Veno-occlusive Research Articles

In vitro grafting of hepatic spheroids and organoids on a microfluidic vascular bed

With recent progress in modeling liver organogenesis and regeneration, the lack of vasculature is becoming the bottleneck in progressing our ability to model human hepatic tissues in vitro. Here, we introduce a platform for routine grafting of liver and other tissues on an in vitro grown microvascular bed. The platform consists of 64 microfluidic chips patterned underneath a 384-well microtiter plate. Each chip allows the formation of a microvascular bed between two main lateral vessels by inducing angiogenesis. Chips consist of an open-top microfluidic chamber, which enables addition of a target tissue by manual or robotic pipetting. Upon grafting a liver microtissue, the microvascular bed undergoes anastomosis, resulting in a stable, perfusable vascular network. Interactions with vasculature were found in spheroids and organoids upon 7 days of co-culture with space of Disse-like architecture in between hepatocytes and endothelium. Veno-occlusive disease was induced by azathioprine exposure, leading to impeded perfusion of the vascularized spheroid. The platform holds the potential to replace animals with an in vitro alternative for routine grafting of spheroids, organoids, or (patient-derived) explants.

Donor-derived T cells specific for tumor antigen and multiple pathogens for prevention of relapse and infection after haemopoietic stem cell transplant (HSCT) for myeloid malignancies (the INTACT trial).

7039 Background: Disease relapse and infection cause significant morbidity and mortality after allogeneic HSCT for acute myeloid leukemia (AML) and myelodysplasia (MDS). Wilms’ tumour 1 (WT1) and preferentially expressed antigen in melanoma (PRAME) are both commonly overexpressed in these conditions. We assessed the safety of a novel combination of tumour associated antigen (TAA) and multipathogen (MP) specific T cells administered prophylactically after HSCT in a phase 1 trial. Methods: Patients with overexpression of WT1 or PRAME by ddPCR on diagnostic tumour samples were eligible. TAA and MP specific T cells were ex vivo expanded from stem cell donors by stimulating apheresis derived mononuclear cells with tumour, viral or fungal peptides. T cells specific for CMV, EBV, Adenovirus (AdV) and Aspergillus (Asp) antigens were produced separately and pooled in equal parts into a MP product. Patients received 1 infusion of MP specific and up to 4 infusions of TAA specific T cells at 4-weekly intervals from 28 days post HSCT (cell dose 2x107/m2 per infusion). Results: Ten HSCT recipients have received a total of 38 infusions. Median age was 48 years (17-67), disease AML (n = 6) or high risk MDS (n = 4), DRI intermediate (n = 4) or high (n = 6), conditioning myeloablative (n = 8) or reduced intensity (n = 2), donor source sibling (n = 7) or matched unrelated (n = 3). Median expression of WT1 on diagnostic bone marrow was 1442 copies/104 copies ABL (0-3870), PRAME 131 copies/104 copies ABL (4-12300). Patients received WT1 (n = 4), PRAME (n = 5) or both WT1 and PRAME specific T cells (n = 1). Mean tumour antigen specificity in the TAA product was 1.4% and 13.3% of CD3+ cells for WT1 and PRAME respectively. Mean total pathogen specificity in the MP product was approximately 44% (CMV = 14.0%, EBV = 14.8% and AdV = 11.6% of CD3+ cells, Asp = 14.8% of CD4+ cells). All patients received MP specific T cells. No immediate infusion related adverse events were reported. At a median 540 days post transplant (80-1265), 8 of 10 patients remain alive and in complete disease remission. Two patients did not proceed after completing 3 of 5 infusions due to the development of graft versus host disease (GVHD); both are in remission. There were 2 deaths; one patient with progressive disease who had persistent high risk MDS pre and post HSCT, and one with multiorgan failure who had multiple post transplant complications (venoocclusive disease, sepsis, GVHD), both prior to infusion. Low level viral reactivations occurred (CMV n = 5, EBV n = 7, BKV n = 3, HHV6 n = 4, AdV n = 1), however none required treatment and there were no cases of viral tissue disease or EBV PTLD. There were no invasive fungal infections. Conclusions: Prophylactic infusions of donor derived WT1/PRAME and multipathogen specific T cells post HSCT are well tolerated and associated with low rates of infection and relapse. Clinical trial information: NCT02895412.

Homogeneity of pathological response (PR) and histopathological growth pattern (HGP) in resected colorectal liver metastases (CRLM) are associated with favorable survival outcome after surgery.

3596 Background: Surgical resection of CRLM aims to maximize patient survival. However, recurrence rates remain high post-surgery. We previously reported the prognostic relevance of tumor regression grading (TRG) and HGP of resected CRLM. Several studies reported the association of tumoral heterogeneity with anti-cancer drug resistance and prognosis. This study aims to explore tumoral heterogeneity for TRG and HGP in patients resected for CRLM and its prognostic implication. Methods: Tumor homogeneity for PR and HGP was evaluated in 2 independent cohorts. Cohort 1 included 57 patients (159 CRLMs) resected after chemotherapy/bevacizumab (prospective BEV-ONCO trial). Cohort 2 included 221 patients (582 CRLMs) operated after preoperative treatment or not. TRG (1 to 5 according complete to no response), HGP (desmoplastic, pushing, replacement or mixed) were evaluated for each CRLM. Max-TRG (higher TRG among all the CRLM) was used to define PR. Homogenous TRG (TRG-h) and HGP (HGP-h) was defined when all CRLMs had the same TRG or HGP pattern. HGP homogeneous desmoplastic (HGP-hd) was defined when all CRLM had a desmoplastic HGP. TRG-h, HGP-h and HGP-hd were combined into a homogeneity score (H-score: 0 to 3, 1 point given for each parameter and summed-up). Overall survival (OS for both cohorts), progression-free survival (PFS for cohort 1) and time to relapse (TTR for cohort 2) were estimated using the Kaplan–Meier method and compared by log-rank tests. Cox proportional hazard models were used for univariate and multivariate analyses. Results: Patient and disease characteristics were comparable in both cohorts excepted for preoperative treatment. In cohort 1, TRG-h and HGP-h were significantly associated with a longer PFS (HR = 0.21; 95CI:0.10-0.43, p < 0.001; HR = 0.27; 95CI = 0.14-0.54, p < 0.001) and better OS (HR = 0.23; 95CI = 0.07-0.70, p = 0.010; HR = 0.32; 95CI = 0.10-0.93, p = 0.037). Interestingly, the same significant results were observed in cohort 2 for TTR (TRG-h: HR = 0.60; 95CI = 0.43-0.85, p = 0.004; HGP-h: HR = 0.68; 95CI = 0.49-0.94, p = 0.017) and OS (TRG-h: HR = 0.51;95CI = 0.33-0.80, p = 0.003; HGP-h: HR = 0.63; 95CI = 0.41-0.97, p = 0.034). HGP-h reported a significant association with TRG-h, a Max-TRG < = 3, the absence of HGP replacement and mixed, a desmoplastic pattern, and the absence of sinusoidal obstruction syndrome in both cohorts. H-score was significantly associated with TTR (score 1-2: HR = 0.57; 95CI = 0.38-0.85, p = 0.004; score 3: HR = 0.4; 95CI = 0.24-0.64, p < 0.001) and OS (score 3: HR = 0.31; 95CI = 0.15-0.64, p < 0.001) in univariate analysis and with OS (HR = 0.74; 95CI = 0.59-0.94, p = 0.011) in multivariate analysis (cohort 2). Conclusions: TRG-h and HGP-h are strongly associated with patient’s survival. H-score could be an easy morphological and prognostic score to assess. Validation studies are needed.

Comparison of different treatment modalities for favorable risk acute myeloid leukemia: Standard-dose anthracycline versus high-dose anthracycline versus addition of gemtuzumab ozogamicin.

e19016 Background: The standard remission induction regimen for medically fit patients with AML consists of a backbone of cytarabine & an anthracycline (“7+3” therapy). However, the choice & dose of the anthracycline varies between institutions & practitioner preference, particularly in patients with favorable risk cytogenetics. Gemtuzumab ozogamicin (GO) may improve outcomes in this patient population but is associated with increased toxicities. Methods: We performed a retrospective analysis on medically fit patients ≥ 18 yo with favorable risk AML from 2015-2020 treated with 7+3 at the University of Virginia. Patients were stratified based on standard dose (45 or 60 mg/m2 daunorubicin) (SD) vs higher dose (90 mg/m2 daunorubicin or 12 mg/m2 idarubicin) (HD) of anthracycline vs the addition of GO. Measures included rates of remission, EFS, RFS, and OS as well as rates of treatment-related complications. Results: In total, 58 patients were identified, of which 33 received induction with SD, 19 received HD, & 6 received GO. The majority (75%) of patients were < 60 years old & 93% had de novo AML. The rates of complete remission in the SD, HD & GO groups were 90.9%, 89.5% & 100%, respectively (p = 0.57). EFS at 2-years was 43.9%, 36.7%, & 66.7%, respectively (p = 0.85). RFS at 2-years was 53.0%, 39.0%, & 100%, respectively (p = 0.18). OS at 2-years was similar between all groups (58.9%, 56.9%, & 66.7%, p = 0.92). The rate & duration of cytopenias after induction were similar among all groups (median duration 29 days), however cytopenias were more common in the GO group following consolidation. The rates of major bleeding, admission to the intensive care unit (ICU), and new onset cardiomyopathy (EF < 50%) were higher in the GO group (major bleeding: 0% in SD, 5.3% in HD, 33.3% in GO; ICU admission: 12.1% in SD, 21.1% in HD, 33.3% in GO; cardiomyopathy: 12.1% in SD, 26.3% in HD, 33.3% in GO). The rate of infection, liver dysfunction, & acute renal injury were similar among all groups. No patients developed veno-occlusive disease. Conclusions: Patients receiving GO had a trend toward improved EFS & RFS, however with a similar OS at the expense of higher rates of cytopenias, major bleeding, ICU admission, & cardiotoxicity. Patients receiving HD had a trend toward worse outcomes than those who received SD. A major limitation of our study is the small sample size & single institution experience, however multi-institutional analysis is ongoing for further investigation.[Table: see text]

A phase II study of hyper-CVAD with sequential blinatumomab (Blina), with or without inotuzumab ozogamicin (INO), in adults with newly diagnosed B-cell acute lymphoblastic leukemia (ALL).

7034 Background: Blina and INO are highly effective in relapsed/refractory B-cell ALL and are associated with high rates of measurable residual disease (MRD) clearance. Use of these agents in the frontline setting may improve outcomes. Methods: Patients (pts) 14-59 years of age with newly diagnosed Philadelphia chromosome (Ph)-negative B-cell ALL, including pts who had received no more than 1 prior cycle of chemotherapy, were eligible. Pts received hyper-CVAD alternating with high-dose MTX/Ara-C for up to 4 cycles, followed by 4 cycles of Blina. Pts with CD20+ disease received 8 doses of an anti-CD20 antibody. Eight doses of IT chemotherapy were given. Maintenance was with alternating blocks of POMP (maintenance cycles 1-3, 5-7, 9-11, and 13-15) and Blina (maintenance cycles 4, 8, and 12). Beginning with pt #39, INO at a dose of 0.3 mg/m2 on day 1 and 8 was added to the 2 cycles of MTX/Ara-C and to 2 cycles of Blina (4 total cycles with INO). Results: Characteristics of the 58 treated pts (38 without INO and 20 with INO) are summarized in Table. Among 45 pts with active disease at study entry, 100% achieved CR. Overall, 76% achieved MRD negativity by flow cytometry after induction and 95% at any time over the course of therapy. The median follow-up of the entire cohort is 26 months (range, 3-61+ months). Overall, 5 pts (9%) relapsed, 18 (31%) underwent transplant in first remission (including an additional 2 pts who relapsed post-transplant), 2 (3%) died in CR, and 33 (57%) remain in continuous remission without transplant. All relapses occurred in pts with established poor-risk features and no relapses have occurred beyond 2 years. For the entire cohort, the estimated 3-year OS is 85% and the 3-year continuous remission duration is 84%. No relapses or deaths have occurred in the INO group, and the estimated 1-year OS is 100%. Treatment was overall well-tolerated. One patient discontinued Blina due to recurrent grade 2 neurotoxicity. No pts have discontinued INO due to toxicity and no cases of veno-occlusive disease have been observed. Conclusions: Hyper-CVAD with sequential Blina is highly effective as frontline treatment of Ph-negative B-cell ALL. The addition of INO to this regimen was safe and early results are encouraging, with no relapses observed to date. Clinical trial information: NCT01371630. [Table: see text]

Updated results from a phase II study of mini-hyper-CVD (mini-HCVD) plus inotuzumab ozogamicin (INO), with or without blinatumomab (Blina), in older adults with newly diagnosed Philadelphia chromosome (Ph)-negative B-cell acute lymphoblastic leukemia (ALL).

7011 Background: INO and Blina improve overall survival (OS) in patients (pts) with relapsed/refractory B-ALL. The use of these agents in older adults in the frontline setting may allow for use of less chemotherapy and improve remission duration and OS compared to standard therapies. Methods: Pts ≥60 years with newly diagnosed Ph-negative B-cell ALL received mini-HCVD for up to 8 cycles. Initially, INO was given at 1.3-1.8mg/m2 on day 3 of cycle 1 and 0.8-1.3mg/m2 on day 3 of cycles 2-4. Rituximab (if CD20+) and prophylactic IT chemotherapy were given for the first 4 cycles. Responding pts received POMP maintenance for up to 3 years. Beginning with pt #50, INO was given in fractionated doses each cycle (0.6 mg/m2 on day 2 and 0.3 mg/m2 on day 8 of cycle 1; 0.3 mg/m2 on day 2 and 8 of cycles 2-4) and 4 cycles of Blina were given following 4 cycles of mini-HCVD plus INO. Maintenance was with 12 cycles of POMP and 4 cycles of Blina (1 cycle of Blina after 3 cycles of POMP). Results: Characteristics of the 80 pts are shown in Table. 6 pts were in complete remission (CR) at enrollment. Among 74 evaluable pts, 73 (99%) responded (CR in 89%). MRD negativity by flow was achieved in 80% of pts after 1 cycle and in 94% overall. The 30-day mortality rate was 0%. Among 79 responders, 11 (14%) relapsed, 4 (5%) underwent SCT, 33 (42%) remain in ongoing continuous remission, and 31 (39%) died in remission. Notably, 6 pts (8%) developed veno-occlusive disease, 1 after subsequent SCT. With a median follow-up of 55 months, the 5-year continuous remission and OS rates were 76% and 47%, respectively. Age ≥70 and poor-risk cytogenetics were associated with worse outcomes. The inferior outcomes in pts ≥70 years was primarily due to higher rates of death in CR. The 5-year OS for pts age 60-69 years without poor-risk cytogenetics (n=37), age 60-69 with poor-risk cytogenetics (n=13), age ≥70 without poor-risk cytogenetics (n=24) and age ≥70 with poor-risk cytogenetics (n=6) were 69%, 39%, 36% and 0%, respectively. Conclusions: The combination of mini-HCVD plus INO, with or without Blina, in older adults with newly diagnosed Ph-negative ALL resulted in an overall response rate of 99% and a 5-year OS rate of 47%. Particularly favorable outcomes were seen in pts age 60-69 years without poor-risk cytogenetics (5-year OS: 69%). Chemotherapy-free regimens may improve outcomes in pts age ≥70 years, and novel agents/regimens are still needed for those with poor-risk cytogenetics. Clinical trial information: NCT01371630. [Table: see text]

Dyspnoea – a valuable clue in a rare disease diagnosis

Abstract Pulmonary veno-occlusive disease (PVOD) is a rare microvasculopathy associated with dyspnoea, pulmonary arterial hypertension (PAH) and poor prognosis. A 42-year-old female, with a known history of cured thyroid neoplasm, complained of severe inspiratory progressive dyspnoea, chest pain, dry cough and asthenia. The initial investigations established the diagnosis of idiopathic PAH. Specific associated vasodilator treatment was initiated but with sildenafil intolerance. The clinical condition continued deteriorating, and thus the investigations were extended. DLCO was unnaturally low (24%). Angiography detected a minimal left distal CTEPH (not suitable for balloon angioplasty). Genetic test came positive for biallelic mutations of EIF2AK4, suggestive for PVOD. Finally, the diagnostic was changed to PAH in the PVOD context. A decision was made to refer the patient for lung transplant and to associate treprostinil treatment (with slight clinical improvement). Therefore, severe dyspnoea, hypoxia, decreased DLCO and poor response to vasodilator treatment compel physicians to search for PVOD and refer to lung transplant.

Interest of the preventive and curative use of defibrotide on the occurrence and severity of sinusoidal obstruction syndrome after hematopoietic stem cell transplant in children.

Defibrotide (DF) is indicated for the treatment of severe sinusoidal obstruction syndrome (SOS) following hematopoietic stem cell transplantation (HSCT), but its prophylactic use against SOS is not recommended yet. This study describes the impact of the preventive and curative use of DF on reducing the incidence and severity of SOS in children. Patients aged 0–19 years, who received allogenic HSCT after myeloablative conditioning regimen with busulfan or total body irradiation in our comprehensive cancer center, between 2013 and 2017, were included. The Baltimore or modified Seattle criteria were used for SOS diagnosis. SOS was graded using the 2017 European Society for Blood and Marrow Transplantation classification defining severity criteria of SOS in children. SOS occurrence tended to decrease with prophylactic DF, but no significant difference was observed in terms of severity. When not treated with preventive DF, 50% (19/38) of the patients with SOS were graded severe to very severe, but only 37% (7/19) had organ dysfunction. Curative DF was administered at a median of 2 days post‐HSCT, for a median of 6.5 days. The absence of fatal SOS supports the use of early curative DF with acceptable toxicities and questions the optimal duration of DF treatment.

P392 A MULTIMODALITY IMAGING DIAGNOSIS OF A CHALLENGING CASE OF CONCOMITANT GROUP 1 PULMONARY HYPERTENSION AND PARADOXICALLY LOW–FLOW, LOW–GRADIENT AORTIC STENOSIS

Abstract A 76 year old woman was admitted to our hospital for self–limiting dyspnoea (NYHA class III) in oxygen dependence and frequent lipothymia following Valsalva manoeuvres. She was previously admitted to a Spoke Centre for heart failure (HF) with preserved ejection fraction (EF) and a new diagnosis of “pre–capillary pulmonary hypertension (PH)”. Despite a diagnosis of PH of unclear aetiology, she was started on macitentan without being reassessed for functional capacity due to Covid emergency; because of worsening symptoms, she was admitted to our Hub Centre. Resting ECG showed right axis deviation, right ventricle (RV) hypertrophy, first–degree atrioventricular block and right bundle branch block. Transthoracic echocardiography (TTE) showed reduced left ventricular (LV) volume with preserved EF (diastolic volume= 37 ml, EF = 88%), severe right atrial and RV dilation with flattening of the interventricular septum, estimated pulmonary artery systolic pressure (PASP) of 124 mmHg, and moderate calcific aortic stenosis (peak aortic velocity 3.3 m/s, mean gradient 25 mmHg, valve area 1.1 cm2). Right and left heart catheterization showed severe pre–capillary PH (mean pulmonary pressure 60 mmHg, mean wedge 11 mmHg, pulmonary vascular resistance 14.41 WU), a severe aortic valve stenosis (aortic valve area 0.68 cmq and peak–to–peak gradient 25 mmHg, slight reduction of cardiac index 2.04 l/min/mq) and no significant coronary artery disease. The degree of aortic stenosis was considered as moderate–severe by integrating data of transesophageal echocardiography (planimetric area 1cm2) and assessment of calcium score (1615 Agatson units). Pneumological causes, chronic thromboembolic PH, rheumatologic diseases, HIV infection, paraneoplastic origin and veno–occlusive disease were all ruled out as potential PH causes and a diagnosis of Idiopathic pulmonary arterial hypertension (IPAH) was finally made. The Heart Team established the best therapeutic option was a transcatheter aortic valve replacement (TAVI) allowing better haemodynamic tolerability of PH therapy. The patient underwent TAVI and was started on PH therapy; a complete atrio–ventricular block developed after the procedure, requiring permanent pacemaker (PM) implantation. Unfortunately, few days later, the patient died following pacemaker’s lead dislocation. Conclusion PH has a diverse aetiology, and prognosis is generally poor, especially in patients with severe comorbidities.

Anesthetic concerns in recipients of hematopoietic stem cell transplant.

Dear Editor, Since the advent of bone marrow transplant in 1957, our understanding of the biology behind Hematopoietic Stem Cell Transplant (HSCT) has improved[1] and almost 50,000 HSCT take place globally in a year.[2] Although anesthetic concerns of patients undergoing solid organ transplantation have been addressed, there is a dearth of literature relating to HSCT, especially after the recent advancements like targeted therapy.[3,4] HSCT entails the regeneration of different blood cell lineages from donor stem cells and embarks on the interplay between recipient T lymphocytes, natural killer (NK) cells and donor antigen presenting cells (APC) and lymphocytes. Allogenic transplant brings forth graft vs. tumor effect (GVT) which helps to prevent recurrences but is shadowed by the graft vs. host disease (GVHD), necessitating chronic immunosuppression. Post HSCT patients are at increased risk of opportunistic infections, especially before engraftment and subtle signs of infections may be missed in the preoperative period as well as there may be delayed wound healing after surgery. While exaggerated increase in host immunity may enhance GVHD, overt diminution by immunosuppressant may lead to secondary infections and reactivation of cytomegalovirus. Therefore, it is prudent to delay elective surgeries before engraftment and while the patient is on immune-modulators.[5] Moreover, anesthesiologist should be aware of long-term adverse effects of chemotherapeutic drugs including potential difficult airway due to gum hypertrophy (cyclosporine) and lymph node enlargement as part of post-transplant lymphoproliferative disorder (PTLD). Acute GVHD may involve different organ systems, leading to potentially dreaded complications like acute lung injury, veno-occlusive disease of liver, thrombotic micro angiopathy (TMA) which should be evaluated during the pre-anesthetic check-up.[5] Surgical stress leads to a temporary state of immunosuppression via various mechanisms like raised catecholamines, angiogenic factors, matrix metalloproteinases (MMPs) and attenuated NK cell activity and cell mediated immunity (CMI). Volatile agents, especially isoflurane may promote tumor growth and spread by reducing NK cell activity, T cell depletion, increased angiogenesis by up-regulation of hypoxia inducible factor (HIF-1 alpha), whereas N2O causes bone marrow suppression. However, sevoflurane was found to stabilize the anti-cancer gene P38. Similar to inhaled agents, ketamine and thiopentone induces T cell apoptosis and NK cell underactivity. Propofol appears to be beneficial by reducing angiogenesis and maintaining T cell activity. Despite report showing impairment of macrophage-monocyte function, midazolam appears to be safer. Action of muscle relaxants may get prolonged due to immunomodulators like cyclosporine, as seen in renal transplant recipients.[6] Although anecdotal reports showed that IV opioids reduced NK cell, T cell and TLR (Toll like Receptor) activity on macrophage, it might enhance tumor lysis by stabilizing P53 and P38 and induce tumor death via NF-kB (nuclear factor kappa beta) and Fas-FasL pathway. Thus, immunomodulating effects of opioids are dose and concentration dependent and judicial perioperative analgesia by opioids seems logical.[7] Whenever feasible, use of regional anesthesia must be emphasized as local anesthetics increase local NK cell activity. Propofol along with paravertebral block have been found to be associated with reducing tumor burden in ER-negative breast cancer. Specific concerns of immune-modulators are provided in Table 1 and perioperative concerns are summarized in Table 2.Table 1: Side effects of commonly used agents and their concernsTable 2: Perioperative concerns in a nutshellInduction by propofol/etomidate, followed by maintenance with total intravenous anesthesia (TIVA) with propofol, intermediate acting muscle relaxants with minimal organ dependent metabolism (e.g., atrcurium, cisatracurium) and use of regional anesthesia may be considered as preferred techniques of choice. With the growing number of HSCTs, the authors feel the need for renewed interest and good quality research in this area. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

Endothelial Activation and Stress Index-Measured Pretransplantation Predicts Transplantation-Related Mortality in Patients with Thalassemia Major Undergoing Transplantation with Thiotepa, Treosulfan, and Fludarabine Conditioning

The use of thiotepa-treosulfan-fludarabine conditioning regimen and peripheral blood stem cell grafts is associated with improved outcomes of hematopoietic stem cell transplantation (HCT) in patients with high-risk thalassemia major. However, there remains a need to identify predictors of poor outcomes in this cohort to further optimize outcomes. The Endothelial Activation and Stress Index (EASIX) is a biomarker shown to predict survival in various settings, including graft-versus-host disease, veno-occlusive disease, and nonrelapse mortality following allogeneic HCT. In this retrospective analysis, we evaluated the role of EASIX-PreTx (measured before conditioning therapy) as a biomarker in predicting day +100 transplantation-related mortality (TRM+100) in 281 patients with thalassemia major who underwent HCT with a uniform conditioning regimen using thiotepa-treosulfan-fludarabine at our center between January 2012 and December 2019. The median patient age was 9 years (range, 1 to 25 years), and 109 (38.8%) were females. According to the Pesaro classification (with Vellore modification), 3 patients (1.1%) were class I, 34 (12.1%) were class II, 134 (47.7%) were class III low risk, and 110 (39.1%) were class III high risk. Stem cell donors were matched sibling (n=218; 77.6%), matched related nonsibling (n=23; 8.2%), or matched unrelated (n=40; 14.2%). Five patients (1.8%) received a bone marrow graft, and the others received a peripheral blood stem cell graft. Thirty-eight patients (13.5%) had TRM+100. EASIX-PreTx was available for 184 patients (65.5%). The median EASIX-PreTx was significantly higher in patients with TRM+100 compared with those without TRM+100 (1.09 versus .75; P=.008). An EASIX-PreTx cutoff of .85 had 70.4% sensitivity and 62% specificity for predicting TRM+100. The TRM+100 for patients with EASIX-PreTx >.85 was significantly higher than those with EASIX <.85 (24.4% versus 7.5%; P=.003). In a uniform subgroup of class III patients undergoing allogeneic HCT (n=156), EASIX-PreTx was an independent predictor of TRM+100.

A Systematic Review on Pulmonary Complications Secondary to Hematopoietic Stem Cell Transplantation.

The main purpose of this systematic review was to identify and synthesize evidence about pulmonary complications following stem cell transplantation to raise awareness among physicians since it is a lesser-known topic. Studies that included targeted pulmonary complications that occurred after stem cell transplantation; in humans; and were randomized controlled trials, cohort studies, and case studies between January 2011 and 2021. Fifteen intervention features were identified and analyzed in terms of their association with successful or unsuccessful interventions. Fifteen of 15 studies that met inclusion criteria had positive results. Features that appeared to have the most consistent positive effects included relevant information consisting of clinical presentations and management of complications. Hematopoietic stem cell transplantation is a therapeutic method that has been introduced for various hematological diseases. Its main objective is to restore the hematopoietic function that has been eradicated or affected. The stem cell transplantation requires a period of administration of chemotherapeutic agents that may lead to infectious and/or non-infectious pulmonary complications that require follow-up.Noninfectious pulmonary complications include bronchiolitis obliterans, alveolar hemorrhage, fibroelastosis, pulmonary hypertension, and infections. Bronchiolitis obliterans syndrome is an obstructive lung disease that affects the small airways, reducing lung function, and it’s the most frequent late-onset complication. Furthermore, diffuse pulmonary hemorrhage is a fatal adverse effect and the most common noninfectious pulmonary complication of acute leukemia, observed within the first weeks after the procedure. Pulmonary hypertension has multiple etiologies, mainly related to the pulmonary veno-occlusive disease. It carries a poor prognosis, with a 55% mortality rate. The area of hematology is very wide and prone to new development of treatments and procedures that could be available for new emerging diseases and improving survival rates.

Perioperative outcomes of sinusoidal obstruction syndrome underwent liver resection for colorectal metastases after neoadjuvant chemotherapy

Yoonkyung WOO, Yoonyoung CHOI, Haneol PARK, Chang Ho SEO, Sung Eun PARK, Joseph AHN, Ho Joong CHOI*, Tae Ho HONG, Young Kyoung YOU. Ann Hepatobiliary Pancreat Surg 2022;26:S68. https://doi.org/10.14701/ahbps.2022S1.OP-2-2

Sinusoidal obstruction syndrome after liver transplantation: A multicenter observational study.

Sinusoidal obstruction syndrome after liver transplantation: A multicenter observational study.

Low-dose unfractionated heparin prophylaxis is a safe strategy for the prevention of hepatic sinusoidal obstruction syndrome after myeloablative adult allogenic stem cell transplant.

Hepatic sinusoidal obstruction syndrome (SOS) is a serious complication after allogeneic stem cell transplantation (allo-HCT). However, there is no uniform consensus on the optimal strategy for SOS prevention. Ursodeoxycholic acid is the most used regimen, even though its administration is challenging in recipients unable to tolerate oral medication. Defibrotide was recently studied in a phase 3 trial, but enrollment was stopped early due to futility. Low dose unfractionated heparin (UFH) is an alternative strategy. However, its efficacy is reputed but unproven increased risk of bleeding has not been fully established. We evaluated 514 adult allo-HCT recipients who received SOS prophylaxis with low dose UFH. Bleeding complications occurred in 12 patients 2.3% of patients of which only 2 (0.4%) had significant grade 3 bleeding. Only 14 patients were diagnosed with hepatic SOS. Univariate analysis showed that day 100 SOS was higher in recipients of unmodified grafts when compared to CD34+ selected ex vivo T-cell depleted grafts (p ≤ 0.001), and patients with hepatitis B and/or C exposure pre-HCT (p = 0.028). Overall, UFH was well tolerated and associated with a low incidence of subsequent hepatic SOS. Low dose UFH prophylaxis can be considered in select patients who cannot tolerate oral ursodiol.

Thrombopoietin accumulation in hepatocytes induces a decrease in its serum levels in a sinusoidal obstruction syndrome model.

Sinusoidal obstruction syndrome (SOS) is a type of fatal hepatic injury, which predominantly occurs following exposure to drugs, such as oxaliplatin, or bone marrow transplantation. Extravasated platelet aggregation (EPA) plays an important role in the development of SOS in rat and mouse models. Furthermore, platelets invading the space of Disse adhere to hepatocytes and are phagocytized in patients with SOS. Aging platelets and platelets in patients with sepsis are phagocytized by hepatocytes through Ashwell‑Morell receptors, and thrombopoietin (TPO) is produced by the JAK2‑STAT3 signaling pathway. The purpose of the present study was to examine the significance of TPO as a biomarker of SOS. SOS was induced in Crl:CD1(ICR) female mice by intraperitoneal administration of monocrotaline (MCT). TPO levels were measured in the serum and liver tissue. Pathological and immunohistochemical studies of the liver were performed to analyze the expression levels of TPO. TPO mRNA expression levels were measured using reverse transcription‑quantitative PCR. In the SOS model, the platelet counts in peripheral blood samples were significantly decreased at 24and48h after MCT treatment as compared with that at 0h. In addition, a pathological change in hepatic zone3 was observed in the SOS model group. Furthermore, the protein levels of TPO in liver tissue were significantly increased in the SOS model group compared with those in the control group, which was confirmed by immunohistochemistry. By contrast, serum TPO protein levels were significantly decreased in the SOS model group compared with those in the control group. These results indicated that EPA may induce sinusoidal endothelial fenestration in a mouse model of SOS, preventing TPO from translocating into the blood. In conclusion, serum TPO levels may be reduced in a mouse model of SOS owing to the accumulation in hepatocytes, suggesting that TPO could be a useful biomarker of SOS.

Inotuzumab ozogamicin as single agent in pediatric patients with relapsed and refractory acute lymphoblastic leukemia: results from a phase II trial

Inotuzumab Ozogamicin is a CD22-directed antibody conjugated to calicheamicin, approved in adults with relapsed or refractory (R/R) B cell acute lymphoblastic leukemia (BCP-ALL). Patients aged 1–18 years, with R/R CD22 + BCP-ALL were treated at the RP2D of 1.8 mg/m2. Using a single-stage design, with an overall response rate (ORR) ≤ 30% defined as not promissing and ORR > 55% as expected, 25 patients needed to be recruited to achieve 80% power at 0.05 significance level. Thirty-two patients were enrolled, 28 were treated, 27 were evaluable for response. The estimated ORR was 81.5% (95%CI: 61.9–93.7%), and 81.8% (18/22) of the responding subjects were minimal residual disease (MRD) negative. The study met its primary endpoint. Median follow up of survivors was 16 months (IQR: 14.49–20.07). One year Event Free Survival was 36.7% (95% CI: 22.2–60.4%), and Overall Survival was 55.1% (95% CI: 39.1−77.7%). Eighteen patients received consolidation (with HSCT and/or CAR T-cells therapy). Sinusoidal obstructive syndrome (SOS) occurred in seven patients. MRD negativity seemed correlated to calicheamicin sensitivity in vitro, but not to CD22 surface expression, saturation, or internalization. InO was effective in this population. The most relevant risk was the occurrence of SOS, particularly when InO treatment was followed by HSCT.

Appendicitis and COVID: cause or effect?

BackgroundVasculitis and phlebitis with vascular occlusion within appendix specimen is rare. Several authors have reported COVID-19 related veno-occlusive disease in hepatic pathology, but lymphoid aggregation with phlebitis is unusual in appendix specimen. We present a case with medium size venule phlebitis in an appendix of a patient recovered from COVID-19 infection.Case presentationA 27-year-old who recently recovered from COVID-19 infection 12 weeks prior, presented with acute appendicitis, confirmed on computed tomography and operative findings. He underwent an uneventful laparoscopic appendicectomy. Histopathology showed veno-occlusive vasculitis within the appendix specimen.ConclusionsVeno-occlusive disease within the appendix is uncommon. Emerging data suggest COVID-19 infection can cause systemic vascular complications. We herein report a case of healthy patient with no past medical history with an unusual findings of medium vessels phlebitis within the appendix post COVID-19 infection.

Physiological reno-portal bypass in liver transplantation with non-tumorous portal vein thrombosis.

Reno-portal anastomosis (RPA) in presence of spleno-renal shunts (SRS) is a physiological option to restore blood flow in liver transplantation with portal vein thrombosis (PVT). Diffuse splanchnic venous system thrombosis (complex PVT) is its main indication but RPA proved to be useful in selected cases of less extensive thrombosis (non-complex PVT). Up until now only two monocentric and one multicentric case series has been published on this topic in addition to few anecdotal reports. After 2014, we introduced RPA in our institution to manage some cases of complex PVT in presence of SRS. Here, we present the evolution of indication to RPA. From 2014 to 2020, we performed ten RPA: nine patients presented non-complex and one complex PVT. Overall early and late complication rates were 66.6% and 50%, respectively. Two patients developed RPA stenosis, treated by interventional radiology. Self-resolving acute kidney injury (AKI) was observed in three cases. No re-transplantation was necessary. RPA was patent in all patients, with a mean follow-up of 41.9months. The overall patient survival was 70% at 1year and 60% at 3 and 5years. Four patients died at 1, 2, 3 and 20months from LT. Causes of deaths were, respectively, stroke, cerebral infection, sepsis (MOF) and sudden variceal bleeding in sinusoidal obstruction syndrome. The relative simplicity and effectiveness of RPA in presence of SRS allowed us to rely more and more often on this technique in liver transplantation with challenging non-complex PVT.

Single‐dose (4.5 mg/m2) gemtuzumab ozogamicin in combination with fludarabine, cytarabine and anthracycline as reinduction therapy in relapsed or refractory paediatric acute myeloid leukaemia

Despite major therapeutic improvements, children with relapsed/refractory Acute Myeloid Leukaemia still have poor outcomes and overall survival does not exceed 40%. New treatments are required to improve their outcome; Gemtuzumab ozogamicin (GO), an anti-CD33 immunoconjugate antibody, is a potent cytotoxic agent whose efficacy has been demonstrated mainly in adults. The main objective of this retrospective multicentre study was to assess the outcome of children treated, between February 2008 and August 2019, with GO at a single 4.5mg/m2 dose, in combination with Fludarabine, Cytarabine and antssshracyclines, in context of a first relapse (n=26) or refractory disease (n=3). The remission rate was 83% (24/29 children) and 20 children (69%) were allografted. With a median follow-up of 1.2 years (range: 0.1-8), the overall survival was 49% (CI95%=33; 72). Most common adverse event was febrile neutropenia with microbiological identification in 55% of cases. Veno-occlusive disease occurred in 6 patients (21%), of which 5 subvened after bone marrow transplantation, and resolved within 2-32 days (median 10.5 days). Administration of GO in combination with FLA-anthracyclines chemotherapy appears to be a good reinduction regimen for relapsed or refractory AML with a good safety profile. These results warrant larger prospective study.