Paroxysmal nocturnal hemoglobinuria-related thrombosis in the era of novel therapies: a 2043-patient-year analysis.

ABSTRACT: Thrombophilia is one of the principal features of paroxysmal nocturnal hemoglobinuria (PNH) and constitutes the main cause of disease morbidity/mortality. Anticomplement treatment has revolutionized the natural history of PNH, with control of the hemolytic process and abolition of thrombotic events (TEs). However, no guidelines exist for the management of thromboembolic complications in this setting, with type and duration of anticoagulation depending on individual practices. Besides, a scarcity of data is present on the efficacy of direct oral anticoagulants (DOACs). Herein, we accrued a large real-world cohort of patients with PNH from 4 US centers to explore features, predictors of TE, and anticoagulation strategies. Among 267 patients followed up for a total of 2043 patient-years, 56 (21%) developed TEs. These occurred at disease onset in 43% of cases, involving more frequently the venous system, typically as Budd-Chiari syndrome. Rate of TEs was halved in patients receiving complement inhibitors (21 vs 40 TEs per 1000 patient-years in untreated cases, with a 2-year cumulative incidence of thrombosis of 3.9% vs 18.3%, respectively), and varied according to PNH granulocytes and erythrocytes clone size, type, disease activity parameters, as well as number (≥2 mutations, or less) and variant allelic frequency of PIGA mutations. Anticoagulation with warfarin (39%), DOACs (37%), and low-molecular weight heparin (16%) was administered for a median of 29 months (interquartile range [IQR], 9-61.8). No thrombotic recurrence was observed in 19 patients treated with DOACs at a median observation of 17.1 months (IQR, 8.9-45) whereas 14 cases discontinued anticoagulation without TE recurrence at a median time of 51.4 months (IQR, 29.9-86.8).

Continuous monitoring is superior to manual measurements in detecting vital sign deviations in patients with COVID-19.

BACKGROUND: Patients admitted to the emergency care setting with COVID-19-infection can suffer from sudden clinical deterioration, but the extent of deviating vital signs in this group is still unclear. Wireless technology monitors patient vital signs continuously and might detect deviations earlier than intermittent measurements. The aim of this study was to determine frequency and duration of vital sign deviations using continuous monitoring compared to manual measurements. A secondary analysis was to compare deviations in patients admitted to ICU or having fatal outcome vs. those that were not. METHODS: Two wireless sensors continuously monitored (CM) respiratory rate (RR), heart rate (HR), and peripheral arterial oxygen saturation (SpO2 ). Frequency and duration of vital sign deviations were compared with point measurements performed by clinical staff according to regional guidelines, the National Early Warning Score (NEWS). RESULTS: SpO2 < 92% for more than 60 min was detected in 92% of the patients with CM vs. 40% with NEWS (p < .00001). RR > 24 breaths per minute for more than 5 min were detected in 70% with CM vs. 33% using NEWS (p = .0001). HR ≥ 111 for more than 60 min was seen in 51% with CM and 22% with NEWS (p = .0002). Patients admitted to ICU or having fatal outcome had longer durations of RR > 24 brpm (p = .01), RR > 21 brpm (p = .01), SpO2 < 80% (p = .01), and SpO2 < 85% (p = .02) compared to patients that were not. CONCLUSION: Episodes of desaturation and tachypnea in hospitalized patients with COVID-19 infection are common and often not detected by routine measurements.

Days alive and out of hospital following primary surgery for oral cavity squamous cell carcinoma.

BACKGROUND: Days Alive and Out of Hospital (DAOH) is a recently introduced, readily obtainable postoperative outcome measure method that expresses procedure and disease-associated morbidity and mortality. In this study, we evaluated DAOH with 30- and 365-days follow-up periods after primary surgery (DAOH30 and DAOH365, respectively) for patients with oral cavity squamous cell carcinoma (OSCC). The aim of this study is to identify patient-, procedure- and disease-associated risk factors for patients treated with primary surgery for primary OSCC. MATERIAL AND METHODS: This retrospective cohort study from a prospective collected database represents patients from Eastern Denmark surgically treated for primary OSCC in the period 2000-2014. DAOH30 and DAOH365 were calculated and associations with patient characteristics including comorbidity, tumor characteristics, clinical outcomes such as length of stay, readmission, and mortality were evaluated. Tests for difference and significance between groups were assessed with Mann-Whitney U test and quantile linear regression. RESULTS: We included 867 patients (63% males, median age: 63 years (IQR 56-70 years)). Median DAOH30 and DAOH365 after OSCC surgery were 25 days (IQR 21-27 days) and 356 days (IQR 336-360 days), respectively. Alcohol consumption had a significant association with a lower DAOH365, p < 0.01, but not with DAOH30. Advanced T-stage, adjuvant radiotherapy (RT) and increased Charlson Comorbidity Index (CCI) score was significantly associated with a lower DAOH30 and DAOH365. CONCLUSION: In this population-based study in OSCC patients treated with primary surgery, we found that DAOH after 30 days was 25 days (83%), while DAOH after 365 days was 356 days (98%). Advanced T-stage acts as a predictor for significant DAOH30 and DAOH365 reduction while excessive alcohol consumption predicts a significant DAOH365 reduction. Readmission within 30 days following surgery was associated with further readmission within one year.

High-dose preoperative glucocorticoid for prevention of emergence and postoperative delirium in liver resection: A double-blinded randomized clinical trial substudy.

BACKGROUND: Emergence delirium (ED) and postoperative delirium (POD) are associated with increased morbidity and mortality and occur in up to one-third of patients undergoing major non-cardiac surgery, where the underlying pathogenesis is multifactorial, including increased inflammation. We aimed to assess the effect of pre-operative high- versus low-dose glucocorticoid on the occurrence of ED and POD. METHODS: This was a substudy from a randomized, double-blinded clinical trial. Patients ≥18 years, undergoing open liver resection were randomized 1:1 to high-dose (HD, 10 mg/kg methylprednisolone) or low-dose (LD, 8 mg dexamethasone) glucocorticoid and assessed for ED and POD for a maximum of 4 days during hospitalization. The 3-min Diagnostic Interview for CAM-defined delirium (3D-CAM) was used for assessment, 15 and 90 min after arrival in the post-anesthesia care unit (PACU), and subsequently once daily in the ward. RESULTS: Fifty-three patients were included in this secondary substudy (26 HD-group and 27 LD-group). ED occurred in n = 5 HD versus n = 6 LD patients 15 min after PACU arrival. At 90 min after PACU arrival, 4 patients had ED, all from LD-group, and resulted in significantly longer PACU admission, 273 versus 178 min in ED versus Non-ED patients. During the first 4 days in the ward, n = 5 patients had at least one occurrence of POD, all from LD-group. CONCLUSIONS: The primary finding of the current substudy was a lower occurrence of ED/POD in the PACU 90 min after arrival and during the first four postoperative days in patients receiving high-dose glucocorticoid compared with patients receiving low-dose glucocorticoid. The two study groups were not evenly balanced concerning known explanatory factors, i.e., age and size of surgery, which calls for larger studies to elucidate the matter.

Personalized Risk Schemes and Machine Learning to Empower Genomic Prognostication Models in Myelodysplastic Syndromes.

Myelodysplastic syndromes (MDS) are characterized by variable clinical manifestations and outcomes. Several prognostic systems relying on clinical factors and cytogenetic abnormalities have been developed to help stratify MDS patients into different risk categories of distinct prognoses and therapeutic implications. The current abundance of molecular information poses the challenges of precisely defining patients' molecular profiles and their incorporation in clinically established diagnostic and prognostic schemes. Perhaps the prognostic power of the current systems can be boosted by incorporating molecular features. Machine learning (ML) algorithms can be helpful in developing more precise prognostication models that integrate complex genomic interactions at a higher dimensional level. These techniques can potentially generate automated diagnostic and prognostic models and assist in advancing personalized therapies. This review highlights the current prognostication models used in MDS while shedding light on the latest achievements in ML-based research.

Early postoperative recovery after peri-acetabular osteotomy: A double-blind, randomised single-centre trial of 48 vs. 8 mg dexamethasone.

BACKGROUND: Peri-acetabular osteotomy is the joint-preserving treatment of choice in young adults with hip dysplasia but is associated with intense pain and high opioid consumption postoperatively. OBJECTIVES: To investigate whether 48 mg of pre-operative dexamethasone was superior to a standard dose of 8 mg on reducing pain in the immediate postoperative phase. DESIGN: A randomised, double-blind trial. SETTING: Single-centre, primary facility. May 2017 to August 2019. PATIENTS: At least 18 years undergoing peri-acetabular osteotomy. INTERVENTIONS: Patients were randomised 1 : 1 to 48 or 8 mg dexamethasone intravenous (i.v.) as a single pre-operative injection. All patients received a standardised peri-operative protocol, including pre-operative acetaminophen and gabapentin, total i.v. anaesthesia and local anaesthetic catheter based wound administration. MAIN OUTCOME MEASURE: Number of patients with moderate/severe pain [>3 on a numeric rating scale (NRS)] in the immediate postoperative phase. RESULTS: Sixty-four patients (32 in each group) were included, and their data analysed. At some point from tracheal extubation until transfer to the ward, the NRS was more than 3 in 75% (24/32) of the 48 mg group and in 66% (21/32) in the 8 mg group, odds ratio 1.571 (95% CI, 0.552 to 4.64), P = 0.585. Patients in the 48 mg group received less opioid [cumulative rescue analgesics, oral morphine equivalents (OMEQ)] during postoperative days 0-4: median [IQR] OMEQ was 36 [15 to 85] mg vs. 79 [36 to 154] mg in the 48 and 8 mg group, respectively, P = 0.034. There were no statistically significant differences regarding complications, rate of infections or readmissions. CONCLUSION: Forty-eight milligram of dexamethasone did not reduce pain in the immediate postoperative phase compared with an 8 mg dose. We observed insignificantly lower pain scores and significantly lower cumulated opioid requirements in the 48 mg group during the first four postoperative days. TRIAL REGISTRATION: Clinicaltrials.gov, NCT03161938, EudraCT (2017-000544-1).

Dexamethasone Dose and Early Postoperative Recovery after Mastectomy: A Double-blind, Randomized Trial.

BACKGROUND: Pain and nausea are the most common challenges in postoperative recovery after mastectomy. Preventive measures include multimodal analgesia with preoperative glucocorticoid. The aim of this study was to investigate whether 24 mg of preoperative dexamethasone was superior to 8 mg on early recovery after mastectomy in addition to a simple analgesic protocol. METHODS: In a randomized, double-blind trial, patients 18 yr of age or older having mastectomy were randomized 1:1 to 24 mg or 8 mg dexamethasone, and all received a standardized anesthetic and surgical protocol with preoperative acetaminophen, total intravenous anesthesia, and local anesthetic wound infiltration. The primary endpoint was number of patients transferred to the postanesthesia care unit according to standardized discharge criteria (modified Aldrete score). Secondary endpoints included pain and nausea at extubation, transfer from the operating room and upon arrival at the ward, length of stay, seroma occurrence, and wound infections. RESULTS: One hundred thirty patients (65 in each group) were included and analyzed for the primary outcome. Twenty-three (35%) in each group met the primary outcome, without significant differences in standardized discharge scores (odds ratio, 1.00 [95% CI, 0.49 to 2.05], P > 0.999). More patients had seroma requiring drainage in the 24 mg versus 8 mg group, 94% versus 81%, respectively (odds ratio, 3.53 [95% CI, 1.07 to 11.6], P = 0.030). Median pain scores were low at all measured time points, numeric rating scale less than or equal to 2 versus less than or equal to 1 in the 24 mg versus 8 mg group, respectively. Six patients in each group (9%) experienced nausea at any time during hospital stay (P > 0.999). Length of stay was median 11 and 9.2 h in the 24 and 8 mg group, respectively (P = 0.217). CONCLUSIONS: The authors found no evidence of 24 mg versus 8 mg of dexamethasone affecting the primary outcome regarding immediate recovery after mastectomy. The authors observed a short length of stay and low pain scores despite a simple analgesic protocol.

Biomimetic Mussel Adhesive Inspired Anchor to Design ZnO@Poly(3-Hexylthiophene) Hybrid Core@Corona Nanoparticles.

The functionalization of zinc oxide (ZnO) nanoparticles by poly(3-hexylthiophene) (P3HT) brush is completed by the combination of a mussel inspired biomimetic anchoring group and Huisgen cyclo-addition "click chemistry." Herein, the direct coupling of an azide modified catechol derivative with an alkyne end-functionalized P3HT is described. This macromolecular binding agent is used to access core@corona ZnO@P3HT with a stable and homogeneous conjugated organic corona. Preliminary photoluminescence measurement proves an efficient electron transfer from the donor P3HT to the acceptor ZnO nanoparticles upon grafting, thus demonstrating the potential of such a combination in organic electronics.

Clonal hematopoiesis-derived therapy-related myeloid neoplasms after autologous hematopoietic stem cell transplant for lymphoid and non-lymphoid disorders.

Therapy-related myeloid neoplasms (tMN) are complications of cytotoxic therapies. Risk of tMN is high in recipients of autologous hematopoietic stem cell transplantation (aHSCT). Acquisition of genomic mutations represents a key pathogenic driver but the origins, timing and dynamics, particularly in the context of preexisting or emergent clonal hematopoiesis (CH), have not been sufficiently clarified. We studied a cohort of 1507 patients undergoing aHSCT and a cohort of 263 patients who developed tMN without aHSCT to determine clinico-molecular features unique to post-aHSCT tMN. We show that tMN occurs in up to 2.3% of patients at median of 2.6 years post-AHSCT. Age ≥ 60 years, male sex, radiotherapy, high treatment burden ( ≥ 3 lines of chemotherapy), and graft cellularity increased the risk of tMN. Time to evolution and overall survival were shorter in post-aHSCT tMN vs. other tMN, and the earlier group's mutational pattern was enriched in PPM1D and TP53 lesions. Preexisting CH increased the risk of adverse outcomes including post-aHSCT tMN. Particularly, antecedent lesions affecting PPM1D and TP53 predicted tMN evolution post-transplant. Notably, CH-derived tMN had worse outcomes than non CH-derived tMN. As such, screening for CH before aHSCT may inform individual patients' prognostic outcomes and influence their prospective treatment plans. Presented in part as an oral abstract at the 2022 American Society of Hematology Annual Meeting, New Orleans, LA, 2022.

Impact of Extraosseous Extramedullary Disease on Outcomes of Patients with Relapsed-Refractory Multiple Myeloma receiving Standard-of-Care Chimeric Antigen Receptor T-Cell Therapy.

The presence of extramedullary disease (EMD) has been associated with poor outcomes in patients with relapsed-refractory multiple myeloma (RRMM). Herein, we report the outcomes of RRMM patients who were treated with standard-of-care (SOC) chimeric antigen receptor (CAR) T-cell therapy and had active extraosseous EMD before the infusion. Data were retrospectively collected from patients at three US institutions with the intent to receive SOC CAR T. Responses were assessed per the International Myeloma Working Group criteria. A total of 152 patients proceeded with infusion, of whom 47 (31%) had EMD (EMD group) and 105 (69%) did not (non-EMD group). Baseline patient characteristics were comparable between the two groups. The EMD group had a higher incidence of high-grade CRS, steroid and anakinra use, and thrombocytopenia on day +30 compared to the non-EMD group. In addition, the EMD group had an inferior overall response rate (58% vs 96%, p < 0.00001), median progression-free survival (PFS) (5.1 vs 12.4 months; p < 0.0001), and overall survival (OS) (12.2 vs 27.5 months; p = 0.00058) compared to the non-EMD group. We further subdivided the non-EMD patients into those with paramedullary disease (PMD-only group, n = 26 [17%]) and those with neither EMD nor PMD (bone marrow-contained group or BM-only group, n = 79 [52%]). Patients with PMD-only had similar median PFS (11.2 vs 13.6 months, p = 0.3798) and OS (not reached [NR] vs 27.5 months, p = 0.6446) compared to patients with BM-only disease. However, patients with EMD exhibited inferior median PFS (5.1 vs 13.6 months, p < 0.0001) and OS (12.2 vs 27.5, p = 0.0008) compared to patients in the BM-only group. Treatment with SOC CAR T yielded meaningful clinical outcomes in real-world RRMM patients with extraosseous EMD, though responses and survival outcomes were suboptimal compared to patients without EMD. The presence of only EMD but not PMD was associated with significantly worse survival outcomes following the CAR T infusion.

Molecular and clinical analyses of PHF6 mutant myeloid neoplasia provide their pathogenesis and therapeutic targeting.

PHF6 mutations (PHF6MT) are identified in various myeloid neoplasms (MN). However, little is known about the precise function and consequences of PHF6 in MN. Here we show three main findings in our comprehensive genomic and proteomic study. Firstly, we show a different pattern of genes correlating with PHF6MT in male and female cases. When analyzing male and female cases separately, in only male cases, RUNX1 and U2AF1 are co-mutated with PHF6. In contrast, female cases reveal co-occurrence of ASXL1 mutations and X-chromosome deletions with PHF6MT. Next, proteomics analysis reveals a direct interaction between PHF6 and RUNX1. Both proteins co-localize in active enhancer regions that define the context of lineage differentiation. Finally, we demonstrate a negative prognostic role of PHF6MT, especially in association with RUNX1. The negative effects on survival are additive as PHF6MT cases with RUNX1 mutations have worse outcomes when compared to cases carrying single mutation or wild-type.

The Heterogeneous Complexity of Myeloid Neoplasm: Multi-Level Approaches to Study the Disease.

Myeloid neoplasms (MNs) include a spectrum of bone marrow malignancies that result from the clonal expansion and arrest of differentiation of myeloid progenitor cells [...].

High-grade large cell neuroendocrine carcinoma of the esophagus: a case report and review of the literature.

BACKGROUND: Neuroendocrine carcinomas are extremely rare in the esophagus as they represent less than 0.04% of all neuroendocrine tumors. To date, only 14 cases of poorly differentiated, high-grade esophageal NEC have been described in the literature. The majority of these patients presented with typical dysphagia symptoms. Due to its rarity, no standardized guidelines have been proposed to treat esophageal neuroendocrine carcinoma, although general recommendations suggest surgery with adjuvant chemoradiotherapy as the treatment of choice. CASE PRESENTATION: A 67-year-old previously healthy White male presented with a year-long intermittent nonspecific retrosternal discomfort, with the absence of any other symptoms. Esophagogastroduodenoscopy revealed an ulcerative mass in his lower esophagus, with concern of malignancy. Endoscopic ultrasound-guided biopsy revealed poorly differentiated neuroendocrine carcinoma of the esophagus with metastasis to a diaphragmatic lymph node. He was treated with neoadjuvant chemoradiation followed by surgery, and he has been in remission for over 5 years. CONCLUSION: Here, we review the literature and report a unique case of a patient with a vague presentation of esophageal neuroendocrine carcinoma as he enters his sixth year of survival following neoadjuvant chemoradiotherapy.

Endocrinopathies from checkpoint inhibitors: Incidence, outcomes, and management.

Immune checkpoint inhibitors are used more and more to treat several types of cancer, significantly extending cancer-free survival. However, concerns are growing about their toxic effects, which are many and varied. Endocrinopathies are some of the most frequently reported adverse effects, and thyroid dysfunction is the most common of these. Here, we review the incidence and severity of each immune checkpoint inhibitor-related endocrinopathy, possible factors related to toxicity risk, and principles of management.

What's Next after Hypomethylating Agents Failure in Myeloid Neoplasms? A Rational Approach.

Hypomethylating agents (HMA) such as azacitidine and decitabine are a mainstay in the current management of patients with myelodysplastic syndromes/neoplasms (MDS) and acute myeloid leukemia (AML) as either single agents or in multidrug combinations. Resistance to HMA is not uncommon, and it can result due to several tumor cellular adaptations. Several clinical and genomic factors have been identified as predictors of HMA resistance. However, the management of MDS/AML patients after the failure of HMA remains challenging in the absence of standardized guidelines. Indeed, this is an area of active research with several potential therapeutic agents currently under development, some of which have demonstrated therapeutic potential in early clinical trials, especially in cases with particular mutational characteristics. Here, we review the latest findings and give a rational approach for such a challenging scenario.

The status of bladder cancer research worldwide, a bibliometric review and recommendations.

Background: Healthcare system costs associated with bladder cancer treatment are among the highest of curable malignancies, and prognosis in advanced disease remains poor. This scoping review examines the worldwide status of bladder cancer research by systematically mapping publications, exploring research topics, support, gaps and limitations that need to be addressed. Methods: We searched the Web of Science database for publications using controlled vocabulary. Results were limited between 2000-2020, and were included in our study based on pre-specified eligibility criteria. Data used for analysis included author's names, country of affiliation, language, journal, citations, and funding. Analysis was conducted using Biblioshiny R and SPSS. Research topics were identified according to sub-filters of title words and strings pre-determined by authors. Results: 40,657 results were retrieved, of which 19,976 original articles and reviews met the pre-specified criteria. 92% of the publications originated from 20 countries and were included in the analysis. Trends show an increase across the world, most of which is due to increasing contributions from USA and China. An increase by 1000% in funded publications has been achieved. Studies focused on Surgery, Pathology, and Diagnosis, while Radiotherapy, Palliative care, quality of life and Epidemiology were the least described. Genetics had the most increase while being the most funded. GDP, incidence, prevalence and mortality were each significantly positively correlated with overall bladder cancer research output. Conclusion: This review described the evolution of bladder cancer research. It also identified significant gaps and limitations that need to be highlighted as priority areas for research investment.

Risk of Venous Thromboembolism in Multiple Myeloma Patients During the Immediate Peri-Autologous Hematopoietic Cell Transplantation Phase.

Venous thromboembolism (VTE) is a serious complication commonly experienced in cancer patients. Incidence of VTE typically brings poor prognosis as it represents the second most common cause of mortality in cancer patients just after the malignancy itself. Studies suggest that multiple myeloma (MM) is among the malignancies with further enhanced risk of VTE, especially in patients undergoing autologous hematopoietic cell transplantation (AHCT). However, risk factors and preventative approaches remain poorly explored. Here, we explore the incidence of VTE in MM patients undergoing AHCT, while also highlighting risk factors and preventions that may aid in preventing VTE in patients who are at higher risk.

Deciphering treatment patterns in non-severe/moderate aplastic anemia: an international observational study.

Non-severe aplastic anemia is a rare bone marrow failure disorder characterized by variable degrees and combination of cytopenias, with limited data on management and outcome. We describe a large multicentric series of 259 patients, focusing on clinical and molecular features, treatment, evolution, and survival. The majority required treatment with cyclosporine (CyA) alone (N = 84) or in combination with anti-thymocyte globulin (ATG,44) or eltrombopag (20), eltrombopag alone (10), or others (25) including androgens. Similar outcomes were observed across different strategies, with a 6-month overall response rate of 73% for CyA, 74% for ATG plus CyA, 68% for CyA plus eltrombopag, 87% for eltrombopag, and 79% for others. Notably, 56 patients (39%), mainly receiving CyA plus eltrombopag, achieved a trilineage response (p = 0.02). Progression to myeloid neoplasms was limited (8%) and not related to mutational status. Hemolytic PNH developed in 10% of cases, being predicted by detection of small clones at diagnosis. Survival was negatively impacted by age, male gender, LDH, platelets/erythrocyte transfusion need, and somatic mutations by NGS, and positively by higher neutrophils at diagnosis, PNH clones, and trilineage response at 6 and 12 months. Multivariable analysis confirmed the detrimental role of age and the favorable association with PNH clone and trilineage response at 6 months.