dataesr/scientific-paragraphs-categorization huggingface dataset:
Finally, 2022's breakthrough in advanced CCA is the arrival of immunotherapy in first-line setting with the phase 3 TOPAZ-1 trial studying CISGEM in combination with durvalumab, an anti-PD-L1 (Programmed death 1 ligand) checkpoint inhibitor, or a placebo, for 8 cycles, followed by a maintenance therapy with durvalumab or placebo. As presented at ASCO GI 2022 congress and recently published, the primary objective was met with an OS of 12. 8 months in the CISGEM-Durvalumab arm versus 11. 5 months in the CISGEM-placebo arm (HR = 0. 80; 95%CI: [0. 66-0. 97]; p=0. 021) following the interim analysis considered as the final analysis. Besides, the estimated 24-month OS seems promising with a rate of 24. 9% in durvalumab arm versus 10. 4% for placebo even though long-term follow-up data are needed.
J o u r n a l P r e -p r o o f Until 2019, no phase 3 study was available to assess the input of second-line (L2) chemotherapy in CCA even though retrospective studies were already in favor of a benefit of L2 in patients with good performance status after first line chemotherapy. Data from retrospective series and systematic reviews suggest that around 30-40% of patients are fit for L2, with a wide range of estimated rates of eligible patients from 15% after CISGEM firstline in ABC-02 trial, to 75% based on retrospective analyses in high volume anticancer centers  (13, (25) (26) (27). In 2020, the ABC-06 phase 3 study showed an OS increase with FOLFOX when compared with best supportive cares alone in ECOG PS of 0-1  (28). However, this gain was inferior to 1 month in median OS (6. 2 vs. 5.
5FU-Naliri showed an improvement in PFS (primary endpoint) with a median of 7. 1 months vs. 1. 4 months in the control arm, HR 0. 56, 95%CI: [0. 39-0. 81], p=0. 0019). There was also a benefit in OS (median: 8. 6 vs. 5. 5 months HR 0. 68, 95%CI: [0. 48-0. 98], p=0. 0349) and objective response rate (14. 8% vs 5. 8%) compared with the 5FU-leucovorin regimen alone  (32). These results are very promising but need to be confirmed in a Western population, which is the purpose of the ongoing European phase 2 study NalIRICC (NCT03043547). Morever, to date, no phase 3 trial compared the benefit of 5FU-based doublets versus 5FU alone in second-line setting of advanced CCA and data from prospective European cohorts suggest J o u r n a l P r e -p r o o f that doublets do not bring a benefit when compared with 5FU alone  (33).
These results clearly confirm that the theoretical benefit of FGFR2 inhibitors, although significant in case of J o u r n a l P r e -p r o o f FGFR2 fusion or rearrangement, seems to drop in case of other FGF/FGFR alterations, as well as in the absence of alterations. Safety profile was acceptable with among all grade treatment-related AEs, hyperphosphatemia as the most frequent AE (55%), followed by alopecia (46%), dysgeusia (38%), diarrhea (34%), asthenia (31%), stomatitis (27%) and dry mouth (29%). Among grade 3 or higher treatment-related AEs, the most frequent were hypophosphatemia (7%), stomatitis (5%), arthralgias (4%), and palmoplantar erythodysesthesia (4%). There was no toxic death  (59). Other inhibitors are being studied, and several randomized phase 3 trials versus CISGEM in first-line therapy are underway, such as the FIGHT-302 trial (pemigatinib; NCT036536), and the FOENIX-CCA3 trial (Futibatinib; NCT04093362) or the PROOF trial (Infigratinib; NCT03773302).
J o u r n a l P r e -p r o o f Recently the combination modified FOLFOX with trastuzumab tested in the single-arm phase 2 trial KCSG-HB19-14 (NCT04722133) reinforced the signal of the interest of anti-HER2 therapies in second line of HER2-amplified CCA patients after progression under CISGEM. Based on unpublished results, tolerance was acceptable, ORR, DCR and PFS were respectively 29. 4% (95%CI 15. 1-47. 5), 79. 4% and 5. 1 months (95%CI 3. 6-6. 7). Median OS was not reached (95%CI 7. 1-NR) and 12-months OS rate was 50. 6% (95%CI 29. 3-63. 6) (65). New therapies are under investigation such as the zanidatamab, a novel bispecific antibody that targets HER2 domains ECD2 and ECD4, resulting in increased antibody binding density and improved receptor internalization and downregulation relative to trastuzumab.
We expect the final results of the phase I ZWI-ZW25-101 (NCT02892123), in which zanidatamab was well tolerated with promising anti-tumor as a single-agent (ORR= 47%, DCR = 65%, duration of response = 6. 6 months), as well as the results of the ongoing single-arm phase 2b trial HERIZON-BTC-01 (NCT04466891) evaluating zanidatamab in monotherapy in patients with HER2-amplified, inoperable, advanced or metastatic CCA  (66, 67). As well, trastuzumab deruxtecan (T-DXd), an antibody-drug conjugate composed of a humanized monoclonal anti-HER2 antibody, a cleavable linker, and a topoisomerase I inhibitor, also showed very promising results in the single-arm phase 2 study DS-8201/ HERB trial in patients with HER2-expressing unresectable or recurrent biliary tract cancer. ORR, DCR, median PFS and OS were respectively 36.
RET fusions (ESCAT I-C) The proto-oncogene RET encodes a transmembrane tyrosine kinase receptor which plays a physiological role in the embryonic development of the nervous system and the kidneys. RET mutation of alteration induce oncogenic transformation with an aberrant activation of RET receptor. RET fusions are found in various cancers including CCA, with a prevalence around 1%, except for non small cell lung cancer (NSCLC) and papillary thyroid cancers in which prevalence reaches respectively 2 and 20% RET fusions  (73, 74). To date, 2 orally bioavailable potent selective RET TKI-inhibitors showed promising preliminary results in solid tumors. The pralsetinib (BLU-667) was tested in the phase 1/2 trial ARROW (NCT03037385) including 29 patients with RET-fusion positive solid tumors. An objective response rate of 57% was observed, with a tumor shrinkage in 91% of the evaluable patients according to RECIST 1.
1 criteria. Two of the 3 CCAs included, experienced tumor response. Safety was acceptable with neutropenia (29%), anemia (14%) and increased aspartate transaminase (AST ; 10%), as the most common grade 3 and more TRAEs  (75). The selpercatinib (LOXO-292), which first showed interesting results in RET-fusion positive thyroid cancer and NSCLC within the pivotal phase 1/2 LIBRETTO-001 (NCT03157128)  (76, 77) , was then evaluated in another cohort of 45 patients with other RET fusion-positive tumors including 2 CCAs. The objective response rate was 43. 9% and the only evaluable CCA experienced tumor response. The duration of response and the PFS were respectively 24. 5 (9. 2-not evaluable) and 13. 2  (7. 4-26. 2) months. The most common grade 3 and more TRAEs were hypertension (22%) increased alanin transaminase (16%), and increased AST (13%).
J o u r n a l P r e -p r o o f CCA is a rare disease with an increasing incidence, a very poor prognosis with a 5-year survival rate of less than 15% for all stages combined, and a limited therapeutic arsenal. Even though recently a significant advance was made in all comers CCA with the arrival of the CISGEM-durvalumab combination in L1, the real change comes from molecular profiling which opens the way to personalized medicine. This profiling is now recommended from the time of the diagnosis due to the frequency of actionable alterations such as IDH1 mutations and FGFR2 rearrangements/fusions in iCCA, as well as HER amplication/overexpression in gallbladder cancers, pCCAs and dCCAs. Even though no direct comparative data are available versus FOLFOX, regarding the oncological results of matched targeted therapies, these treatments should be proposed from the second line in patients with actionable alterations.
8 vs 9. 7 m IDH1 mutation NCT02989857 multicenter phase 3 L2-L3 Placebo : 2 vs 0% 2. 7 vs 1. 4 m (HR 0. 69, 95%CI: 0. 44-1. 10 p=0. 060) IDH1mut -inhibitor Lancet 2020 (58) versus Placebo ESCAT I-A (HR:0. 37; 95%CI:0. 25-0. 54, p<0. 001) Placebo (RPSFT-adjusted OS): 6. 0 m (HR 0. 46 95%CI:0. 28-0. 75; p=0. 0008) Pemigatinib FIGHT-202 Single-arm n=147 pts ORR Cohort fusion: 12m-PFS: 29% in N/A NCT02924376 multicenter phase 2 (107 pts with 35. 5% fusion cohort FGFR1/2/3 inhibitor Lancet Oncol 2020 (59) FGFR2-fusions) (0% in other cohorts) L2+ Other alterations: 0% Futibatinib FOENIX-CCA2 Single-arm n=103 pts ORR 41. 7% 9. 0m 21. 7m FGFR2 alterations FGFR1-4 inhibitor NCT02052778 Cancer Res 2021 (Abst) (60) multicenter phase 2 (78% of pts with FGFR2-fusion) L2+ ESCAT I-B Infigratinib (BGJ398) NCT02150967 CBGJ398X2204 multicenter phase 2 Single-arm (48 pts with n=61 pts 14.
8% 5. 8m N/A FGFR1/2/3 inhibitor J Clin Oncol 2017 (61) FGFR2-fusions) Cohort fusion: L2+ 18. 8% Derazantinib FIDES-01 Single-arm n=28 pts 3m-PFS 8. 7% 7. 3m N/A (ARQ 087) NCT03230318 multicenter phase 2 L2+ J Clin Oncol 2022 3m-PFS: 76. 3% FGFR1/2/3 inhibitor (Abst) (62) 6m-PFS: 50. 3% Trastuzumab-pertuzumab myPathway Single-arm n=39 pts ORR 23% 4. 0m 10. 9m NCT02091141 multicenter phase 2 L2+ HER n overexpressio amplification / Anti-HER2 Ab Chemo + anti-HER2 Ab FOLFOX-trastuzumab Lancet Oncol 2021 (64) (Abst) (65) J Clin Oncol 2022 NCT04722133 KCSG-HB19-14 multicenter phase 2 Single-arm L2-L3 n=34pts ORR 29. 4% 5. 1m not reached ESCAT II-B (T-DXd; DS-8201) Trastuzumab-deruxtecan JMA-IIA00423 HERB trial multicenter phase 2 Single-arm (24 HER2-positive n=32pts in HER-ORR 36. 4% HER-positive: HER-positive: 4.
MR distal jet The use of Color Doppler mode allows to appraise the presence, origin, timing (with M-mode), and direction of the MR regurgitant(s) jet(s). All echocardiographic views should be checked. It is worth using biplane mode from a bi-commissural view (TTE: apical 2-chamber, parasternal short-axis views; TEE: 60-90°) and sweep the Doppler line from one commissure to another across the MV coaptation line with simultaneous Doppler color mode comparison  (67). However, only a full MV 3D color-coded data set with sufficient framerate can objectively document MR regurgitant(s) jet(s), especially when several jets ("multi-jet") are present  (68). Color Doppler analysis of the jet(s) helps in understanding the MR mechanism(s) (69, 70) (Figure  3 ). Indeed an isolated posterior MV prolapse is expected to induce an eccentric anterior MR jet towards the interatrial septum  (71).
Main message for the clinician It is of upmost importance to conciliate MR quantitative measurements and hemodynamic findings when grading MR severity. If there are inconsistencies, either at individual patientor study-level, the echocardiographic raw data should be carefully checked  (26, 138). MR RegVol values estimated by PISA or indirect quantitative methods can differ markedly. Also, a unique MR RegVol cut-off of 60 ml to define MR severity does not fit to all patients with primary MR. MR RegFrac by the volumetric method relates the MR RegVol to the patient's LV dimensions and cardiac stroke volume. From a practical approach, a MR RegFrac assessed by the volumetric method of 40% or more is highly specific of significant (3+ or 4+) MR  (182). Its routine calculation may allow to reconcile at least in part alleged discrepancies between echocardiography and CMR in grading MR.
A laser vibrometer (POLYTEC VFX-BW-500, Polytec GmbH, Waldbronn, and Germany) is used to monitor the vibrational and frictional responses of the samples (i. e. , switching between sticking and sliding contact conditions) during the experiments, as close as possible the contact interface (see Figure  1 ). All signals coming from the sensors are acquired with an 8-channel isolated data acquisition system (Dewesoft SIRIUSi, Dewesoft, Roma, and Italy), allowing high resolution acquisition up to 200kHz sampling frequency. The setup is equipped with a 3D piezoelectric force sensor to measure the normal and tangential contact forces over the time. The force sensor (KISTLER 9047C, Kistler Italia, Milano, and Italy) provides high stiffness and high sensitivity ensuring precision in measuring contact forces while maintaining the alignment at the contact interface.
Acknowledgments This paper was prepared by researchers who are part of the Blue Food Assessment (BFA; https://www. bluefood. earth/), a comprehensive examination of the role of aquatic foods in building healthy, sustainable, and equitable food systems. The key messages and recommendations in this paper were derived from several papers that are part of the BFA as well as related materials. A complete list of BFA papers can be found at https://www. bluefood. earth/science/.
Materials and Methods The website https://clinicaltrials. gov (Last accessed on 17 October 2022) was scrutinized to identify clinical trials and 17 searches were conducted with the following pre-defined terms: "Graft failure", "Relapse" (restricted to "HSCT"), "Minimal residual disease", "Stem Cell Transplant Complications", "Transplant; Complication, Rejection", "Chronic graft versus host disease" (cGVHD), "Bronchiolitis obliterans", "Cryptogenetic organizing pneumonia", "Idiopathic pneumonia syndrome", "Diffuse alveolar hemorrhage", "Veno-occlusive disease", "Sinusoidal Obstruction Syndrome", "Engraftment syndrome", "Capillary Leak Syndrome", "Thrombotic Microangiopathies", "Thrombotic Thrombocytopenic Purpura", and "Hemolytic Uremic Syndrome". Eligibility criteria were defined a priori.
Results The search at clinicaltrials. gov yielded 895 studies (Figure  1 ). Forty-nine fulfilled the eligibility criteria: (a) graft failure (n = 5); (b) prevention of relapse (n = 12); (c) cGVHD (n = 19); (d) non-infectious pulmonary complications (n = 4); and (e) complications of endothelial origin (n = 9). Three additional studies for prevention of relapse were identified with cross-references (*) and one for GF (*) (Table  1 ). Figure  2  depicts the strategies explored in children by mechanism of action.
Graft Failure Primary GF is characterized by the absence of initial donor cell engraftment; secondary GF occurs after initial engraftment and subsequent loss of donor cells not related to relapse, infection, or toxicity  [1]. The incidence has been reported to be <5% in the matched allo-HSCT setting and 10% in haploidentical or cord blood transplant  [2]. Well-established risk factors for GF are HLA mismatch, graft source, gender incompatibility between donor and receptor, non-malignant diseases, presence of anti-HLA antibodies, and splenomegaly in the receptor  [1]. Treatment has mainly consisted of maximizing supportive care and tailoring immunosuppression, but in some cases the only alternative option is a second transplantation. To reduce the recipient cellular activity, a phase 2 trial (NCT02105766) for patients with severe sickle cell disease and B-thalassemia receiving allogeneic peripheral blood stem cell (PBSC) transplants from HLA-matched family donors, is investigating whether low dose radiation (300 rads), oral cyclophosphamide, pentostatin, alemtuzumab, and sirolimus can reduce the engraftment failure rate.
The intensified non-myeloablative approach aims to reduce the T cells mediating leukocyte rejection and the B/plasma cells that produce antidonor erythrocyte antibodies. Another phase 2 study (NCT05126186) is testing the addition of post-transplant cyclophosphamide which targets alloreactive T cells after haploidentical HSCT for prevention of GF in patients with hematological diseases. Plerixafor and G-CSF were evaluated for prevention of GF after TCR αβ-depleted grafts in patients with Wiskott-Aldrich syndrome (WAS). Plerixafor antagonizes the alpha chemokine receptor CXCR4, which plays an important role in stem cell homing. The combination with G-CSF mobilizes bone marrow stem cells into peripheral blood and blocks CXCR4 chemokine receptors to prevent stem cell homing, producing a free stromal space in the marrow for engraftment.
Sixteen patients were prospectively included and compared with a historical cohort of eighteen patients. The conditioning regimen was treosulfan, fludarabine, and melphalan, with G-CSF 10 µg/kg on days -8, -7, -6, -5, and -4 and plerixafor 240 µg/kg on days -6, -5, and -4. The prospective and historical groups had comparable baseline characteristics. No patients in the prospective cohort developed GF, compared to 39% in controls  [3]. Based on these findings, this combination is currently being tested in patients with chronic granulomatous disease, a non-malignant disease notorious for its risk of graft rejection (NCT03547830). A phase 2 study (NCT04731298) has evaluated emapalumab, an interferon gamma (IFNγ)-blocking antibody, in children at high risk of GF. Serum levels of interferon (IFN)-γ and CXCL9 (a chemokine specifically induced by IFNγ) are found to be significantly higher in patients experiencing GF  [5]  but the results are not yet published.
Eltrombopag is being investigated in a phase 2 study (NCT03948529) to improve poor graft function after allo-HSCT. Eltrombopag interacts with the thrombopoietin receptor and stimulates proliferation and maturation of megakaryocytes. A randomized study in adults showed that eltrombopag leads to a higher percentage of patients achieving a platelet count of ≥50 × 10 9 /L compared to those given placebo  [4]. N-acetylcysteine could be considered as a treatment for preventing graft failure as endothelial progenitor cells (EPCs) play a crucial role in the regulation of hematopoiesis and thrombopoiesis in the bone marrow microenvironment  [7]  and N-acetyl-L-cysteine (NAC, a reactive oxygen species [ROS] scavenger) can enhance bone marrow EPCs. In a prospective clinical trial (NCT03236220) including children, N-acetylcysteine was administered to patients with leukemia whose bone marrow endothelial cells were less than 0.
Cellular Therapies Donor lymphocyte infusion (DLI) is a minimally manipulated product that stimulates GVL reactions. However, the utility of DLI is limited by the risk of GVHD and by variable responses  [11]. To enhance the response to DLI in preventing leukemia, the phase 2 NCT02458235 trial tested post-transplant consolidation with DLI and the hypomethylating agent (HMA) azacytidine. No severe toxicity attributable to azacytidine was observed and the combined intervention was deemed feasible and only 2 of the 11 patients developed a relapse  [12]. In the phase 2 (NCT02673008) trial, preemptive DLI was administered monthly to patients with persistent MRD positivity after transplant and prophylactically to those when donor lymphocytes were available without active GHVD  [13]. The combined approach of sequential intensified conditioning and DLI resulted in a reduced incidence of relapse compared to historical controls in patients with relapsed ALL and AML.
Tumor-reactive lymphocytes are being tested in clinical trials including αβ-T lymphocytes, γδ-T lymphocytes, natural killer (NK) cells, and NK-T cells. A clinical trial (NCT04439721) is testing the safety and effectiveness of a donor γδT cell infusion, a population of cells with both innate and adaptive immune properties with potent in vitro anti-tumor responses. To increase the GVL effect without causing any GVHD, a phase 2 trial (NCT03849651) is being conducted where TCRαβ-and CD19-depleted graft infusions are followed by CD45RA-depleted DLI at least two weeks after engraftment. In addition, in this study for CD19-positive B-ALL patients, blinatumomab will be given at least one week post-DLI for 28 days. In the allogeneic setting, donor NK cells can kill recipient cells through missing selfrecognition and offer the advantage of inducing a GVL effect without necessarily promoting GVHD.
The NCT04024761 trial is studying cytokine-induced memory-like natural killer (CIML-NK) cells plus IL-2 which leads to activation and expansion of the NK cells  [14]  in patients above 12 years with myeloid malignancies who relapsed or remain MRD positive after haploidentical HSCT. The NCT02050347 trial tests donor CD19/CD28 chimeric receptor T cells in leukemia and lymphoma patients with residual disease at transplantation or post-transplant evidence of MRD positivity (or relapse).
Hypomethylating Agents (HMA) HMA may permit epigenetic manipulation of the alloreactive response, through conversion of alloreactive donor T cells into suppressive regulatory T cells via hypomethylation of the FOXP3 promoter and suppression of alloreactive T cell proliferation  [15]. In a recent trial in adults with AML and myelodysplastic syndrome (MDS) who developed MRD positivity after complete remission after chemotherapy or HSCT, the participants were offered azacytidine; relapse free survival at 12 months was 58%  [16]. On the other hand, a study of post-HSCT azacytidine maintenance in adults with AML and MDS, starting 40 to 100 days after allo-SCT and continuing for up to 12 months, failed to show relapse or survival benefits  [17]. The NCT01995578 trial, also including children from 12 years old, tests azacytidine post-T cell-depleted allo-SCT for patients with MDS and AML.
NCT04945096 will study decitabine maintenance to reduce relapse and restore the bone marrow microenvironment by repairing endothelial cells and endothelial progenitor cells, as well as cytokines and chemokines, which are crucial to hematopoietic cell proliferation and differentiation promoting platelet recovery. Co-administration of histone deacetylase inhibitors, such as vorinostat, is reported to improve the clinical activity of azacitidine in children with relapsed AML  [18]. Based on this premise, the NCT03843528 trial is testing the addition of vorinostat to azacitidine as a post-HSCT maintenance treatment.
Targeted Therapy Tyrosine Kinase Inhibition Multiple adult studies have reported that BCR-ABL TKI after HSCT improves relapsefree survival in patients with Philadelphia-positive ALL (Ph+ ALL)  [19]. The only randomized trial published to date compared prophylactic (in MRD-negative patients) with preemptive (MRD-triggered) administration of imatinib in adult Ph+ ALL patients and demonstrated that both arms had improved survival when compared to historical controls, although most patients had to interrupt treatment due to poor tolerability. The NCT03793478 trial  [20]  is evaluating the administration of quizartinib, a potent and selective FLT3 TKI after transplantation in patients with FLT3-mutated AML.
Monoclonal Antibodies/Bispecific T-Cell Engagers For BCP-ALL, five different studies are exploring blinatumomab's effect on posttransplant patients (NCT03849651 was described in Section 3. 2. 1). A single arm prospective trial in adults with B-ALL evaluated the administration of four cycles of blinatumomab after HSCT at count recovery and at 6, 9, and 12 months. No differences in efficacy were seen when compared to a contemporary cohort  [21]. In children, a phase 2 study (NCT04785547) will treat post-HSCT patients with 28 consecutive days of blinatumomab in two different cohorts, MRD-positive pre-HSCT and patients who became MRD positive after HSCT. The NCT02790515 trial is assessing the safety and feasibility of blinatumomab in the early post-engraftment period in patients with CD19+ malignancies after TCRαβand CD45RA-depleted haploidentical donor progenitor cell HSCT following a reduced intensity conditioning regimen.
A similar approach is being used in NCT04746209, in which blinatumomab is administered at day +100 while administering αβ T cell-and B celldepleted allogeneic hematopoietic cell transplantation. The NCT04044560 trial terminated earlier due to slow recruitment and explored blinatumomab given for up to four cycles. For AML, gemtuzumab ozogamicin, an antibody against CD33 conjugated to the chemotherapy calicheamicin, has been evaluated as a maintenance treatment with azacitidine after HSCT in a small series of 10 AML adult patients. Concerns about this approach are related to hematologic toxicity and the risk of post-HSCT development of hepatic venoocclusive disease (VOD)  [22]. In addition, in a phase 1/2 study, sabatolimab, a humanized monoclonal antibody (hIgG4, S228P) directed against the human T-cell immunoglobulin domain and mucin domain-3 (TIM-3) aimed to enhance T-cell killing and inflammatory cytokine production by dendritic cells  [23] , will be combined with azacytidine to treat MRD-positive AML patients post-HSCT (NCT04623216).