Citations

The NCCN Guidelines for Cervical Cancer provide recommendations for all aspects of management for cervical cancer, including the diagnostic workup, staging, pathology, and treatment. The guidelines also include details on histopathologic classification of cervical cancer regarding diagnostic features, molecular profiles, and clinical outcomes. The treatment landscape of advanced cervical cancer is evolving constantly. These NCCN Guidelines Insights provide a summary of recent updates regarding the systemic therapy recommendations for recurrent or metastatic disease.

Background: Gestational diabetes mellitus (GDM) is a common complication of pregnancy that carries lasting risks. For women who have a history of GDM, the risk of developing type 2 diabetes mellitus (T2DM) increases by 50 to 60%. To monitor and prevent the development of T2DM, guidelines suggest screening those with a history of GDM at 6-weeks and 3-years post-delivery. For patients with abnormal lab results at the 6-week mark, it is advised to complete lab work sooner, at the 1-year mark. Data suggests that these guidelines are not being followed globally, and most do not receive adequate screening for T2DM. Methods: A retroactive chart review of 203 women between 18 and 55 years old with a past medical history significant for GDM was conducted to determine if patients with GDM completed screening for T2DM at 6-week, 1-year, and 3-year timestamps post-delivery. Patient demographics (age, race, ethnicity, language), clinical characteristics (body mass index), provider gender, and whether prediabetes or T2DM developed were recorded. Patients who did not complete the required follow-up received educational materials via the online portal system, and hemoglobin A1c (HbA1c) screening tests were ordered. Results: Ninety days post-intervention, 38 patients (50%) completed the HbA1c screening test, which exceeded our goal of a 5% improvement. Age and BMI 1-year postpartum were found to be significant factors in whether a patient completed HbA1c screening, with 16/18 (89%) completing screening with a healthy BMI 1-year postpartum (18.5 ≤ BMI < 25.0) but only 11/41 (27%) completing screening for patients under 40 years with an unhealthy BMI 1-year postpartum. Of the 38 patients who completed HbA1c screening, 9 (23.7%) had abnormal screening results. Conclusion: Follow-up surveillance for T2DM among women with a history of GDM is poor. Electronic health records can be used to identify and rectify gaps in care. Dissemination of standardized educational materials and electronic order entry for patients improved screening between the handoff from obstetrics to primary care.

Background: Skeletal related events (SREs) including pathologic fractures, surgery or radiation to bone, and spinal cord compression contribute to diminished quality of life in patients with multiple myeloma. Bone modifying agents (BMA) such as denosumab or the bisphosphonates zoledronic acid and pamidronate, are used to inhibit osteoclast activity to prevent SREs. The Bone Working Group of the International Myeloma Working Group suggests monthly administration of zoledronic acid for 12 months in newly diagnosed myeloma patients. This is followed by an option to discontinue or decrease administration frequency to every 3, 6, or 12 months if a very good partial response or better is achieved. The ideal start time of BMA from diagnosis and the duration of administration has not been adequately established to optimize reduction of SREs. Methods: This was a retrospective, single-center study that included newly diagnosed myeloma patients treated at the Mayo Clinic between 9/1/2018 and 9/1/2020 who had received at least one dose of a BMA. The primary objective was to evaluate the impact of BMA dosing frequency and duration on SREs. Secondary objectives included time to BMA initiation, time to relapse or progressions following BMA start, and safety. Data was summarized using frequencies and percentages for categorical data, and medians and interquartile ranges (IQR) for continuous data. A spline plot and cut-point analysis were used to assess the association of time from multiple myeloma diagnosis to BMA initiation with skeletal related outcomes. Rates of SREs were estimated using the Aalen-Johansen method, where death was treated as a competing risk. Associations of factors with SREs were assessed using Cox proportional hazards regressions, and these associations were summarized using hazard ratios (HR) and corresponding 95% confidence intervals (CI). Variables that could change throughout follow-up including BMA frequency, cumulative BMA dose, and duration of BMA were treated as time-dependent covariates in the Cox proportional hazards models, where the information for these variables was updated each time an additional dose of BMA was given. All analyses were performed using SAS version 9.4 software (SAS Institute, Inc.; Cary, NC) and R version 4.2.2 (R Core Team, R Foundation for Statistical Computing, Vienna, Austria). Results: Sixty-seven patients were included with a median age of 65 years old. The most frequently used BMA was zoledronic acid (88.1%), followed by pamidronate (7.5%), and denosumab (4.5%). Fifty-five patients (82.1%) had bone disease at baseline. Within 2 years of starting BMA, SREs occurred in 42.2% of patients with baseline bone disease and 8.3% of patients without (p=0.054). Median time to BMA initiation after diagnosis was 45 days (IQR 14-105) in patients with baseline bone disease and 87 (IQR 32-496) in patients without. Among the 26 patients with a SRE, median time from start of BMA to SRE was 170 days (IQR 32-496). No significant association was found between time to initiation and development of a SRE (Figure 1). BMA dosing frequencies of every 3 months and 6 months had a HR for SREs of 1.67 and 0.47, respectively compared to every 1 month, (P-values &gt;0.25). After excluding patients without baseline bone disease, compared to every 1 month dosing, dosing every 3 months and every 6 months increased the risk of SRE, although the differences were not statistically significant (3 months: HR=1.92, 95% CI 0.76-4.88, p=0.17; and 6 months: HR=1.26, 95% CI 0.14-10.94, p=0.84). Patients without bone disease at baseline remained on BMAs for a median of 1.8 years while patients with bone disease received BMAs for a median of 2 years. There was no statistically significant difference found with varying duration or cumulative dose and SRE development (Table 1). Relapse or progression occurred in 32.1% of patients within 2 years of starting BMA, while death occurred in 7.5% of patients. Osteonecrosis of the jaw occurred in 1 patient with bone disease at baseline who received zoledronic acid every 3 months for a duration of 596 days. Conclusions: No significant association between time of BMA initiation, dosing frequency, or duration on development of SREs were observed. This suggests delaying the start time of BMAs to allow for dental clearance and initial treatment would not increase risk of SREs. Prospective trials are needed to confirm these findings.

Introduction: Use of validated risk stratification tools for work up of suspected pulmonary embolism (PE) is an endorsed recommendation of the American Society of Hematology and the American College of Emergency Physicians. Due to variations in clinical practice, electronic health record (EHR) systems, and medical provider trainings, the use, documentation, and implementation of these tools vary widely. Current processes do not allow for electronic capture and quality reporting at most institutions. Methods: We sought to design and implement clinical pre-test probability (PTP) tools at three large healthcare institutions for use in emergency departments (ED). At each site, a hematologist partnered with ED physician leadership and local information technology experts to design and implement PTP tools in clinical workflows. Overall, 38 EDs (high volume tertiary EDs and smaller regional EDs) located in the United States along the East Coast and Midwest regions were involved. A major goal of implementation was integration into clinical workflow and automatic documentation. After design and implementation, awareness and education of the new EHR tool was distributed electronically to ED providers. After implementation, use of PTP tools was analyzed between September 12, 2022 and January 11, 2023. PTP use was examined as percent of visits for which patients underwent CT pulmonary angiography (CTPA). Results: Each institution chose the 3 tier Wells' Score for implementation while one site designed an integrated Wells'/PERC or YEARS score calculator. Two sites implemented the tool as an optional flowsheet and one site implemented the tool as mandatory parameters within the orders for PE imaging studies. The mandatory tool could be bypassed with prespecified selections or if a D-dimer existed within 48 hours . Complete details of the site-specific implementation are shown in Table 1. Over the 4-month evaluation timeframe, there was a total of 270,214 ED encounters. Uptake and utilization of the PTP tools are shown in Table 2. Use of PTP was highest at the site with forced PTP documentation which ranged from 49-53% of ordered CTPAs, compared to Site 2 where use was 2-3%, and Site 1 where use ranged from 1-3%. At Site 1, use of PTP increased slightly over the study period with signs that PE yield on imaging was increasing as well (3.4% to 5.9%). At Site 2, PE yield on imaging was overall high (9-10%), and remained similar with similar use of PTP tools over the study period. Use of PTP and PE yield (6-8%) on imaging also remained similar throughout the study at Site 3. Conclusion: Forced use of PTP within the orders for CTPA led to the highest use of PTP (Site 3) but this did not result in meaningfully higher PE yield on CTPA compared to the other sites. PE yield at each site was at or above the 5% yield for PE on CTPA which has been previously reported. Given that PTP uptake was relatively stable over the measurement period at Site 2 and 3, this indicates the process had mostly stabilized and that other strategies are needed to improve uptake of PTP, reduce utilization of CTPA, and further increase yield on CTPA. Increasing PTP use and rising PE yield at Site 1 demonstrated ongoing potential for improvements past this study timeframe.

Background: It has been recently demonstrated that altered lipid metabolism involving increased free fatty acids (FFAs) uptake supports the growth and proliferation of MM cells (Panaroni et al. Blood 2022; Farell et al. Elife 2023). Whether the availability of FFAs in the bone marrow (BM) microenvironment is associated with the pathogenesis of MM from MGUS has not been previously evaluated. Thus, we evaluated if individual species of FAs or FA-containing lipids such as triacylglycerols (TAGs), diacylglycerols (DAGs), and monoacylglycerols (MAGs) are differentially present between the BM microenvironment of MGUS and MM patients. Methods: Lipid profiles of BM plasma samples (reflective of the BM microenvironment) from patients with a spectrum of plasma cell disorders (22 MGUS and 24 MM (15 newly diagnosed and 9 relapsed/refractory)) were acquired by liquid chromatography (LC)/tandem mass spectrometry (MS), and individual lipid species were quantified based on single-point quantification using 55 isotopically labeled internal standards. Concentration-based lipid species data was analyzed by the web-based tool MetaboAnalyst 5.0. Data was normalized by quantile normalization, log transformed and scaled by Pareto scaling. p values &lt;0.05 were considered significant. Results: A total of 993 distinct lipid species were quantified by the MS-based targeted lipidomics assessment. Of these lipid species, the levels of individual mid-chain (≤50 carbon chain length) and long-chain (≥52 carbon chain length) polyunsaturated TAGs were the most differentially present in the BM plasma of MM compared to MGUS patients (Figure 1A). Even though a principal component analysis (PCA) involving all lipid species showed moderate separation of MM from MGUS patients, five MGUS patients (categorized as MGUS-other (MGO)) who clustered more towards MM patients compared to the remaining MGUS patients had a distinct pattern of individual mid and long-chain polyunsaturated TAG levels that were comparable to MM patients (Figure 1B). Furthermore, the proliferation rate of clonal plasma cells in the BM of these MM and MGUS as measured by the S-phase% was found to be directly correlated with the level of long-chain polyunsaturated TAGs. Conclusions: Mid and long-chain polyunsaturated TAGs are present in lower and higher levels, respectively, in the BM microenvironment of MM compared to MGUS patients. These findings continue to support the importance of FA-containing TAGs and other lipids in the pathogenesis of MM. Future confirmatory studies evaluating the biological significance of these differences are required to determine if they can be exploited for diagnostic and therapeutic purposes.

Introduction: Telomere biology disorders (TBD) are multisystem diseases often associated with bone marrow failure (BMF) and pulmonary fibrosis. TBD are clinically diagnosed when mean telomere lengths (TL) in blood cells measured by clinical flowFISH assays fall &lt;1 st percentile, in comparison to age-matched reference controls. This information has limitations, e.g. TL in blood cells may not represent TL in other organs (e.g. lung, liver) and moreover, individuals with high clinical suspicion of TBD can show borderline average TL which complicates their diagnosis. The likely reason for this is that cell senescence can be triggered by shortening of a subset, or even a single chromosome arm telomere, a situation that may be missed when measuring average TL. Previous approaches to measure individual chromosome-arm telomere length (CA-TL) are only available for a small number of chromosome arms or can only estimate the number of shortened telomeres without matching them to specific chromosome arms. Taking advantage of recent developments in long-read next generation sequencing (NGS) and the availability of the recently published telomere-to-telomere (T2T) reference human genome, our group developed Telogator, (Stephens Z. et al, 2022) a bioinformatic tool that estimates CA-TL for most chromosome arms using long-read NGS data. Here we use Telogator to describe for the first time the CA-TL pattern in TBD patients in comparison with a control non-TBD cohort. Methods: TBD patients were identified through the Pre-Myeloid and Bone Marrow Failure Specialty Clinic at Mayo Clinic. All patients underwent flowFISH and genetic testing. Age-matched non-TBD patients identified at the Center for Individualized Medicine (Mayo Clinic) were used as reference controls. Informed consent was obtained from all individuals with approval from the Mayo Clinic Institutional Review Board. DNA from peripheral blood mononuclear cells was sequenced using PacBio Sequel II following the manufacturer indications for HiFi sequencing. BAM files were aligned to the T2T reference and CA-TL was calculated using Telogator as described in Stephens Z. et al. 2022. Average TL, CA-TL, and percent of short telomeres (both defined as &lt;5 kb and &lt;3.2 kb) were calculated. Comparisons of average TL and percent of short telomeres were performed using t-test, while Wilcoxon rank-sum test was used to compare CA-TL. Results: Four TBD patients [median age = 58.5 (52-60), 50% female] and 6 non-TBD controls [Median age = 56 (50-63), 33% female] were included in the analysis. All TBD patients presented average TL below the 1 st centile in both lymphocytes and granulocytes, and TBD-related phenotype (100% with pulmonary fibrosis, 50% with BMF, 25% with liver fibrosis). Three had a pathogenic variant in a TBD related genes [2 in TERT (NM_198253.3: c.2030G&gt;A, p.(Gly677Asp) and c.2515_2533del, p.(Thr839Alafs*29)) and 1 in NHP2 (NM_017838.3: c.459_460delAT; p.(X154Argext29))]. The average TL calculated by Telogator showed high correlation with flowFISH values (r 2 = 0.9883, p = 0.0059) and was lower in TBD patients than controls (p = 0.0012). Next, when comparing individual CA-TL between groups, only half of CA-TL was statistically different in the TBD group compared to controls (1p, 3q, 4p, 5p, 5q, 6q, 7p, 7q, 8q, 9p, 9q, 10q, 11p, 12q, 12q, 16p, 16q, 18q, 19p, 19q, 20p, 20q, 21q - Figure 1). The percentage of telomeres &lt;5kb and &lt;3 kb was significantly increased in TBD patients compared to controls (p= 0.014 and 0.0333, respectively). Discussion: Using a novel informatic tool, we replicate previous results obtained using classic approaches and were able to expand on these studies by measuring specific CA-TL in TBD patients. We identified statistically significant differences at the CA-TL level in these patients when compared to age-matched controls, while other CA-TL were not statistically different. Future studies and the inclusion of additional TBD patients will help define the clinical relevance of the differential CA-TL shortening and its prevalence among TBD patients. While limited by the small number of samples in the study, we show the feasibility of using this approach to study TL with unprecedented resolution and show that Telogator offers important advantages compared to classic methods to study telomere biology that can be used in other relevant fields like aging and/or cancer. Our results pave the way to advance the mechanistic understanding of TBD.

Introduction: Risk stratification approaches using clinical criteria or biomarkers in acute graft-versus-host disease (GVHD) have traditionally been implemented at diagnosis or initiation systemic treatment with corticosteroids. For patients who require second-line treatment, the significance of biomarkers at salvage therapy and the relationship between biomarker risk and choice of therapy are unknown. Methods: We studied adult patients who received second-line treatment for acute GVHD between January 2016 and December 2021 in the Mount Sinai Acute GVHD Consortium (MAGIC) database, which collects clinical data and longitudinal serum samples from allogeneic HCT recipients using a rigorous PRoBE study design. Exclusion criteria included relapse of underlying malignant disease prior to second-line therapy, missing response data, or missing serum sample. Serum samples collected from 7 days prior to 3 days after initiation of second-line therapy met criteria for biomarker analysis. The MAGIC algorithm probability (MAP) was calculated as a single value based on concentrations of ST2 and REG3α and was stratified at a threshold of 0.290 to define high MAP and low MAP groups. The primary objective evaluated the association between MAP and survival for patients receiving second-line therapy for acute GVHD. The key secondary objective was to investigate the MAP and choice of second-line systemic agent on Day 28 overall response rate (ORR) and survival. Results: In total, 316 adult patients received second-line treatment for acute GVHD; 149 patients (47%) were excluded for disease relapse (n=27), missing response data (n=48), or missing sample (n=74).Of the 167 evaluable patients, most had steroid-refractory acute GVHD (n=146, 87%), rather than steroid-dependent (n=8, 5%) or steroid-sensitive (n=14, 8%) disease. 62 patients received ruxolitinib while 102 received other systemic agents (best available therapy: BAT). Baseline clinical characteristics of the study population according to treatment choice were similar, except for donor type (Rux: MRD 15%, MUD 74%, haplo 11%; BAT: MRD 30%, MUD 67%, haplo 3%; P=0.014) and median days from corticosteroids to second-line treatment (Rux: 18, BAT: 12; P=0.02).In total, 81 patients had high MAPs and 86 patients had low MAPs, with similar distribution in each treatment cohort (P=0.53). For the entire cohort, the median follow-up for survivors was 22 months (range, 1.5-27).The MAP separated patients into 2 groups (high vs low) with significantly different mortality (NRM at 2 years, 76% vs 29%, P&lt;.0001) and survival (OS at 2 years, 12% vs 63%, P&lt;.0001). Patients who received ruxolitinib as second-line therapy had lower mortality (NRM at 2 years, 35% vs 60%, P&lt;.002) and improved survival (OS at 2 years, 51% vs 32%, P&lt;.008), compared to those who received other systemic agents. However, the outcomes of patients with high MAP were poor, regardless of second-line treatment choice ( Figure 1A). The MAP (low vs high), time from corticosteroids to second-line treatment (≥14 days vs &lt; 14 days), GVHD grade at second-line (0-2 vs 3-4), and choice of second-line therapy (Rux vs BAT) were all significant (P&lt;0.05) predictors of lower NRM and higher OS in multivariate analysis. The MAP also separated patients into 2 groups with significantly different D28 ORR (low: 49%, high: 30%, P&lt;.0001). In agreement with prospective trials, ruxolitinib resulted in higher D28 response rates compared to other systemic therapies (ORR 54.9% vs 30.5%, P=0.005), which was observed in both low MAP (ORR, 64.5% vs 38.5%, P=0.017) and high MAP cohorts (ORR, 42.9% vs 22.6%, P=0.06) ( Figure 1B). The MAP (low vs high), GVHD grade at second line (0-2 vs 3-4), and choice of second-line therapy (Rux vs BAT) were significant predictors (P&lt;0.05) of higher D28 ORR in multivariate analysis. Conclusion: The MAP measured at the initiation of second-line systemic treatment for acute GVHD predicts NRM and OS, as well as treatment response. The outcomes of patients with high MAP are poor, regardless of second-line treatment choice, and the higher CR rate in low MAP patients may drive higher survival rates. Incorporation of MAP into clinical trials in this setting warrants investigation. The results also support the current use of ruxolitinib as second-line treatment for acute GVHD, particularly in patients with low MAP.