JT-like rearrangement may represent an early sign of occurring 1q-JT. Treatments (hypomethylating agents) and unique structures of the short arms of acrocentric chromosomes may contribute to 1q-JT formation in myeloid malignancies. The median overall survival after identification of a JT was 10 months (95% confidence interval, 5-15 months). Our cohort represents the largest number of myeloid malignancies from multi-centers with before and after the 1q-JT event analyzed to date. Overall, this study identified specific molecular profiles that are associated with 1q-JT in myeloid malignancies. 1q-JT could serve as a poor prognosis biomarker in myeloid malignancies, which could be important in making well-informed clinical decisions and treatment strategies.

Dosimetric advantages of volumetric modulated arc therapy (VMAT) with deep inspiration breath hold (DIBH) technique in Halcyon Linac for left breast cancer treatment.

To evaluate the dosimetric advantages of incorporating the deep inspiration breath hold (DIBH) technique into left breast cancer volumetric modulated arc therapy (VMAT) treatment under Halcyon Linac and to investigate the correlation between mean heart dose (MHD) and distance from the heart to target volumes in left breast cancer VMAT treatment. Fifteen Post-lumpectomy, left-sided breast patients treated between January 2017 and October 2020 were selected. Two plans were generated for each patient using Eclipse treatment planning system (TPS) with the prescription of 50.4 Gy to planning target volume (PTV) breast and 58.8 Gy to PTV boost in 28 fractions. For each patient, DIBH and free breathing (FB) VMAT treatment plans under Halcyon Linac were generated. Dosimetric parameters, monitor unit and beam-on time of both DIBH and FB groups were compared. Three-dimensional distances from heart surface to each target volume were measured on computed tomography images using the TPS contouring tool and their correlation with MHD was evaluated by Pearson's correlation coefficient (r). Comparable target coverage was shown in both groups. Mean dose to heart, left anterior descending artery, and left ventricle in Halcyon-DIBH-VMAT group were significantly reduced by 0.49 Gy, 1.19 Gy, and 0.57 Gy, respectively, compared to Halcyon-FB-VMAT (p < 0.001). A significant lung dose reduction was also achieved in Halcyon-DIBH-VMAT group. There was also a strong negative correlation between MHD and distance from heart surface to PTV boost in both FB and DIBH group (r = -0.741, p < 0.001), but not observed for distance from heart surface to PTV breast. Incorporating DIBH into left breast cancer VMAT treatment under Halcyon Linac demonstrated significant cardiac and lung dose reduction. It was also demonstrated that MHD had a strong negative correlation with distance from heart surface to PTV boost but relatively independent of distance from heart surface to PTV breast. Recognizing the distance from the heart surface to PTV boost as the main factor in affecting MHD could potentially facilitate clinical treatment planning workflow and decision.