RESUMO
ABSTRACT: Inotuzumab ozogamicin (InO) is an antibody-drug conjugate that delivers calicheamicin to CD22-expressing cells. In a retrospective cohort of InO-treated patients with B-cell acute lymphoblastic leukemia, we sought to understand the genomic determinants of the response and resistance to InO. Pre- and post-InO-treated patient samples were analyzed by whole genome, exome, and/or transcriptome sequencing. Acquired CD22 mutations were observed in 11% (3/27) of post-InO-relapsed tumor samples, but not in refractory samples (0/16). There were multiple CD22 mutations per sample and the mechanisms of CD22 escape included epitope loss (protein truncation and destabilization) and epitope alteration. Two CD22 mutant cases were post-InO hyper-mutators resulting from error-prone DNA damage repair (nonhomologous/alternative end-joining repair, or mismatch repair deficiency), suggesting that hypermutation drove escape from CD22-directed therapy. CD22-mutant relapses occurred after InO and subsequent hematopoietic stem cell transplantation (HSCT), suggesting that InO eliminated the predominant clones, leaving subclones with acquired CD22 mutations that conferred resistance to InO and subsequently expanded. Acquired loss-of-function mutations in TP53, ATM, and CDKN2A were observed, consistent with a compromise of the G1/S DNA damage checkpoint as a mechanism for evading InO-induced apoptosis. Genome-wide CRISPR/Cas9 screening of cell lines identified DNTT (terminal deoxynucleotidyl transferase) loss as a marker of InO resistance. In conclusion, genetic alterations modulating CD22 expression and DNA damage response influence InO efficacy. Our findings highlight the importance of defining the basis of CD22 escape and eradication of residual disease before HSCT. The identified mechanisms of escape from CD22-targeted therapy extend beyond antigen loss and provide opportunities to improve therapeutic approaches and overcome resistance. These trials were registered at www.ClinicalTrials.gov as NCT01134575, NCT01371630, and NCT03441061.
Assuntos
Resistencia a Medicamentos Antineoplásicos , Inotuzumab Ozogamicina , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico , Humanos , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico/genética , Resistencia a Medicamentos Antineoplásicos/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Feminino , Mutação , Masculino , Antineoplásicos Imunológicos/uso terapêutico , Antineoplásicos Imunológicos/farmacologia , Adulto , Pessoa de Meia-Idade , Estudos Retrospectivos , AdolescenteRESUMO
The last decade has seen remarkable progress in our understanding of disease biology of chronic lymphocytic leukaemia (CLL) and the development of novel targeted therapies. Randomised clinical trials have reported improved progression-free survival and overall survival with targeted therapies compared with chemoimmunotherapy, and thereby the role of chemoimmunotherapy in todays' era for treatment of CLL is limited. Bruton tyrosine kinase (BTK) inhibitors, BCL2 inhibitors, and CD20 monoclonal antibodies have been established as appropriate therapy options for patients with CLL, both as the first-line treatment and in the treatment of relapsed or refractory CLL. Several ongoing phase 3 trials are exploring different combinations of targeted therapies, and the results of these trials might change the treatment framework in first-line treatment of CLL. Non-covalent BTK inhibitors, chimeric antigen receptor T-cell therapy, and other therapeutic strategies are being investigated in relapsed CLL. Some of the therapies used in relapsed CLL, such as non-covalent BTK inhibitors, are now being pursued in earlier lines of therapy, including first-line treatment of CLL.
Assuntos
Tirosina Quinase da Agamaglobulinemia , Leucemia Linfocítica Crônica de Células B , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/terapia , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Inibidores de Proteínas Quinases/uso terapêutico , Terapia de Alvo Molecular , Antineoplásicos/uso terapêutico , Imunoterapia/métodosRESUMO
Patients with chronic lymphocytic leukemia (CLL) respond well to initial treatment with the Bcell lymphoma 2 (BCL2) inhibitor venetoclax. Upon relapse, they often retain sensitivity to BCL2 targeting, but durability of response remains a concern. We hypothesize that targeting both BCL2 and B-cell lymphoma-extra large (BCLXL) will be a successful strategy to treat CLL, including for patients who relapse on venetoclax. To test this hypothesis, we conducted a pre-clinical investigation of LP-118, a highly potent inhibitor of BCL2 with moderate BCLXL inhibition to minimize platelet toxicity. This study demonstrated that LP-118 induces efficient BAK activation, cytochrome C release, and apoptosis in both venetoclax naïve and resistant CLL cells. Significantly, LP-118 is effective in cell lines expressing the BCL2 G101V mutation and in cells expressing BCLXL but lacking BCL2 dependence. Using an immunocompetent mouse model, Eµ-TCL1, LP-118 demonstrates low platelet toxicity, which hampered earlier BCLXL inhibitors. Finally, LP-118 in the RS4;11 and OSU-CLL xenograft models results in decreases in tumor burden and survival advantage, respectively. These results provide a mechanistic rationale for the evaluation of LP-118 for the treatment of venetoclax responsive and relapsed CLL.
RESUMO
Here we report on the first prospective study evaluating the safety and long-term survival when an escalating dose of inotuzumab ozogamicin (INO) (0.6, 1.2, or 1.8 mg/m2 on day 13) was added to one alkylator-containing conditioning regimen in patients with relapsed CD22 (+) lymphoid malignancies who were candidates for hematopoietic stem cell transplantation (HSCT). Twenty-six patients were enrolled. Six (23%) of these patients entered the phase 1 study: four were treated at an INO dose of 0.6 mg/m2 and two at dose of 1.2 mg/m2. None of these patients experienced dose-limiting toxicities. The remaining 20 (77%) patients entered the phase 2 part of the study at the maximum dose of 1.8 mg/m2. One patient developed VOD; this patient had received nivolumab immediately before HSCT while simultaneously experiencing hyperacute graft-vs-host disease (GVHD). Treatment-related mortality (TRM) at 5 years was 12%. With a median follow-up of 48.7 months, the 5-year overall survival (OS) and progression-free survival (PFS) rates were 84% and 80%, respectively. Compared with a historical cohort who received same conditioning for HSCT but without INO (n = 56), the INO group showed no significant differences in incidence of liver toxicity, engraftment time, TRM, or risk of acute GVHD. Patients with lymphoma who received INO had a trend for a better 5-year OS (93% versus 68%) and PFS (93% versus 58%) than those in the control group. In conclusion, our results showed that INO is safe with no increased risk of VOD when combined with one alkylator-containing regimen of HSCT.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Humanos , Inotuzumab Ozogamicina , Estudos Prospectivos , Recidiva , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Doença Enxerto-Hospedeiro/etiologia , Alquilantes , Condicionamento Pré-Transplante/métodosRESUMO
INTRODUCTION: Promotion of self-efficacy can enhance engagement with health care and treatment adherence in patients with cancer. We report the outcomes of a pilot trial of a digital health coach intervention in patients with leukemia with the aim of improving self-efficacy. METHODS: Adult patients with newly diagnosed acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL) were randomized 1:1 to a digital health coach intervention or standard of care. The primary outcome of self-efficacy was measured by the Cancer Behavior Inventory (CBI) score. RESULTS: A total of 147 patients (37 AML, 110 CLL) were enrolled from July 2020 to December 2022. In the AML cohort, there was a mean increase in CBI score of 7.03 in the digital health coaching arm compared to a mean decrease of -3.57 in the control arm at 30 days (p = 0.219). There were no significant associations between the intervention and other patient-reported outcomes for patients with CLL. CONCLUSION: There were numerical, but not statistically significant increases in self-efficacy metrics in AML patients who received digital health coaching. Although this trial was underpowered due to enrollment limitations during a pandemic, digital health coaching may provide benefit to patients with hematologic malignancy and warrants further investigation.
RESUMO
BACKGROUND: To determine the effectiveness of applying the Sydney Triage to Admission Risk Tool (START) in conjunction with senior early assessment in different Emergency Departments (EDs). METHODS: This multicentre implementation study, conducted in two metropolitan EDs, used a convenience sample of ED patients. Patients who were admitted, after presenting to both EDs, and were assessed using the existing senior ED clinician assessment, were included in the study. Patients in the intervention group were assessed with the assistance of START, while patients in the control group were assessed without the assistance of START. Outcomes measured were ED length of stay and proportion of patients correctly identified as an in-patient admission by START. RESULTS: A total of 773 patients were evaluated using the START tool at triage across both sites (Intervention group n = 355 and control group n = 418 patients). The proportion of patients meeting the 4-hour length of stay thresholds was similar between the intervention and control groups (30.1% vs. 28.2%; p = 0.62). The intervention group was associated with a reduced ED length of stay when compared to the control group (351 min, interquartile range (IQR) 221.0-565.0 min versus 383 min, IQR 229.25-580.0 min; p = 0.85). When stratified into admitted and discharged patients, similar results were seen. CONCLUSION: In this extension of the START model of care implementation study in two metropolitan EDs, START, when used in conjunction with senior early assessment was associated with some reduced ED length of stay.
Assuntos
Admissão do Paciente , Triagem , Humanos , Tempo de Internação , Triagem/métodos , Alta do Paciente , Serviço Hospitalar de EmergênciaRESUMO
This review focuses on non-surgical treatment options for rotator cuff injuries and highlights the potential of mesenchymal stem cells (MSCs) as a potential regenerative approach. MSCs, sourced from various tissues like bone marrow and adipose tissue, exhibit promising mechanisms in vitro, influencing tendon-related gene expression and microenvironment modulation. Animal studies support this, showcasing MSCs' ability to reduce inflammation, improve tissue remodeling, and enhance repaired tendon strength. Human trials, while varied and limited, suggest that MSCs might lower retear rates and enhance post-repair outcomes, but randomized controlled trials yield mixed results, emphasizing the necessity for standardized investigations. Ultimately, while cell-based therapies demonstrate an excellent safety profile, more rigorous clinical trials are necessary to determine their efficacy in improving patient outcomes and achieving lasting structural changes in rotator cuff injuries.
Assuntos
Procedimentos de Cirurgia Plástica , Lesões do Manguito Rotador , Animais , Humanos , Lesões do Manguito Rotador/terapia , Manguito Rotador/cirurgia , Tendões/cirurgia , Terapia Baseada em Transplante de Células e Tecidos , Resultado do TratamentoRESUMO
Purpose: The Shock Index Pediatric Age-Adjusted (SIPA) score is a useful tool for identifying pediatric trauma patients at a risk of poor outcomes and for triaging. We are studying the relationship between elevated SIPA score and specific outcomes in pediatric trauma patients. Materials and Methods: A retrospective study was conducted in which case records of 58 pediatric patients with blunt abdominal trauma were evaluated and tabulated for their SIPA scores only at the time of their initial presentation and categorized into two groups - normal SIPA and elevated SIPA. The primary outcomes were need for blood transfusion, need for any intervention, and need for emergency surgery, and the secondary outcomes were need for computed tomography (CT) scan, need for a ventilator, intensive care unit (ICU) stay, length of hospital stay, and mortality. Statistical methods were applied to find a relationship between elevated SIPA score and the primary and secondary outcomes. Results: An elevated SIPA score was noted in 27 (46%) patients. There was a significant relationship between elevated SIPA scores and patients needing blood transfusion (68.75%, n = 11) and length of hospital stay (10.48 ± 7.54 days). A significant relationship between elevated SIPA score and need for emergency surgery (54.54%, n = 6), need for a CT scan (56%, n = 14), and ICU stay (50%, n = 2) was not found. Conclusion: We have seen in our study that elevated SIPA scores at presentation are significantly related to need for blood transfusion and length of hospital stay. In more than half of the patients, elevated SIPA was associated with need for emergency surgery and requirement of CT scan, but it was statistically not significant. Therefore, assessment of this parameter can help in identifying such poor outcomes.
RESUMO
Background: Accidental ingestion of foreign bodies in children is critical, as the inability to effectively communicate can potentially lead to devastating consequences. We aimed to determine the epidemiology of foreign body ingestion and variability according to age, gender, type, and location of foreign body, and describe its management. Aim and Objective: The aim was to study the various types of foreign body ingestions in children admitted to pediatric surgery and their management. Materials and Methods: A retrospective study was conducted from January 2020 to June 2022 on children under the age of 12 years with a confirmed diagnosis of foreign body ingestion. Patients were clinically and radiologically assessed, after which standard protocols were followed wherein patients were followed by either observation or emergent management. Emergent management included removal of the foreign body by either endoscopy or surgery. Comparisons among multiple age groups, gender, type of foreign body, location of foreign body, and their management were analyzed. Results: Out of 99 subjects in our study, there were 76 boys and 23 girls. The median age of presentation was 5 years. Most children were asymptomatic at presentation. The most frequently ingested foreign body was a coin in all age groups. The majority of the foreign bodies were suspected to be in the small bowel. The foreign bodies that had crossed the duodenojejunal flexure (n = 74, 74.7%) were managed conservatively with the observation of a variable period of a minimum of 24 h and a maximum of 48 h. 21 cases were managed by endoscopic removal, while three cases required surgical intervention. Conclusions: Overall, the most common gastrointestinal foreign body was a coin in all age groups. Button battery is the most worrisome foreign body; however, depending on its position, it can be managed conservatively. Upper GI foreign bodies can be safely removed endoscopically. Parental counseling is very important for the prevention of ingestion of foreign bodies.
RESUMO
Magnetic foreign body ingestion poses a threat especially if more than one is ingested. If consumed alone, small magnetic foreign bodies are likely to pass without significant event; however, when multiple magnets are ingested, they can be attracted to each other through the intestinal wall, which may lead to serious consequences and complications, including bowel perforation, obstruction, peritonitis, and death. We report a case of a 2-years male child patient presented with multiple small round magnetic beads ingestion from a magnetic pendant that appeared like a necklace pearl after conglomeration on abdominal radiograph. On exploration, we found multiple perforations involving ileum, cecum, and transverse colon, with multiple conglomerated beads extruding from the perforation sites.
Assuntos
Anemia , Mielofibrose Primária , Humanos , Mielofibrose Primária/tratamento farmacológico , Mielofibrose Primária/complicações , Anemia/tratamento farmacológico , Anemia/etiologia , Feminino , Proteínas Recombinantes de Fusão/uso terapêutico , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , IdosoAssuntos
Imidazóis , Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras , Piridazinas , Recidiva , Humanos , Piridazinas/uso terapêutico , Piridazinas/efeitos adversos , Piridazinas/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Imidazóis/uso terapêutico , Imidazóis/efeitos adversos , Imidazóis/administração & dosagem , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Adulto , Antineoplásicos/uso terapêutico , Antineoplásicos/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/efeitos adversosRESUMO
Inotuzumab ozogamicin (INO) is an anti-CD22 antibody-drug conjugate that was first evaluated in B-cell lymphomas but was subsequently shown to be highly effective in acute lymphoblastic leukemia (ALL). INO improved response rates and survival in a randomized study in adults with relapsed/refractory B-cell ALL, leading to its regulatory approval in the United States in 2017. While the formal approval for INO is as monotherapy in relapsed/refractory ALL, subsequent studies with INO administered in combination with chemotherapy and/or blinatumomab both in the frontline and salvage settings have yielded promising results. In this review, we discuss the clinical development of INO in ALL, highlighting lessons learned from the initial clinical trials of INO, as well as the many ongoing studies that are seeking to expand the role of INO in ALL.
Assuntos
Inotuzumab Ozogamicina , Leucemia-Linfoma Linfoblástico de Células Precursoras , Inotuzumab Ozogamicina/uso terapêutico , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Antineoplásicos Imunológicos/uso terapêutico , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
Patients with systemic lupus erythematosus (SLE) frequently show symptoms of central nervous system involvement, termed neuropsychiatric SLE (NPSLE). Central nervous system (CNS) vasculitis is one of the neurological pathologies seen in CNS lupus. Patients with NPSLE typically present with nonspecific symptoms such as headache and cognitive impairment. Due to a lack of specific neuroradiological findings, diagnosis and management of such patients remain a big challenge. We report a 5-year-old girl who presented with fever and headache as the only neurological symptoms. Magnetic resonance imaging (MRI) of the brain showed focal grey and white matter lesions, suggestive of inflammatory or demyelinating ethology. Even though MR imaging findings may not be diagnostic of CNS lupus vasculitis, the study is routinely performed as a part of initial evaluation in patients with juvenile SLE showing neurological signs and symptoms.
RESUMO
The complex structure of biopharmaceutical products poses an inherent need for their thorough characterization to ensure product quality, safety, and efficacy. Analytical size exclusion chromatography (SEC) is a widely used technique throughout the development and manufacturing of monoclonal antibodies (mAbs) which quantifies product size variants such as aggregates and fragments. Aggregate and fragment content are critical quality attributes (CQAs) in mAb products, as higher contents of such size heterogeneities impact product quality. Historically, SEC methods have achieved sufficient separation between the high molecular weight (HMW) species and the main product. In contrast, some low molecular weight (LMW) species are often not sufficiently different in molecular mass from the main product, making it difficult to achieve appropriate resolutions between the two species. This lack of resolution makes it difficult to consistently quantify the LMW species in mAb-based therapeutics. The following work uses a design of experiments (DoE) approach to establish a robust analytical SEC procedure by evaluating SEC column types and mobile phase compositions using two mAb products with different physiochemical properties. The resulting optimized procedure using a Waters™ BioResolve column exhibits an improved ability to resolve and quantify mAb size variants, highlighting improvement in the resolution of the LMW species. Additionally, the addition of L-arginine as a mobile phase additive showed to reduce secondary interactions and was beneficial in increasing the recoveries of the HMW species.
Assuntos
Anticorpos Monoclonais , Produtos Biológicos , Anticorpos Monoclonais/química , Cromatografia Líquida de Alta Pressão , Cromatografia em Gel , Peso MolecularRESUMO
The outcome of Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) has improved significantly following the introduction of the BCR::ABL1 tyrosine kinase inhibitors (TKIs). The addition of newer-generation and more potent TKIs resulted in higher rates of molecular responses and better survival. Achieving a complete molecular remission (CMR; disappearance of the BCR::ABL1 transcripts) within the first 3 months of therapy is an important endpoint in newly diagnosed Ph-positive ALL that identifies patients who have an excellent long-term survival and who may not need to receive an allogeneic hematopoietic stem cell transplantation (HSCT) in first complete remission (CR). Chemotherapy-free combinations with blinatumomab plus TKIs showed encouraging results with estimated 2 to 4 year overall survival (OS) rates of 80% to 90%. Treatment with blinatumomab and ponatinib resulted in a CMR rate of 84%, a 2-year event-free survival (EFS) of 78%, and a 2-year OS rate of 90%; only 1 patient underwent HSCT. The detection of measurable residual disease (MRD) is the most important factor predicting for disease relapse. Studies have shown that the next-generation sequencing (NGS) assay is more sensitive than RT-PCR for the detection of MRD in Ph-positive ALL. Approximately 15% to 30% of patients who achieve NGS MRD negativity at a sensitivity of 1 × 10-6 may still have detectable BCR::ABL1 transcripts by RT-PCR. Achieving NGS MRD negativity can also identify patients who may have durable remissions with a low risk of relapse. Herein, we discuss the current approach to the management of adults with Ph-positive ALL, the role of HSCT, MRD monitoring, and future therapies.
Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Cromossomo Filadélfia , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Transplante de Células-Tronco Hematopoéticas/métodos , Proteínas de Fusão bcr-abl/genética , Neoplasia ResidualRESUMO
ABSTRACT: Total hip arthroplasty is an effective procedure to improve pain, range of motion, and function for a variety of conditions, including osteoarthritis and posttraumatic arthritis. Up to 28% of patients had persistent pain at the surgical site 12-18 mos after total hip arthroplasty, even in the absence of surgical complications. Currently, there are no widely accepted nonpharmacological treatments for persistent postoperative pain for total hip arthroplasty. This case report details the successful management of a 53-yr-old man with chronic pain and weakness after posttraumatic total hip arthroplasty. He was initially treated with a single-lead percutaneous peripheral nerve stimulator near the right femoral nerve for 4 weeks with 100-Hz frequency sensory-level parameters. Four weeks after implantation, the frequency was changed to 12 Hz with a goal of motor-level stimulation. During the after 3-week time period, his hip flexion strength improved from 10.36 kg to 23.04 kg. His Lower Extremity Functional Scale improved from 35/80 (43.75%) to 54/80 (67.5%) within a 5-wk time period. This case's success demonstrates how peripheral nerve stimulation may help improve postoperative persistent pain and weakness in many patients, including those with posttraumatic arthroplasty.
Assuntos
Artroplastia de Quadril , Dor Pós-Operatória , Humanos , Masculino , Pessoa de Meia-Idade , Dor Pós-Operatória/etiologia , Dor Pós-Operatória/terapia , Nervo Femoral , Terapia por Estimulação Elétrica/métodos , Estimulação Elétrica Nervosa Transcutânea/métodos , Amplitude de Movimento Articular , Dor Crônica/etiologia , Dor Crônica/terapiaRESUMO
ABSTRACT: Reverse total shoulder arthroplasty (rTSA) is an effective procedure to improve shoulder pain, range of motion, and function for a variety of conditions, including glenohumeral osteoarthritis and rotator cuff arthropathy. However, up to 22% of patients have persistent shoulder pain 12 to 24 months following rTSA, even in the absence of surgical complications. Currently, there are no widely accepted non-pharmacological treatments for persistent postoperative pain after rTSA. This case report details the successful management of a 64-year-old woman with chronic postoperative shoulder pain following rTSA. She was treated with single-lead percutaneous peripheral nerve stimulation to the right axillary nerve for eight weeks with 12 Hz motor-level stimulation. She demonstrated improvement in shoulder flexion active range of motion, shoulder flexion strength, and shoulder abduction strength. Her Shoulder Pain and Disability Index total score improved from 26.93% to 8.46% one year following treatment. She reported an overall Global Rating of Change of +7 one year following treatment. This case's success demonstrates that short term peripheral nerve stimulation may provide long-term improvement of persistent post-operative pain and dysfunction in patients with painful rTSA.
RESUMO
Quantum key distribution (QKD) enables two remote parties to share encryption keys with security based on the laws of physics. Continuous-variable (CV) QKD with coherent states and coherent detection integrates well with existing telecommunication networks. Thus far, long-distance CV-QKD has only been demonstrated using a highly complex scheme where the local oscillator is transmitted, opening security loopholes for eavesdroppers and limiting potential applications. Here, we report a long-distance CV-QKD experiment with a locally generated local oscillator over a 100-kilometer fiber channel with a total loss of 15.4 decibels. This record-breaking distance is achieved by controlling the phase noise-induced excess noise through a machine learning framework for carrier recovery and optimizing the modulation variance. We implement the full CV-QKD protocol and demonstrate the generation of keys secure against collective attacks in the finite-size regime. Our results mark a substantial milestone for realizing CV quantum access networks with a high loss budget and pave the way for large-scale deployment of secure QKD.