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Supplementary Figure from Distinct Patterns of Clonal Evolution Drive Myelodysplastic Syndrome Progression to Secondary Acute Myeloid Leukemia

Supplementary Table from Distinct Patterns of Clonal Evolution Drive Myelodysplastic Syndrome Progression to Secondary Acute Myeloid Leukemia

Clonal evolution in myelodysplastic syndrome (MDS) can result in clinical progression and secondary acute myeloid leukemia (sAML). To dissect changes in clonal architecture associated with this progression, we performed single-cell genotyping of paired MDS and sAML samples from 18 patients. Analysis of single-cell genotypes revealed patient-specific clonal evolution and enabled the assessment of single-cell mutational cooccurrence. We discovered that changes in clonal architecture proceed via distinct patterns, classified as static or dynamic, with dynamic clonal architectures having a more proliferative phenotype by blast count fold change. Proteogenomic analysis of a subset of patients confirmed that pathogenic mutations were primarily confined to primitive and mature myeloid cells, though we also identify rare but present mutations in lymphocyte subsets. Single-cell transcriptomic analysis of paired sample sets further identified gene sets and signaling pathways involved in two cases of progression. Together, these data define serial changes in the MDS clonal landscape with clinical and therapeutic implications.Significance:Precise clonal trajectories in MDS progression are made possible by single-cell genomic sequencing. Here we use this technology to uncover the patterns of clonal architecture and clonal evolution that drive the transformation to secondary AML. We further define the phenotypic and transcriptional changes of disease progression at the single-cell level.See related article by Menssen et al., p. 330 (31).See related commentary by Romine and van Galen, p. 270.This article is highlighted in the In This Issue feature, p. 265

Clonal evolution in myelodysplastic syndrome (MDS) can result in clinical progression and secondary acute myeloid leukemia (sAML). To dissect changes in clonal architecture associated with this progression, we performed single-cell genotyping of paired MDS and sAML samples from 18 patients. Analysis of single-cell genotypes revealed patient-specific clonal evolution and enabled the assessment of single-cell mutational cooccurrence. We discovered that changes in clonal architecture proceed via distinct patterns, classified as static or dynamic, with dynamic clonal architectures having a more proliferative phenotype by blast count fold change. Proteogenomic analysis of a subset of patients confirmed that pathogenic mutations were primarily confined to primitive and mature myeloid cells, though we also identify rare but present mutations in lymphocyte subsets. Single-cell transcriptomic analysis of paired sample sets further identified gene sets and signaling pathways involved in two cases of progression. Together, these data define serial changes in the MDS clonal landscape with clinical and therapeutic implications.Significance:Precise clonal trajectories in MDS progression are made possible by single-cell genomic sequencing. Here we use this technology to uncover the patterns of clonal architecture and clonal evolution that drive the transformation to secondary AML. We further define the phenotypic and transcriptional changes of disease progression at the single-cell level.See related article by Menssen et al., p. 330 (31).See related commentary by Romine and van Galen, p. 270.This article is highlighted in the In This Issue feature, p. 265

TPS4611 Background: The utilization of neoadjuvant immune checkpoint inhibitor (ICI) therapy, including anti-PD1/L1 agents, prior to radical cystectomy (RC), is an emerging paradigm in muscle invasive bladder cancer (MIBC). Pathologic complete responses (pCR) have been observed in 25-40% of patients with neoadjuvant PD1/L1 inhibitor monotherapy for cisplatin-ineligible MIBC. In situ vaccination using stereotactic body radiation therapy (SBRT) may augment T-cell responses to tumor-specific antigens through immunogenic cell death. Sasanlimab (PF-06801591) is a humanized IgG monoclonal antibody that targets PD-1 selectively, for which there are both Phase 1 data and ongoing Phase 3 trials in early-stage urothelial carcinoma. There exists a strong rationale to evaluate a novel strategy of combination neoadjuvant ICI therapy with SBRT as an in situ vaccine to improve loco-regional control and decrease the risk of distant recurrence in cisplatin-ineligible patients with MIBC. Methods: This is a prospective, investigator-initiated, single-arm, single-institution, phase II trial that evaluates neoadjuvant sasanlimab in combination with SBRT as neoadjuvant therapy for patients with MIBC before RC. Eligibility requires patients to be cisplatin-ineligible (one of the following: ECOG-PS=2, creatinine clearance

Germ cell tumors (GCTs) of the testis are cured with the successful integration of surgery, chemotherapy, and/or radiation therapy in most cases. The favorable results are a consequence of improved risk stratification, risk-adapted chemotherapy, reduced morbidity of treatment, and appropriate integration of multimodal therapy. The success of these approaches depends on accurate staging with imaging studies of the testis, retroperitoneum, and thorax. This article reviews the indications for imaging and performance characteristics of modalities in the diagnosis, staging, surveillance, and follow-up of patients with GCTs. We also highlight the current guideline recommendations for imaging in treatment of patients with GCTs.

Lonicera japonica has been shown to have antibacterial, antiviral, and anti-inflammatory properties. Given these properties, varying preparations of L. japonica are being used increasingly as immune enhancers. However, isolated compounds from L. japonica can inhibit lymphocyte functions, which would oppose the ability of L. japonica to serve as an immune enhancer. Prior studies in our laboratory demonstrated that an herbal powder extracted from the leaves of L. japonica inhibits T lymphocyte proliferation and survival. Because both T- and B-cell functions and interactions are required for effective immune responses, the effect of L. japonica on LPS-stimulated B-lymphocyte functions was assessed. Our data demonstrate that while total and IgM+ B cells are not largely diminished as a result of L. japonica treatment, IgM production was decreased, potentially as a consequence of suppressed proliferation.

87 Background: We previously developed screening nomograms to predict 15-year risk of all-cause mortality, prostate cancer diagnosis, and prostate cancer mortality, and incorporated them into a graphical patient decision aid (PtDA). Our objective was to prospectively recruit primary care patients interested in shared-decision making regarding prostate specific antigen (PSA) screening and assess the impact of individualized counseling using our new PtDA. Methods: 50 patients from one internal medicine practice were enrolled in a single-arm sequential trial design, with face-to-face clinician counseling and questionnaires. Eligibility criteria included men age 50-69 years old and life expectancy > 10 years. Patients were excluded for a personal history of prostate cancer or PSA screening within the prior year. Participants completed baseline questionnaires regarding prior PSA testing, demographic information, health literacy, and the Control Preferences Scale (CPS). They then received standardized counseling (based on large trial and epidemiologic data) regarding PSA screening, followed by individualized counseling using our new PtDA. Participants then made a screening decision, and completed a post decision questionnaire including a Decisional Conflict Scale. Results: The median age was 60 (IQR 54; 65). 41 (82%) had a prior PSA test, while 9 (18%) had not. 42 (84%) of participants received some education beyond high school, 41 (82%) demonstrated high health literacy, and 45 (90%) desired to have an active role in decision-making based on the CPS. After undergoing counseling, 34 (68%) participants chose to undergo initial or repeat PSA screening, 8 (16%) chose against future screening, and 8 (16%) remained uncertain. 45 (90%) participants found individualized counseling using the PtDA more useful than standardized counseling. Finally, patients reported reduced decisional conflict compared to historical controls (P < 0.001). Conclusions: Our process of standardized counseling followed by individualized counseling using our new PtDA was effective in reducing decisional conflict. The majority of participants found the PtDA more useful for decision making than standardized counseling. Clinical trial information: NCT03387527.

110 Background: Recommendations for PSA screening encourage shared decision making between patients and providers, rather than population-based screening. Nomograms provide individualized risk predictions potentially enhancing informed decisions to undergo screening. Our objective was to develop PSA screening nomograms using demographic and follow-up data from two large randomized screening trials: the Göteborg Screening Trial ( Lancet Oncol. 2010;11:725-32) and Prostate, Lung, Colon, and Ovarian (PLCO) Cancer Screening Trial ( N Engl J Med. 2009;360:1310-9). The endpoints of the models were PCDx, PCM, and ACM at 15 years. Methods: Patients with screening prior to trial entry were excluded, leaving 59,951 total subjects: 19,899 and 40,052 from Göteborg and PLCO, respectively. Demographic information including age, family history of PCDx, ethnicity, Charlson Comorbidity Index, marital status, education, and control vs. screening arm were used as predictive variables. If screened, baseline PSA was used as an additional continuous variable. Models for ACM were first developed, then models predicting PCDx and PCM using competing risk analysis. Predictive accuracy was assessed using the concordance index (c-index) and calibration plots. Results: On multivariable analysis, all variables were significant (P < 0.05) for predicting at least one outcome. Nomograms predicting PCDx, PCM, and ACM demonstrated reasonable discrimination: c-index 0.60, 0.65, 0.70, respectively. When a single baseline PSA was included, discriminative accuracy improved for PCDx and PCM, but remained the same for ACM: c-index 0.78, 0.74, 0.69, respectively. Estimates were well-calibrated for all endpoints. Conclusions: Using demographic information, we developed PSA screening nomograms, with good discrimination and calibration in predicting all three outcomes. A single baseline PSA improved nomogram discrimination substantially for PCDx and PCM. We will study the implementation of these nomograms into clinic practice to aid decisions for previously unscreened patients, or whether to continue PSA screening for patients with a known prior PSA.

Reservoir 29 and Lake B are extremely acid lakes (epilimnion pHs of 2.7 and 3.2, respectively), because they receive acidic discharges from coal refuse piles. They differ in that the pH of profundal sediments in Reservoir 29 increased from 2.7 to 3.8 during the period of thermal stratification, whereas permanently anoxic sediments in Lake B had a pH of 6.2. The pH rise in Reservoir 29 sediments was correlated with a temporal increase in H 2 S concentration in the anaerobic hypolimnion from 0 to >1 mM. The chlorophyll a levels in the epilimnion of Reservoir 29 were low, and the rate of primary production was typical of an oligotrophic system. However, there was a dense 10-cm layer of algal biomass at the bottom of the metalimnion. Production by this layer was low owing to light limitation and possibly H 2 S toxicity. The specific photosynthetic rates of epilimnetic algae were low, which suggests that nutrient availability is more important than pH in limiting production. The highest photosynthetic rates were obtained in water samples incubated at pH 2.7 to 4. Heterotrophic bacterial activity (measured by [ 14 C]glucose metabolism) was greatest at the sediment/water interface. Bacterial production (assayed by thymidine incorporation) was as high in Reservoir 29 as in a nonacid mesotrophic Indiana lake.