A Rare Case of Epithelioid Trophoblastic Tumor Presenting as Hematoma of a Caesarean Scar in the Lower Uterine Segment

Epitheliod trophoblastic tumor (ETT) account for only 1–2% of all the cases of gestational trophoblastic neoplasia (GTN), with a reported mortality rate of 10–24%. ETT is derived from chorionic type intermediate trophoblastic cells, which appears to be the reason for the only slightly elevated βhCG levels in these patients. We present a case of a 42-year-old patient who was admitted to the clinic eight months after Caesarean delivery, for irregular vaginal bleed with normal values of beta-human chorionic gonadotropin (βhCG). A 6 × 5 cm hematoma was evacuated from the isthmic uterine segment during the operation, and the histopathological exam of the tissue surrounding the hematoma revealed ETT. There were no metastatic lesions on the thoracal, abdominal, and pelvic CT. The second ultrasonographic exam revealed tumefaction of 5 cm at the site from the previous surgical procedure. Color Doppler imaging revealed no central nor peripheral blood flow. The patient underwent a total abdominal hysterectomy with bilateral adnexectomy without adjuvant chemotherapy. This appears to be one of the shortest intervals from the anteceded gestational event until the diagnosis of this tumor, along with the absence of the significant ultrasonographic feature of the ETT-peripheral Doppler signal pattern. We underline that, even with normal values of βhCG, irregular vaginal bleeding following the antecedent gestational event should always arouse suspicion of GTN.

Microcirculation and tissue oxygenation in the head and limbs during hyperbaric oxygen treatment

Introduction: Hyperbaric oxygen (HBO) exposure for 10−15 min has been shown to reduce peripheral blood flow due to vasoconstriction. However, the relationship between decreased peripheral blood flow and the therapeutic effects of HBO treatment on peripheral circulatory disorders remain unknown. Longer exposures have been reported to have vasodilatory effects and increase peripheral blood flow. This study investigated the effect of HBO treatment on blood flow and transcutaneous oxygen pressure (TcPO2). Methods: Twenty healthy volunteers aged 20-65 years (nine males) participated in this study. All participants breathed oxygen for 60 min at 253.3 kPa. Peripheral blood flow using laser Doppler flowmetry and TcPO2 on the ear, hand, and foot were continuously measured from pre-HBO exposure to 10 min post-exposure. Results: Peripheral blood flow in each body part decreased by 7-23% at the beginning of the HBO exposure, followed by a slow increase. Post-exposure, peripheral blood flow increased 4-76% in each body part. TcPO2 increased by 840-1,513% during the exposure period, and remained elevated for at least 10 min after the exposure. Conclusions: The findings of the current study suggest vasoconstriction during HBO treatment is transient, and even when present does not inhibit the development of increased tissue oxygen partial pressure. These findings are relevant to studies investigating changes in peripheral blood flow during HBO treatment in patients with circulatory disorders.

5-HT Receptors and Temperature Homeostasis

The present review summarizes the data concerning the influence of serotonin (5-HT) receptors on body temperature in warm-blooded animals and on processes associated with its maintenance. This review includes the most important part of investigations from the first studies to the latest ones. The established results on the pharmacological activation of 5-HT1A, 5-HT3, 5-HT7 and 5-HT2 receptor types are discussed. Such activation of the first 3 type of receptors causes a decrease in body temperature, whereas the 5-HT2 activation causes its increase. Physiological mechanisms leading to changes in body temperature as a result of 5-HT receptors’ activation are discussed. In case of 5-HT1A receptor, they include an inhibition of shivering and non-shivering thermogenesis, as well simultaneous increase of peripheral blood flow, i.e., the processes of heat production and heat loss. The physiological processes mediated by 5-HT2 receptor are opposite to those of the 5-HT1A receptor. Mechanisms of 5-HT3 and 5-HT7 receptor participation in these processes are yet to be studied in more detail. Some facts indicating that in natural conditions, without pharmacological impact, these 5-HT receptors are important links in the system of temperature homeostasis, are also discussed.

A Prospective Study of Clonal Evolution in Follicular Lymphoma: Circulating Tumor DNA Correlates with Overall Tumor Burden and Fluctuates over Time without Therapy

Background: Follicular lymphoma (FL) shows marked variation in clinical course including spontaneous regression and histologic transformation (HT). Watchful waiting (W&W) is routinely applied to pts with newly diagnosed FL, but monitoring strategies are not standardized. Pts with progression within 1-2y of diagnosis have worse outcomes, but the biologic basis is unclear and biologic-based classifiers are not routinely applied at diagnosis. Circulating tumor DNA (ctDNA) is a highly tumor-specific biomarker that is prognostic in aggressive B-cell lymphomas, but its ability to serially monitor FL remains undefined. We applied a next-generation sequencing assay to identify tumor clonotypes for serial monitoring of peripheral blood in pts with untreated FL as part of an ongoing prospective clinical trial [NCT03190928]. Methods: Pts with grade I-II or 3A FL are eligible if evaluable disease on CT or FDG-PET, age ≥18, ECOG ≤2, no evidence of HT, and no prior systemic therapy. Pts undergo W&W until they meet uniform protocol-defined treatment criteria and remain on study until second-line therapy. Baseline testing includes labs, peripheral blood flow cytometry, BM biopsy/aspirate, CT and FDG-PET scans, and research biopsy. Pt have clinic visits every 4m for 2y, every 6m in years 3-5, then annually. CT scans are every 8m for 2y, then annually. FDG-PET scans are at baseline, at 2y, and any time of suspected progression. Peripheral blood samples including Streck tubes (plasma) and PBMCs are drawn at each clinic visit and stored. For ctDNA analysis, tumor DNA was amplified from FFPE using locus-specific primer sets for the Ig heavy-chain and light-chain loci along with BCL1/BCL2 translocations (Adaptive Biotechnologies). Amplified products were sequenced and tumor clonotypes were identified in plasma and PBMCs. Serial tracking of ctDNA was done in plasma and blinded to clinical outcomes. Results: 77 pts enrolled between July 2017 and July 2021. Median age was 57 (range 24-83) including 14 (18%) low-risk, 29 (38%) intermediate-risk, and 34 (44%) high-risk by FLIPI. Fourteen (18%) pts had stage I-II disease. Forty-three (56%) pts had monoclonal B-cells on peripheral blood flow cytometry. Twenty-nine (38%) pts progressed requiring frontline therapy including 7 (9%) pts with HT. Twenty-five (32%) pts were monitored ≥2y with no progression including 10 (13%) pts with evidence of at least some spontaneous regression by CT. Twenty (26%) pts were on study for <2y and 3 (4%) pts were unevaluable. Of 36 pts with FFPE analyzed, 35 (97%) had ≥1 dominant tumor clonotype identified for tracking. Of these, 32 (91%) had ≥1 dominant clonotype identified in plasma suitable for tracking. Three pts without available FFPE had the dominant clonotype identified from plasma that was used for tracking. In 28 pts, plasma was compared to PBMCs, and ≥1 clonotype was identified in both compartments in 21 (75%), plasma only in 5 (18%), and neither in 2 (7%). The median overall levels of baseline plasma ctDNA was 104.7 counts/mL (range 4-2096); progressors had median levels of 136.0 counts/mL (range 4-1493) compared to 40.9 count/mL (32-2096)(p=0.85) for non-progressors (Figure 1A). Baseline ctDNA correlated with the total metabolic tumor volume (TMTV) on FDG-PET scan (r=0.49, p=<0.006)(Figure 1B). Pts who required immediate treatment often had very high baseline levels of ctDNA (black dots, Figure 1C) and serial monitoring prior to progression demonstrated patterns of sharp increases in ctDNA prior to progression or relatively stable levels in others (Figure 1C). Notably, significant fluctuations were noted in ctDNA for non-progressing pts with an overall trend for decreasing values including four pts with evidence of spontaneous regression by CT with corresponding decreases in ctDNA over time (Figure 1D). As a notable examples, FL_14 had baseline ctDNA level of 2096 counts/mL with decreases to 101 counts/mL after 4 months, 14 counts/mL at 16 months, and no detectable ctDNA at 2 years. Conclusions: ctDNA quantified from plasma in FL mirrors TMTV. Serial monitoring of ctDNA in patients without therapy demonstrated various patterns of fluctuation, including some patients in which ctDNA became undetectable coincident with spontaneous clinical regressions. ctDNA thus provides a non-invasive platform to monitor the natural history of FL, enabling future studies of tumor immune surveillance in this disease. Figure 1 Figure 1. Disclosures Jacob: Adaptive Biotechnologies: Current Employment, Current equity holder in publicly-traded company. Bagaev: BostonGene Corp.: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties: BostonGene. Meerson: BostonGene: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties: BostonGene. Postovalova: BostonGene Corp.: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties: BostonGene. Kudryashova: BostonGene: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties: BostonGene. Kotlov: BostonGene Corp: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties. Fowler: BostonGene: Current Employment, Current holder of stock options in a privately-held company.

Risk Factors for Progression from Early to Advanced Stage Mycosis Fungoides: A Single Center Retrospective Analysis at the Winship Cancer Institute of Emory University

Introduction: Advanced stage mycosis fungoides (MF) has a median survival of 3-5 years, while early stage MF is a chronic disease typically associated with an excellent prognosis and a median survival of 20 years or more. Prior studies suggest approximately 20% of early stage MF may progress to advanced stage, but risk factors for progression remain poorly studied, particularly among African American (AA) patients. We aimed to identify clinic features associated with progression to advanced stage MF in a large urban medical center. Methods We performed a retrospective review of 388 patients with early stage (1A-2A) MF at the Winship Cancer Institute of Emory University diagnosed between 1970 and 2021. Clinical data collected from the electronic medical record included demographics, laboratory values, disease characteristics, and therapy. Our primary endpoint was to identify variables associated with progression to advanced stage MF. Progression to advanced stage was defined as a highest overall TNMB stage of 2B-4B. Overall survival (OS) was measured from time of diagnosis to date of death or last follow-up. Kaplan-Meier curves for OS were generated for the whole cohort and by progression group. Descriptive analysis was performed for each variable, and a comparison between patients who did or did not progress to advanced stage was performed using ANOVA for numerical covariates and chi-square test for categorical covariates. The association of baseline variables with OS was modeled by Cox proportional hazards model and multivariable analyses were performed on significant variables. Results Among 388 patients, the median follow up was 5 years (range 0-51). There was even distribution among male (49.0%) and female (51.0%) patients. The median age at diagnosis was 53 years (range 8-95). This population included 41.4% AA, 55.0% White, 2.3% Asian, and 1.3% other races. Stage distribution was as follows: 34.2% (n=133) stage 1A, 51.5% stage 1B (n=200), and 14.2% stage 2A (n=55). Forty-nine patients had hypopigmented MF (45 AA), and 9.4% (n=34) patients developing large cell transformation (LCT) during their disease course. Treatment at diagnosis was topical in 52.3% (n=203), systemic in 1.8% (n=7), radiation in 3.4% (n=13), and multimodality in 29.4% (n=114). Overall, 93 patients (24.1%) progressed to advanced stage. Progression to a higher stage was statistically associated with higher overall TNMB stage at diagnosis (p<0.001), T2 tumor stage (p<0.001), nodal involvement (p=0.031), positive blood flow cytometry (<0.001), T-cell receptor (TCR) clonality in the blood (p=0.014), LCT (p<0.001), and elevated lactate dehydrogenase (LDH) (p<0.001). Patients with hypopigmented MF were less likely to progress (hazard ratio 0.32 (95% CI 0.12-0.84) p=0.020), Sex, race, age, blood stage, and white blood cell count were not associated with risk for progression. Univariate logistic regression is summarized in figure 1. Progression to advanced stage was associated with an increased risk of death (4.75 (0.05-7.38), p < 0.001, figure 2). The median survival for patients who did and did not progress were 11 years (95% CI 7, 15) and 31 years (95% CI 25, not reached), p<0.001 respectively. Other factors associated with an increased risk of death included age > 60 (p <0.001), higher TNMB stage at diagnosis (log rank p<0.001), advanced nodal stage, (p=0.005), positive peripheral blood flow (p=0.010), TCR clonality in the blood (p=0.039), LCT (p< 0.001), elevated LDH (p<0.001), and elevated WBC (p<0.001), while hypopigmented MF was associated with a decreased risk of death (0.28 (0.09-0.90), p=0.021). On multivariable survival analysis controlling for hypopigmented MF, LCT, and stage at diagnosis, only age > 60 (3.32 (2.00-5.51), p<.001) and progression to advanced stage (4.02 (2.38-6.79), p<0.001) remained statistically significant. Conclusions We demonstrate that progression to advanced stage is associated with several baseline laboratory and disease characteristics, which bear immediate clinical relevance to the work up and staging of early stage MF. These data suggest that consistent staging and laboratory analyses with imaging for lymph node assessment, peripheral blood flow cytometry, and TCR in all newly diagnosed MF patients may aid in identifying patients at risk for progression to advanced stage disease. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Myeloid/Lymphoid Neoplasm with Eosinophilia and a Novel RUFY1-Pdgfrb Rearrangement

Myeloid/lymphoid neoplasms associated with eosinophilia (MLN-Eo) and tyrosine kinase fusion genes include rearrangements of PDGFRB with over 30 different partner genes, most commonly ETV6-PDGFRB. Rearrangements are evident by cytogenetic analysis and fluorescence in situ hybridization (FISH) break-apart probes. Herein, we describe a novel rearrangement partner for PDGFRB. A 25-year-old man with a medical history significant for gout and hypertension presented to medical care after several days of progressive dyspnea, chest pain, fatigue, epistaxis, and rash. Physical exam revealed palpable cervical, axillary, and inguinal lymphadenopathy and massive splenomegaly. By CT scan the spleen measured 25 cm and diffuse lymphadenopathy was identified in the chest, abdomen and pelvis with the largest lymph node mass measuring 8.9 x 2.5 cm. Transthoracic echocardiogram showed normal heart function and no evidence of myocardial injury. The patient subsequently developed respiratory failure requiring intubation and mechanical ventilation, shock requiring vasopressors, and renal failure requiring renal replacement therapy. Initial laboratory evaluation demonstrated a leukocytosis to 83.3 x 10 9/L with neutrophilic predominance with left shift and eosinophilia (10% of WBCs, absolute eosinophil count of 8.2 x 10 9/L); hemoglobin of 8.3 g/dL and hematocrit of 25%; and thrombocytopenia to 50 x 10 9/L. Ferritin was 660 ng/mL, lactate dehydrogenase 384 U/L, and uric acid 10.4 mg/dL. Secondary causes of eosinophilia including infection, immunodeficiency, atopy, medications, and rheumatologic disease were ruled out. The patient was positive for strongyloides IgG antibodies and received ivermectin. Core biopsy of a lymph node was non-diagnostic and could not repeated safely due to progressive severe thrombocytopenia. Skin biopsy demonstrated a perivascular leukocytoclasis, but no abnormal B or T cell population. Bone marrow aspirate and biopsy revealed a hypercellular marrow (90%) with mild trilineage dysplasia, granulocytic hyperplasia, moderate reticulin fibrosis, and slightly increased mast cells. Blasts were not increased and no hemophagocytic histiocytes were identified. Eosinophils accounted for 6.9% of myeloid cells. Flow cytometry did not reveal an abnormal B or T lymphoid, blast or myeloid population. Peripheral blood flow cytometry did not reveal an abnormal B or T-cell population and T-cell rearrangement studies showed an oligoclonal population. No clonal B cell population was identified. FISH, which identified a rearrangement of PDGFRB in 28% of cells, confirmed the diagnosis. Karyotype analysis revealed an abnormal male karyotype with a paracentric inversion of 5q with breakpoints at 5q32 and 5q35. FusionPlex® Solid Tumor Panel (Clinical Genomics Laboratory, University of Washington SOM) identified a novel fusion between RUFY1 and PDGFRB. RUFY1 is expressed in most tissues and encodes a protein that contains a RUN domain and a FYVE-type zinc finger domain and plays a role in early endosomal trafficking (Figure). We are currently demonstrating the fusion is oncogenic and sensitive to tyrosine kinase inhibition in Ba/F3 cells. The patient's remarkable clinical response, however, supports imatinib sensitivity and is in keeping with other published reports of MLN-Eo with PDGFRB rearrangements. Initial treatment included high dose steroids for 7 days and hydroxyurea briefly. Imatinib 400 mg daily was started, then decreased to 200 mg daily due to gastrointestinal toxicity. Follow-up is limited (8 weeks). However, the patient has recovered clinically. Six weeks after starting imatinib he had renal recovery and has achieved a complete hematologic response except for mild anemia due to resolving acute kidney injury. Splenomegaly and peripheral lymphadenopathy have resolved. PDGFRB FISH has declined to 9%. Inversions of chromosome 5 have very rarely been described in association with eosinophilia, but only one report has specifically identified a rearrangement of PDGFRB. This report described a novel rearrangement involving exons 12 to 23 of PDGFRB at 5q32 and the 5′ (UTR) of G3BP1 at 5q33.1. Notably, this specific rearrangement was undetectable by PDGFRB break-apart FISH. These reports and ours highlight the clinical relevance of NGS in identifying novel rearrangement partners. Furthermore, patient-specific ddPCR assays can be designed for sensitive monitoring. Figure 1 Figure 1. Disclosures Oehler: BMS: Consultancy; OncLive: Honoraria; Pfizer: Research Funding; Takeda: Consultancy; Blueprint Medicines: Consultancy.