Citations

ABSTRACTBackgroundPsychological safety is critical to early and continued engagement with healthcare providers, yet no studies have explored this concept in relationship to cancer care. Black/African American (“Black”) individuals experience disparities in breast and ovarian cancer beyond what can be explained biologically.AimsWe explored factors influencing psychological safety among Black breast and ovarian cancer patients and their family members.MethodsSocioeconomically diverse patients with a personal diagnosis or family history of breast and/or ovarian cancer were invited to complete a semi‐structured qualitative interview on their cancer and healthcare experiences between September 2020 and April 2021. Informed by principles of grounded theory, interview transcripts were qualitatively analyzed for thematic content related to psychological safety.ResultsBlack breast and ovarian cancer patients and their family members described personal and community experiences and structural components of the healthcare system that suggested they may receive differential cancer care due to their race, placing them on guard. This posture was mediated by several self‐identified factors that added to or detracted from their comfort, including provider racial and gender concordance in healthcare, personalized care, and effective communication. The priorities and perceptions of care in participants receiving care in safety net clinics were more focused on what was feasible given resource limitations rather than what was ideally desired.ConclusionsImplementation of strategies to promote psychological safety with Black cancer patients may foster improved patient experiences, as well as encourage early screening, patient engagement, and treatment continuation.

Abstract Background: Ovarian high-grade serous carcinomas (HGSC) comprise four distinct molecular subtypes based on mRNA expression patterns, with differential survival. Understanding risk factor associations is important to elucidate the etiology of HGSC. We investigated associations between different epidemiologic risk factors and HGSC molecular subtypes. Methods: We pooled data from 11 case–control studies with epidemiologic and tumor gene expression data from custom NanoString CodeSets developed through a collaboration within the Ovarian Tumor Tissue Analysis consortium. The PrOTYPE-validated NanoString-based 55-gene classifier was used to assign HGSC gene expression subtypes. We examined associations between epidemiologic factors and HGSC subtypes in 2,070 cases and 16,633 controls using multivariable-adjusted polytomous regression models. Results: Among the 2,070 HGSC cases, 556 (27%) were classified as C1.MES, 340 (16%) as C5.PRO, 538 (26%) as C2.IMM, and 636 (31%) as C4.DIF. The key factors, including oral contraceptive use, parity, breastfeeding, and family history of ovarian cancer, were similarly associated with all subtypes. Heterogeneity was observed for several factors. Former smoking [OR = 1.25; 95% confidence interval (CI) = 1.03, 1.51] and genital powder use (OR = 1.42; 95% CI = 1.08, 1.86) were uniquely associated with C2.IMM. History of endometriosis was associated with C5.PRO (OR = 1.46; 95% CI = 0.98, 2.16) and C4.DIF (OR = 1.27; 95% CI = 0.94, 1.71) only. Family history of breast cancer (OR = 1.44; 95% CI = 1.16, 1.78) and current smoking (OR = 1.40; 95% CI = 1.11, 1.76) were associated with C4.DIF only. Conclusions: This study observed heterogeneous associations of epidemiologic and modifiable factors with HGSC molecular subtypes. Impact: The different patterns of associations may provide key information about the etiology of the four subtypes.

ABSTRACTParents of children with Down syndrome have historically reported poor experiences receiving a prenatal diagnosis. In a 2003 survey, mothers reported that their physicians pitied them, emphasized negative aspects of Down syndrome, and encouraged them to terminate the pregnancy. This study assesses whether parents' perceptions have since improved. Community‐based organizations that had distributed the original 2003 survey distributed a similar survey to parents who have had a child with Down syndrome since 2003. Compared to the 2003 survey, parents continued to report dissatisfaction with their prenatal medical care (N = 60). Though subgroups became likelier to view their testing experience positively, parents' experiences worsened on certain metrics. Most parents reported dissatisfaction when providers conveyed pity or attempted to influence their decision‐making about the pregnancy. Interventions to date have failed to improve parents' perceptions of their prenatal medical support, urging new strategies to improve parents' care.

Importance Eligibility criteria for randomized clinical trials (RCTs) are designed to select clinically relevant patient populations. However, not all eligibility criteria are strongly justified, potentially excluding marginalized groups, and limiting the generalizability of trial findings. Objective To summarize and evaluate the justification of exclusion criteria in published RCTs in critical care medicine. Evidence Review A systematic sampling review of parallel-group RCTs published in the top 5 general internal medicine journals by impact factor ( The Lancet, New England Journal of Medicine, Journal of the American Medical Association, British Medical Journal, and Annals of Internal Medicine ) between January 1, 2018, and February 23, 2023, was conducted. RCTs enrolling adults in intensive care units (ICUs) and RCTs enrolling critically ill patients who required life-sustaining interventions typically initiated in the ICU were included. All study exclusion criteria were categorized as either poorly justified, potentially justified, or strongly justified, adapting previously established criteria, independently and in duplicate. Findings In total, 225 studies were identified, 75 of which were included. The median (IQR) number of exclusion criteria per trial was 19 (14-24), with 1455 total exclusion criteria. Common exclusion criteria were related to the risk of adverse reaction to interventions (302 criteria [20.8%]), followed by inability to obtain consent (120 criteria [8.2%]), and treatment limitation decisions (97 criteria [6.7%]). Most exclusion criteria were either strongly justified (1080 criteria [74.2%]) or potentially justified (297 criteria [20.4%]), whereas 5.4% (78 criteria) were poorly justified. Of the 78 poorly justified exclusion criteria, the most common were pregnancy (19 criteria [24.4%]), communication barriers (11 criteria [14.1%]), lactation (10 criteria [12.8%]), and lack of health insurance (10 criteria [12.8%]). Overall, 45 of 75 studies (60.0%) had at least 1 poorly justified exclusion criteria. Conclusions and Relevance Most exclusion criteria in critical care medicine RCTs were strongly justifiable. Across poorly justified criteria, the most common exclusions were pregnant or lactating persons, those with communication barriers, and individuals without health insurance. This highlights the need to carefully consider exclusion criteria when designing trials to minimize the inappropriate exclusion of participants and enhance generalizability.

Overview: Despite advances in therapies targeting the tumor-intrinsic aspects of the disease, multiple myeloma (MM) remains functionally incurable. Given that new alternatives such as T cell redirected therapy and monoclonal antibodies engage ADCC and CDC by leveraging other elements of the immune system, we believe that deeper studies of the tumor microenvironment are warranted. In particular, we believe that certain macrophages are associated with tumor progression, serve as markers of future relapses, are immunosuppressive, and reduce the effectiveness of otherwise successful therapies. Methods: We performed 5' scRNAseq analysis of 189,025 cells collected from spleen or bone marrow of 4 wild type, 14 de novo, and 40 tumor bearing Vk*MYC mice treated with vehicle or effective anti-MM therapies. Discoveries were cross-referenced against a set of 45,626 human bone marrow cells collected from 35 samples at different stages of disease and treatment. We experimentally recreated in vitro the cross-talk between MM cells and macrophages by co-culturing bone marrow derived macrophages (BMDM) with MM cells or their conditioned medium, and correlated changes in gene expression as well as the ability of polarized BMDM to inhibit CAR T mediated killing of MM cells in vitro. Results: Gene expression analysis of murine in vivo C1q macrophages and in vitro polarized BMDM revealed a common signature identified in lipid-associated macrophages and Kupffer cell-like macrophages1 (high expression of Fabp5, ApoE, Cd63, C1qa/b/c, Cd163, Cd5l, Vcam1, Fcgr4, Folr2, Maf) which is associated with immunosuppression and disease progression. Ligand-receptor analysis via LIANA identified C1qb ligand in macrophages with C1qbp in tumor among the top interactions in both human and murine single cell analyses. C1qbp is a crucial element of cell adhesion and metastasis,2 and this link between tumor and macrophage can severely limit effective therapy: BMDM following stimulation/polarization with MM lines, but not naïve/unstimulated BMDM, strongly inhibit anti-BCMA CAR T in vitro cytotoxic activity. In total, a complement-related connection between tumor and macrophage is capable of directing an immunosuppressive, chemokine response that imparts resistance to therapy. While effective therapies reduce tumor and C1q expressing macrophage populations,3 retention of C1q expressing cells may be associated with future relapses. Presence of a specific subset of C1Q expressing cells, even in very low numbers, in human samples following ASCT was associated with early relapse (6 of 8 good responding samples had zero C1Q+ cells while 12 of 16 poor responding samples had 1 or more C1Q+ cells-Fisher test p-value < 0.05). In addition to high expression of C1QA/B/C, these cells are also highly upregulated in TYROBP (known to relate to macrophage polarization4 and found in a spatial transcriptomic analysis of cells at the periphery of MM and its environment5) as well as FCER1G (known to relate to macrophage infiltration6). Conclusion: As advanced therapies manipulate elements of the immune microenvironment to impart effective treatment, the connection between tumor and macrophage should not be overlooked since macrophages likely help create an immunosuppressive niche that assists in disease growth and eventual revival. 1. Ma, R.-Y., Black, A. & Qian, B.-Z. Macrophage diversity in cancer revisited in the era of single-cell omics. Trends Immunol. 43, 546-563 (2022). 2. Wang, Y. et al. C1QBP suppresses cell adhesion and metastasis of renal carcinoma cells. Sci. Rep. 7, 999 (2017). 3. Stein, C. K., Meermeier, E., Welsh, S. J., Chesi, M. & Bergsagel, P. L. Key Subsets of Immune Cells in Bone Marrow Myeloid Compartment Indicate Degree of Tumor Infiltration and Avenues for Successful Immunotherapy in Multiple Myeloma. Blood 140, 7082-7083 (2022). 4. Liang, T. et al. TYROBP, TLR4 and ITGAM regulated macrophages polarization and immune checkpoints expression in osteosarcoma. Sci. Rep. 11, 19315 (2021). 5. Sudupe, L. et al. Spatial Transcriptomics Unveils Novel Potential Mechanisms of Disease in a MI cγ1 Multiple Myeloma in vivo Model. Blood 142, 4076 (2023). 6. Dong, K. et al. FCER1G positively relates to macrophage infiltration in clear cell renal cell carcinoma and contributes to unfavorable prognosis by regulating tumor immunity. BMC Cancer 22, 140 (2022).

Introduction: MPAL is a rare and heterogenous subtype of acute leukemia characterized by a single blast population with phenotypic expression of both myeloid and lymphoid lineages (biphenotypic) or multiple co-existing lineages of blasts that satisfy criteria for both acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). MPAL presents both a diagnostic and therapeutic challenge given its rarity and resistance to traditional therapies. Data suggest ALL-directed or hybrid therapies are most effective at inducing durable remissions as a bridge to allogeneic stem cell transplantation (Allo-SCT; Lazzarotto 2023, Rasekh 2021); however, many are single-institution with limited sample sizes. Methods: A retrospective analysis at 7 US academic centers was performed. Adult patients (pts) with a confirmed diagnosis of MPAL between 2003-2023 were included. Comparisons of categorical and continuous variables utilized the Fisher exact test and Wilcoxon rank-sum or Kruskal-Wallis test as appropriate. Time-to-event outcomes were calculated using the Kaplan-Meier method and compared using log-rank test. Results: A total of 79 pts with MPAL were included in this study. Median age at diagnosis was 61 years (range, 18-89); 52% were ≥ 60 years. Majority of pts were male (60%), non-Hispanic white (64%), and had an ECOG ≤ 1 (83%). Of the 50 pts with baseline CSF analysis, 5 (10%) had CNS disease. Phenotypically, the predominant blast population was biphenotypic in 68%, myeloid in 17%, and lymphoid in 15% of cases. KMT2A-rearrangement and BCR::ABL1 translocation constituted 4% and 14% of cases, respectively, and 30% of pts had complex cytogenetics. Most common mutations at baseline included RUNX1 (33%), DNMT3A (30%), FLT3-ITD (26%), TET2 (19%), WT1 (19%), NRAS (18%), TP53 (17%), and ASXL1 (14%) mutations. Of the 79 pts, 61 (77%) received intensive chemotherapy (IC), 12 (15%) received HMA-based regimens, 4 (5%) received other non-intensive regimens, and 2 (3%) transitioned to hospice prior to therapy. Among those receiving IC, 37 (61%) received ALL-directed therapies, 16 (26%) AML-directed, and 8 (13%) received hybrid regimens which included FLAG-VIPR (6/8), 7+3+vincristine (1/8), and cladrabine/low-dose cytarabine/vincristine/dexamethasone (1/8). Therapies were phenotype-discordant in 4/61 pts receiving IC; 3 myeloblast-predominant MPAL pts received ALL-directed therapy and one lymphoid-predominant pt received AML-directed therapy. Among 54 pts with predominant biphenotypic blasts, 52% received ALL-directed regimens. Of the 11 pts with BCR::ABL1 translocation, 8 (73%) received dasatinib, 2 (18%) ponatinib, and 1 (9%) received both. Only 30% of pts with FLT3-ITD mutated MPAL (5/17) received a FLT3 inhibitor. Overall, 56% of pts achieved complete remission (CR) or CR with incomplete count recovery (CRi), with a median duration of response of 16.7 months (IQR: 8.1-46.1). The rates of CR/CRi were 39%, 56%, and 75% for myeloid, biphenotypic, and lymphoid MPAL, respectively. All pts with CNS disease (5/5) cleared after induction. Thirty-seven percent of pts proceeded with Allo-SCT in first remission (23% of myeloid pts, 58% lymphoid, 35% biphenotypic). Thirty-two percent of responders (CR/CRi; 14/44) relapsed with a median time to relapse of 9.4 months (range, 0.5-42). Median overall survival (OS) for the entire cohort was 51 months (95% CI: 15-89). The 2-year OS rate was higher in pts with lymphoid-predominant phenotype (83%) compared to biphenotypic (55%) or myeloid-predominant phenotype (38%; p=0.16). Median OS was significantly longer in transplant versus non-SCT recipients (121 vs 14 months) with a 1-year OS rate of 97% vs. 59% (p<0.0001), respectively. Among pts who achieved CR/CRi, median OS significantly longer in transplant versus non-SCT recipients (121 vs 55 months, p=0.031), with a 2-year OS rate of 91% vs 75%. Conclusions In this large multi-center study, there were differences in survival based on predominant blast phenotype, with improved OS in lymphoid-predominant MPAL. Although most pts with biphenotypic-predominant MPAL received ALL-directed regimens, OS was worse in this subtype compared to lymphoid-predominant MPAL. There was significantly improved OS among Allo-SCT recipients underscoring the importance of Allo-SCT in this subtype of acute leukemia. Additional studies are needed to understand this rare and heterogenous disease.

Introduction Genomic alterations are common in multiple myeloma precursor stages, monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). However, commonly used stratification systems do not include somatic alterations that play a role in the disease. To address this clinical need, we generated a comprehensive genomic map of MM and precursors by harmonizing and analyzing mostly WGS data from 1,030 patients. We used these data to define a simple MM-like score, that is able to discriminate which premalignant patients are at risk to progress. Methods We collected, enriched, and performed WGS of tumor plasma cells and matched normals from 138 participants with MGUS or SMM, including those in low, intermediate, and high-risk groups. We combined our precursor dataset with genomic profiles from MM (n=20) and external sources of 872 individuals with MGUS (n=18), SMM (n=62), and MM (n=792) for a cohort of 1,030 individuals with MM or a precursor condition. In 16 patients, we could perform WGS serially from the bone marrow or circulating tumor cells (n=39) and reassess the presence of mutations. Results To develop a simple score that reflects the similarity of precursor genomes to full-blown multiple myeloma disease, we searched among the 107 common driver events (occurring in >1% of patients) and initiating translocations for ones that are differently altered in precursor conditions versus MM. We found 26 differentially altered events: only MAF and MAFB translocations were enriched in MGUS/SMM whereas 24 events were enriched in MM, including known drivers MYC, KRAS, FAM46C, del(1p) and gain(1q). We then defined a simple “MM-like” score for each tumor as the number of MM-enriched drivers minus the number of MGUS-enriched drivers. As expected, the MM-like score in our cohort increased throughout MM development (MM-like score median of 1 in MGUS, 2 in SMM, and 3 in MM). Even among SMM patients, we found a gradual increase of the MM-like score from low- (median=1), to intermediate (median=2), to high-risk (median=3) groups that match the overall medians in MGUS, SMM and MM (p=2e-5). We tested whether the MM-like score can be used to estimate risk of progression. Among untreated SMM patients characterized with WGS, an MM-like score greater than 2 was associated with a higher likelihood of progression (HR=5.3, P=0.03). Using an independent dataset of 87 patients with SMM, we were able to validate that a MM-like score greater than 2 was indeed associated with a higher risk of progression (HR=3.3, P=5x10-5). 11 patients who did not progress and for whom we performed longitudinal WGS, has stable MM-like scores over time, while three patients clinically progressed and their MM-like score increased at the time of progression (due to newly detected mutations in KRAS and NRAS). For the two remaining patients, their MM-like score increased, and we observed growth of the subclone that acquired the additional MM-like driver. In the first patient with MGUS/low-risk SMM, a novel hyperdiploid clone was detected in addition to a TP53 bi-allelic hit and t(11;14) translocation and was shown to increase in clonal fraction with tumor burden (light chains +104% within three years). In the second non-progressor with an increasing MM-like score, a novel del(1p) was detected, and other subclones in the phylogenetic tree either shrank or were stable over three years. Finally, because the MM-like score can place tumors on a gradual axis of evolution towards a more genomically-mature tumor, we tested whether the MM-like score was also predictive of survival in patients treated with a newly diagnosed MM. To do so, we calculated the MM-like score in patients from the publicly available CoMMpass database. We found that an increased score significantly correlated with shorter progression-free survival (median PFS1: 3 years in high score, versus 5 years in low/intermediate score; p=1e-3) and overall survival (median OS: 4.5 years in high score, versus not reached in low/intermediate score; p=1e-5). Conclusion Overall, we demonstrate that it is possible to stratify precursor stages of MM by discovering drivers, detecting those that are associated with the stage of the disease, and defining a genomically-based score that can be used to assess risk of progression and is easy to implement in the clinic.