Autologous Transplantation Research Articles

OTHR-05. ROLES OF GEMCITABINE-OXALIPLATIN (GEMOX) ADD-ON THERAPY IN INFANT-TYPE BRAIN TUMORS: A SINGLE CENTER EXPERIENCE

Abstract BACKGROUND Combined gemcitabine and oxaliplatin (GemOx) was evaluated in recurrent pediatric solid tumors, showing safety but limited activity. In neuro-oncological infant patients, chemotherapy intensified to high doses (HDC) represents the cornerstone, avoiding radiotherapy toxicities. We describe the roles of GemOx towards autologous transplantation in infant-type brain tumors. METHODS From May 2017 to January 2024, at the Meyer Children’s Hospital IRCCS in Florence, six children (median age 19 months, sex equally distributed, three high-grade gliomas, a metastatic medulloblastoma MM, a pineoblastoma, a choroid plexus carcinoma CPC) completed GemOx after induction chemotherapy delivered according to Italian program for malignant brain tumors under 3 years. GemOx was administered to achieve clinical and neuroradiological permissiveness to HDC and to raise the possibility of second look neurosurgery. RESULTS Gemcitabine 1000 mg/m2 and Oxaliplatin 100 mg/m2 were given every 14-28 days for 1-6 cycles. At re-assessment, maximum every four cycles, disease control was optimal (five stable diseases and one partial response according to RECIST criteria). After GemOx, one patient was also subjected to further neurosurgery. The treatment was overall well tolerated, except for Common Terminology Criteria for Adverse Events (CTCAE) grade 4 platelet toxicity in two patients (one of whom also developed hydrocephalus CTCAE 3 and hyponatremia CTCAE 4 during treatment). All patients were safely exposed to HDC (1-2 courses). MM and CPC patients progressed respectively 4 ad 19 months after the end of GemOx. The latter underwent second look neurosurgery, and a radiotherapy course was delivered to both, considering the achievement of permissive age. To date all patients are alive. CONCLUSIONS In brain infant-type malignant tumors strategies are limited due to the extremely vulnerable age. GemOx treatment should be considered a reasonable and safe option waiting for intensified treatment, especially in radiotherapy delaying programs, and it should result incisive in the therapeutic or palliative choice.

MDB-51. PHASE II INTERVENTIONAL STUDY TO EVALUATE THE SAFETY AND EFFICACY OF STANDARD AND HIGH-DOSE CHEMOTHERAPY COMBINED WITH CRANIOSPINAL IRRADIATION WITH PROTON THERAPY IN PATIENTS WITH METASTATIC MEDULLOBLASTOMA AND OTHER EMBRYONIC CANCERS: PRELIMINARY RESULTS

Abstract BACKGROUND The high risk medulloblastoma remains a leading cause of cancer-related death in children. METHODS A total of 18 patients have been enrolled from February 2018 to May 2022.The median age was 7,5 years (range; 12 males and 6 female). The protocol predicted the first phase of induction with 4 cycles of chemotherapy. After induction patients with favorable histology without evidence of disease were enrolled to proton therapy (with concomitant vinorelbine biweekly). The maintenance phase with Lomustine repeated every 9 weeks and vinorelbine every 3 weeks for overall 12-18 months (PR). Conversely LC/A MB, were subjected to consolidation phase with high dose of chemotherapy with tiothepa followed by autologous HSC transplant and successive maintenance phase of 6 months. RESULTS At October 2023, the median follow up was 24 months. After the induction phase 14 patients showed CR, 2 PR, 1PD, 1SD. At subsequent re-evaluations two with PR, showed disease control, one CR and the other SD and the patient with PD showed CR. Patient with SD showed an unchanged state of the disease. During the reporting period two patient died for progression of the underlying disease. At 24 months from the start of treatment the PFS was 75,4 % (95% CI: 34.1% - 87.6%) and at 15 months the OS was 86,1% (95% CI: 68.1% - 99.2%). The principal expected side effects of chemotherapy were hematology toxicity and 58% rate of GH deficiency. Among the unexpected side effect was CMV retinopathy with complete blindness and leukoencephalopathy after high dose of thiotepa and proton irradiation. We reported only one case of ototoxicity. CONCLUSIONS The use of proton therapy combined with intensive chemotherapy and myeloablative chemotherapy only in selected cases and always before irradiation has proven feasible and effective in the treatment of high-risk patients medulloblastomas and other embryonic tumors.

ATRT-18. ALISERTIB USED IN PEDIATRIC ATRT

Abstract BACKGROUND Atypical rhabdoid tumor (ATRT) is a rare and aggressive primary CNS tumor caused by variants or deletions in the tumor suppressor gene SMARCB1 (aka INI 1). SMARCB1 targets Aurora A kinase (AURKA), an important oncoprotein of the cell cycle. AURKA dysregulation can lead to genomic instability through its oncogenic effects. Alisertib is a selective AURKA inhibitor that has been explored for treatment in various cancers, including pediatric malignancies. METHODS Retrospective chart review of five patients diagnosed with ATRT, treated with Alisertib, at Nicklaus Children’s Hospital from 2019 - 2024. RESULTS of the 5 patients; three were females and two males, with a median age at diagnosis of 2 years. Only one patient had a germline mutation while the rest had somatic mutations. Prior to starting Alisertib therapy, all five patients received chemotherapy per multiple protocols; four patients underwent focal radiation therapy, three patients underwent resection, and two patients underwent tandem autologous transplants. All five patients were treated solely with Alisertib, median dose of 60 mg/m2 PO daily. Two patients had reduced doses during therapy secondary to cytopenia. One patient completed therapy over 13 months with partial response based on imaging. One patient presented progression of disease while on therapy and for that reason treatment was stopped. Three patients continue treatment: two with only Alisertib, one using Avastin and Sirolimus concurrently. CONCLUSIONS Prognosis in patients with ATRT is usually poor given its aggressive nature and high rate of recurrence despite intervention. It is important to note that treatment of ATRT is highly individualized and typically involves a combination of therapeutic modalities. While Alisertib is one of the newest treatment options, there’s limited literature of clinical improvement in patients with ATRT using this treatment. Therefore, further research on novel treatment options is warranted for the future.

Therapeutic approach to ocular coloboma - a case report of a 37-year-old patient with high myopia and choroidal coloboma of the right eye

Introduction: Coloboma is a congenital malformation caused by a defect of optic fissure closure. We report a rare case of choroidal coloboma and management of possible complications. Clinical case: A 37-year-old patient presented for the current evaluation of uveal coloboma located in the inferior-nasal quadrant with the involvement of the optic disc and advanced high myopia. Conclusions: The management of coloboma includes follow-up of visual acuity level, anterior segment and fundus evaluations. Retinal detachment, cataract and choroidal neovascularization may occur secondary to the defect. Pars plana vitrectomy, autologous neurosensory retinal transplantation and laser therapy are considered methods in present case.

Percutaneous vertebroplasty/kyphoplasty contributes to the improved outcome in patients with newly diagnosed multiple myeloma: A single center cohort study

ObjectiveTo evaluate the efficacy and prognosis of percutaneous vertebroplasty/kyphoplasty (PVP/PKP) in patients with newly diagnosed multiple myeloma (NDMM). MethodsClinical data of NDMM patients who underwent PVP/PKP during front-line regimen at Peking Union Medical College Hospital from January 1, 2003, to June 30, 2023, were analyzed. Patients with comparable bone diseases not receiving orthopedic surgery were selected as controls. Visual analogue scale (VAS) score, progression-free survival (PFS), and overall survival (OS) were compared. ResultsBaseline characteristics were matched between the surgical group (n = 51 with 56 surgeries) and non-surgical group (n = 102), including demographics, tumor load, International Staging System (ISS), bone diseases, cytogenetic abnormalities, first-line treatment, and autologous stem-cell transplantation (ASCT). Bone lesions for PVP/PKP were located at thoracic vertebrae (53.6 %, 30/56) or lumbosacral vertebrae (46.4 %, 26/56). The postoperative VAS score was significantly improved (2.25 ± 0.81 vs 5.92 ± 1.05, P < 0.001). The median follow-up time was 51[38–70] months. Kaplan-Meier survival analysis suggested that both PFS (37[17–89] vs 23[12–61] months, HR 0.648, 95 %CI 0.431–0.973, P = 0.047) and OS (not reached vs 66[28-NR] months, HR 0.519, 95 %CI 0.296–0.910, P = 0.045) were significantly prolonged in the surgical group. COX multivariate analysis suggested that PVP/PKP was an independent prognostic factor for PFS (P = 0.021, HR 0.589, 95 %CI 0.376–0.922) and OS (P = 0.038, HR 0.496, 95 %CI 0.255–0.963). Subgroup analysis confirmed that patients with ISS II/III or non-ASCT achieved better PFS and OS in the surgical group (PFS: P = 0.033, P = 0.040; OS: P = 0.024, P = 0.018 respectively), while similar survival outcome was observed in patients with ISS I or ASCT between two groups. ConclusionFor NDMM patients, not only does PVP/PKP alleviate bone pain, meanwhile, it improves the PFS and OS in advanced subpopulation or non-transplant myeloma patients, which suggests that shortening the gap from symptom onset to diagnosis by orthopedic surgery favors clinical prognosis.

Перспективні методи лікування передчасної недостатності яєчників

Premature ovarian failure (PОF) in women under 40 is a medical condition in which ovarian follicles are exhausted and cease to function normally as both reproductive and endocrine organs. This condition often leads to infertility because it is associated with hypoestrogenia, which causes menstrual irregularities and pregnancy failure. Decreased estrogen secretion also causes many menopausal symptoms, such as hot flashes, night sweats, and insomnia. In addition, the longterm consequences of POF increase the risk of lifelong skeletal vulnerability and cardiovascular as well as neurocognitive disorders. The purpose of the work is to collect, analyze and summarize data from recent years about promising methods of treatment of premature ovarian failure, namely about autologous ovarian tissue transplantation, creation of artificial ovaries and oocytes, treatment with iron nanoparticles, intraovarian injections of autolytic platelet-rich plasma. It should be noted that premature ovarian failure (POF) differs from menopause in that ovarian failure may not be permanent; in such patients with POF, pregnancy is spontaneous and occurs infrequently. Our analysis and summarization of data from recent years suggests that 1) because autologous ovarian tissue transplantation requires tissue collection, this method is generally applicable to a specific patient group, women who are expected to have ovarian failure after cancer therapy, and a group of patients who experience gamete depletion as a result of a prognosis or even a diagnosis of POF. Ovarian tissue transplantation, which has been known for two decades, still has significant risks and technical limitations and is not recognized as a reliable method in clinical practice. 2) the concept of "artificial ovary" remains at the stage of experimental development of cellular systems in animals. Whereas, by creating artificial oocytes from several different sources (cell types), live birth has already been achieved in animals. And expectations are aimed at a steady progression to their clinical use in humans. 3) the use of zero-valent iron nanoparticles under the conditions of experimental immune complex failure has a certain corrective effect on the disorder of ovarian function. There is reason to believe that the effect of the treatment with zero-valent iron nanoparticles is fundamentally different from the macroscopic one in the effects on cells and, apparently, in the mechanisms of action - which requires further study. 4) treatment with platelet-rich plasma (PRP) remains an invasive ultrasound-guided procedure with risks that are not yet fully understood. At this point, PRP should still be considered an experimental procedure for patients with POF (premature ovarian failure). It is relevant to continue research on the influence of PRP components on the ovary, to evaluate the effect of the PRP concentration, which could play a key role in the proliferation and differentiation of mesenchymal cells; and to establish the optimal time intervals between PRP procedures, the volume treatment, and the maximum and minimum number of such procedures. In general, the proposed promising methods (autologous ovarian tissue transplantation, creation of artificial ovaries and oocytes, use of nanomaterials (iron nanoparticles), intraovarian injections of autolytic platelet-rich plasma) are achievements in biomedical engineering aimed at overcoming infertility, associated with premature ovarian failure.

How framing bias impacts preferences for innovation in bone tissue engineering.

It is currently unknown if surgeons and biomaterial scientists &or tissue engineers (BS&orTE) process and evaluate information in similar or different (un)biased ways. For the gold standard of surgery to move "from bench to bedside", there must naturally be synergies between these key stakeholders' perspectives. Because only a small number of biomaterials & tissue engineering innovations have been translated into the clinic today, we hypothesised this lack of translation is rooted in the psychology of surgeons and BS&orTE. Presently, both clinicians and researchers doubt the compatibility of surgery and research in their daily routines. This has led to the use of a metaphorical expression "squaring of the circle," which implies an unsolvable challenge. As bone tissue engineering belongs to the top 5 research areas in tissue engineering we choose the field of bone defect treatment options for our bias study. Our study uses an online survey instrument for data capture: incorporating a behavioural economics cognitive framing experiment methodology. Our study sample consisted of surgeons (n=208) and BS&orTE (n=59). And we employed a convenience sampling method, with participants (conference attendants) being approached both in person and via email - 22 October 2022-13 March 2023. We find no distinct positive-negative cognitive framing differences by occupation. That is, any framing bias present in this surgical decision-making setting does not appear to differ significantly between surgeon and BS&orTE specialisation. When we explored within group differences by frames, we see statistically significant (p<0.05) results for surgeons in the positive frame ranking autologous bone graft transplantation lower compared to surgeons in the negative frame. Further, surgeons in the positive frame rank Ilizarov bone transport method higher compared to surgeons in the negative frame (p<0.05).

Outcomes Following the Use of Extracellular Matrix Cartilage Allograft for the Management of Osteochondral Lesions of the Talus: A Systematic Review.

Extracellular matrix cartilage allograft (EMCA) is a novel biological strategy utilized to augment the repair of osteochondral lesions of the talus (OLTs). However, there is no consensus on the precise role and outcomes following its use in the treatment of OLTs. The purpose of this systematic review was to evaluate the clinical and radiological outcomes following the use of EMCA for the treatment of OLT.During July 2023, the PubMed, Embase, and Cochrane Library databases were systematically reviewed to identify clinical studies examining outcomes following EMCA for the management of OLTs.In total, 162 patients (162 ankles) across five studies received EMCA as part of their surgical procedure at a weighted mean follow-up time of 23.8±4.2 months. Across all five studies, there were improvements in subjective clinical outcomes following the use of EMCA, regardless of the clinical scoring tool utilized. Two studies demonstrated superior postoperative magnetic resonance observation of cartilage repair tissue (MOCART) scores in the EMCA cohort compared to the bone marrow stimulation (BMS) cohort alone.In the EMCA-BMS cohort, there were seven complications (9%) and three failures (4.1%). In the autologous osteochondral transplantation (AOT) cohort, there were 10 complications (38.5%), zero failures, and six secondary surgical procedures (23.1%). In the EMCA alone cohort, there were zero complications and three failures (4.3%), all of which underwent an unspecified revision procedure. This current systematic review demonstrated improvements in both clinical and radiological outcomes following the use of EMCA for the treatment of OLTs.Further prospective comparative studies with longer follow-up times are warranted to determine the precise role of EMCA in the management of OLT.

CLINICAL OUTCOMES OF AUTOLOGOUS OSTEOCHONDRAL TRANSPLANTATION FOR OSTEOCHONDRAL LESIONS OF THE TALUS: AN AGE-BASED MULTIVARIABLE ANALYSIS

IntroductionThe purpose of this study was to examine trends in patient characteristics and clinical outcomes that occur with age as a statistical variable when performing autologous osteochondral transplantation (AOT) for the treatment of osteochondral lesions of the talus (OLT).MethodsA retrospective cohort study for AOT procedures on 78 patients from 2006 to 2019. was conducted Clinical outcomes were evaluated via FAOS scores. A multivariable linear regression was used to assess the independent factors predictive of the first post-operative FAOS after AOT. The independent variables included pre-operative FAOS, age, defect size, shoulder lesion, cystic lesion, prior traumatic injury, and history of microfracture surgery. A p-value &lt;.05 was considered significant and 95% confidence limits (95% CL) for regression coefficient estimates (est.) were calculated.Results78 patients were included with a mean age of 35.5 ± 13.6years at a mean follow-up was 54.4 ± 18.9 months. The mean pre-operative FAOS was 54.3 ± 19.4 and the mean post-operative FAOS was 83.4 ± 13.6. The mean defect size was 109.3±62.4 mm2. The multivariable linear regression showed that the pre-operative FAOS was associated with a higher post-operative FAOS (est., 95% CL: 0.16, 0.012 – 0.307; p=0.034). Defect size (est., 95% CL: −0.05, −0.097 – −0.003; p=0.0358), having a shoulder lesion (est., 95% CL: −9.068, −15.448 – −2.688; p=0.006), or having a prior microfracture surgery (est., 95% CL: −7.07, −13.118 – −1.021; p=0.0226) were associated with a lower post-operative FAOS.ConclusionPatient age was not an independent risk factor for inferior clinical outcomes after AOT for OLT. Additionally, cystic lesions, or lesions with a traumatic aetiology were not significantly associated with post-operative FAOS. Having a shoulder lesion had the largest marginal effect on post-operative FAOS. These findings provide important information for providers when counseling and selecting patients for AOT procedure for treatment of OLT.

Trends in Outcomes After Upfront Autologous Transplant for Multiple Myeloma Over Three Decades

Upfront autologous stem cell transplantation (auto-SCT) remains standard of care for eligible patients with newly diagnosed multiple myeloma (NDMM), although recently its role has been questioned. The aim of the study was to evaluate trends in patient characteristics, treatment, and outcomes of NDMM who underwent upfront auto-SCT over three decades. We conducted a single-center retrospective analysis of patients with NDMM who underwent upfront auto-SCT at MD Anderson Cancer Center between 1988 to 2021. Primary end points were progression-free survival (PFS) and overall survival (OS). Patients were grouped by the year of auto-SCT: 1988-2000 (n = 249), 2001-2005 (n = 373), 2006-2010 (n = 568), 2011-2015 (n = 815) and 2016-2021 (n = 1036). High-risk cytogenetic abnormalities were defined as del (17p), t (4;14), t (14;16), and 1q21 gain or amplification by fluorescence in situ hybridization. We included 3041 MM patients in the analysis. Median age at auto-SCT increased from 52 years (1988-2000) to 62 years (2016-2021), as did the incidence of high-risk cytogenetics from 15% to 40% (P < .001). Comorbidity burden, as measured by a Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI) of >3, increased from 17% (1988-2000) to 28% (2016-2021) (P < .001). Induction regimens evolved from predominantly chemotherapy to immunomodulatory drug (IMiD) and proteasome inhibitor (PI) based regimens, with 74% of patients receiving IMiD-PI triplets in 2016-2021 (39% bortezomib, lenalidomide and dexamethasone (VRD) and 35% carfilzomib, lenalidomide and dexamethasone [KRD]). Response rates prior to auto-SCT steadily increased, with 4% and 10% achieving a ≥CR and ≥VGPR compared to 19% and 65% between 1988-2000 and 2016-2021, respectively. Day 100 response rates post auto-SCT improved from 24% and 49% achieving ≥CR and ≥VGPR between 1988-2000 to 41% and 81% between 2016-2021, respectively. Median PFS improved from 22.3 months between 1988-2000 to 58.6 months between 2016-2021 (HR 0.42, P < .001). Among patients with high-risk cytogenetics, median PFS increased from 13.7 months to 36.8 months (HR 0.32, P < .001). Patients aged ≥65 years also had an improvement in median PFS from 33.6 months between 2001 and 2005 to 52.8 months between 2016-2021 (HR 0.56, P = .001). Median OS improved from 55.1 months between 1988-2000 to not reached (HR 0.41, P < .001). Patients with high-risk cytogenetics had an improvement in median OS from 32.9 months to 66.5 months between 2016-2021 (HR 0.39, P < .001). Day 100 non-relapse mortality from 2001 onwards was ≤1%. Age-adjust rates of second primary malignancies were similar in patients transplanted in different time periods. Despite increasing patient age and comorbidity burden, this large real-world study demonstrated significant improvements in the depth of response and survival outcomes in patients with NDMM undergoing upfront auto-SCT over the past three decades, including those with high-risk disease.

Phase-changing citrate macromolecule combats oxidative pancreatic islet damage, enables islet engraftment and function in the omentum

Clinical outcomes for total-pancreatectomy followed by intraportal islet autotransplantation (TP-IAT) to treat chronic pancreatitis (CP) are suboptimal due to pancreas inflammation, oxidative stress during islet isolation, and harsh engraftment conditions in the liver’s vasculature. We describe a thermoresponsive, antioxidant macromolecule poly(polyethylene glycol citrate- co - N -isopropylacrylamide) (PPCN) to protect islet redox status and function and to enable extrahepatic omentum islet engraftment. PPCN solution transitions from a liquid to a hydrogel at body temperature. Islets entrapped in PPCN and exposed to oxidative stress remain functional and support long-term euglycemia, in contrast to islets entrapped in a plasma-thrombin biologic scaffold. In the nonhuman primate (NHP) omentum, PPCN is well-tolerated and mostly resorbed without fibrosis at 3 months after implantation. In NHPs, autologous omentum islet transplantation using PPCN restores normoglycemia with minimal exogenous insulin requirements for &gt;100 days. This preclinical study supports TP-IAT with PPCN in patients with CP and highlights antioxidant properties as a mechanism for islet function preservation.

Yttrium-90 anti-CD25 BEAM conditioning for autologous hematopoietic cell transplantation in Peripheral T-cell lymphoma

AbstractPeripheral T-cell lymphomas (PTCLs) have a poor prognosis with current treatments. High-dose chemotherapy followed by autologous hematopoietic cell transplant (AHCT) is used as a consolidation strategy after achieving clinical remission with first-line therapy, as well as in chemotherapy-sensitive relapse if allogeneic transplant is not an option. CD25 is a targetable protein often highly expressed in PTCLs. In this phase 1 clinical trial, we tested the addition of β-emitting 90yttrium (90Y)–labeled chimeric anti-CD25 basiliximab (aTac) to BEAM (carmustine, etoposide, cytarabine, and melphalan) as conditioning for AHCT for patients with PTCL. Twenty-three AHCT-eligible patients were enrolled, and 20 received therapeutic 90Y-aTac-BEAM AHCT. Radiation doses of 0.4, 0.5, and 0.6 mCi/kg were tested. With no observed dose-limiting toxicities, 0.6 mCi/kg was deemed the recommended phase 2 dose. The most prevalent adverse effect, grade 2 mucositis, was experienced by 80% of patients. As of this report, 6 (30%) of the treated patients had died, 5 due to progressive disease and 1 due to multiple organ failure (median time of death, 17 months [range, 9-21]) after AHCT. Median follow-up was 24 months (range, 9-26) overall and 24 months (range, 13-26) for surviving patients. For patients who received therapeutic 90Y-aTac-BEAM AHCT, the 2-year progression-free and overall survival were 59% (95% confidence interval [CI], 34-77) and 68% (95% CI, 42-84), respectively. 90Y-aTac-BEAM appears to be safe as an AHCT conditioning regimen for PTCL, with no increased toxicity over the toxicities historically seen with BEAM alone in this patient population. This trial was registered at www.ClinicalTrials.gov as #NCT02342782.

Shortfalls of free autologous internal limiting membrane transplantation for highly myopic refractory macular holes in a long term follow-up.

The aim of this study is to evaluate long-term anatomical and functional outcomes of autologous internal limiting membrane (ILM) transplantation in refractory highly myopic macular holes (HMMHs). Retrospective interventional analysis of 13 eyes with refractory HMMH undergoing autologous ILM transplantation with gas tamponade. Best-corrected visual acuity (BCVA, Snellen), optical coherence tomography and fundus photography were scheduled at baseline and every follow-up visit (1, 3, 6, 12, 18, 24 months and the most recent). Preoperatively, we collected minimum linear diameter (MLD) and basal diameter (BD). Post-operatively, rates of external limiting membrane (ELM)/ellipsoid zone (EZ) restoration, excessive gliosis and subfoveal retinal pigmented epithelium (RPE) atrophy were evaluated. Average AXL was 31.45 ± 2.07mm and mean follow-up was 47.2 ± 31.4 months. Anatomical success was reached in 7/13 eyes (54%), while 2 cases showed persisting HMMH, 2 cases had early recurrence and 2 cases late recurrence. BCVA went from 0.19 ± 0.18 to 0.22 ± 0.20 at final follow-up (p = 0.64), improving in 5/13 eyes (38%). One eye showed continuous ELM and EZ lines, while another eye showed an irregular ELM but no EZ. Post-operatively, 5 eyes (71%) developed progressive atrophy of the subfoveal RPE, while excessive gliosis was reported in 3 eyes (43%). Furthermore, one patient developed post-operative chronic macular edema-like changes in the perifoveal area. Autologous ILM transplantation showed controversial anatomical outcomes and and poor visual results in refractory HMMH. Moreover, progressive subfoveal patchy atrophy and excessive gliosis are possible post-operative complications.

A Novel CRISPR-Cas9 Strategy to Target DYSTROPHIN Mutations Downstream of Exon 44 in Patient-Specific DMD iPSCs.

Mutations in the DMD gene cause fatal Duchenne Muscular Dystrophy (DMD). An attractive therapeutic approach is autologous cell transplantation utilizing myogenic progenitors derived from induced pluripotent stem cells (iPSCs). Given that a significant number of DMD mutations occur between exons 45 and 55, we developed a gene knock-in approach to correct any mutations downstream of exon 44. We applied this approach to two DMD patient-specific iPSC lines carrying mutations in exons 45 and 51 and confirmed mini-DYSTROPHIN (mini-DYS) protein expression in corrected myotubes by western blot and immunofluorescence staining. Transplantation of gene-edited DMD iPSC-derived myogenic progenitors into NSG/mdx4Cv mice produced donor-derived myofibers, as shown by the dual expression of human DYSTROPHIN and LAMIN A/C. These findings further provide proof-of-concept for the use of programmable nucleases for the development of autologous iPSC-based therapy for muscular dystrophies.

Biofunctionalisation strategies of material surface and the inspired biological effects for bone repair

AbstractDue to trauma and disease, bone defects endanger the healthy life of human beings. At present, the gold standard for bone defect repair is still autologous bone transplantation and allogeneic bone transplantation. However, its insufficient source, potential disease transmission and immune rejection limit its clinical application. Therefore, the development of bone repair materials plays an important role in promoting bone repair. As the interface between material and tissue, the surface of the material plays an important role in the reaction after implantation, which determines the effectiveness of defect repair treatment. With the development of surface engineering and technology, bone repair materials have developed from biological inertia to biological activity by endowing various biological functions by controlling the composition, topological morphology and structure of the material surface etc. The inspired biofunctionalisation of material surface includes the capacities of inducing osteogenesis, promoting angiogenesis, antibacterial, immune regulation etc., as well as integration of postoperative repair and treatment. The authors review the biofunctionalisation of biomaterial surface and the inspired biological effects for bone repair, mainly including physical and chemical properties of material surface to regulate osteogenesis, and functional strategy of bone repair material surface.

Clinical impact of a change in antibiotics or the addition of glycopeptide antibiotics for persistent febrile neutropenia after autologous stem cell transplantation

BackgroundA change in empirical antibiotics or the addition of glycopeptide antibiotics is often applied in cases of persistent febrile neutropenia (FN) despite the administration of broad-spectrum antibiotics. However, the clinical benefit of these approaches remains unclear. MethodsWe conducted a retrospective study to evaluate the effectiveness of a change in antibiotics or the addition of glycopeptide antibiotics for persistent FN after autologous hematopoietic cell transplantation (auto-HCT). We retrospectively reviewed the records of 208 patients who received auto-HCT at our institution between 2007 and 2019. FN that lasted for 4 days or longer was defined as persistent FN. We compared the time to defervescence between patients whose initial antibiotics were changed and/or who additionally received glycopeptide antibiotics, and those without these antibiotic modifications. ResultsAmong patients who fulfilled the criteria of persistent FN (n = 125), changes in antibiotics were not significantly associated with the time to defervescence in a multivariate analysis (hazard ratio [HR] 0.72, p = 0.27). On the other hand, the addition of glycopeptide antibiotics was paradoxically associated with a delay in defervescence (HR 0.56, p = 0.033). ConclusionsAlthough there may be differences in patient backgrounds, no significant differences were observed in either a univariate or multivariate analysis. Since neither a change in antibiotics nor the addition of glycopeptide antibiotics was associated with earlier defervescence in persistent FN after auto-HCT, routine antibiotic modifications might not be necessary in this setting.

Improving clinical outcomes in multiple myeloma: Weight maintenance strategies to reduce complications during autologous hematopoietic transplantation.

e19533 Background: Multiple myeloma (MM) is the second most prevalent hematological disease. The introduction of melphalan as high-dose therapy followed by autologous hematopoietic cell transplantation (HDT/ASCT) for younger patients has dramatically changed treatment outcomes. Monitoring daily weights has been well documented in Acute promyelocytic leukemia (APL) induction, though little has been documented in myeloma patients receiving ASCT. Monitoring daily weights can be a useful tool in maintaining patients' euvolemic status and can help to facilitate appropriate resuscitation of patients who are otherwise prone to sepsis and fluid overload. At our center over the last few years, we have standardized an approach to monitoring and maintaining the weights of MM patients at or near their pre-admission level with fluids and diuresis, as needed. We report outcomes of weight monitoring on morbidity and mortality during ASCT for MM. Methods: We conducted a retrospective chart review of MM patients receiving ASCT at our center between January 2019 and December 2022. Patients whose weights were monitored and maintained within 3 kilograms of admission weight were identified. We looked at the length of stay (LOS) and ICU transfers during this time. We reviewed the records of 205 patients induced at our center. Results: The mean age was 62 years at the time of transplant (34-78). 119 of the 205 patients identified as men (58%). Out of 205 patients, 152 patients did not have their weights maintained. Of these 152 patients, 7 were transferred to ICU. 53 patients had weights maintained, of which 1 patient was transferred to ICU (OR 0.089 (95% CI 0.018-0.6725) (p = 0.019)). The mean LOS for all patients was 12.97 days. Mean LOS was 12.41(n = 53) and 13.18(n = 152) days for patients whose weights were and were not followed, respectively (mean difference of 0.77 days) (95 % CI of -0.15 to 1.68) (p = 0.0992). 3 of the 205 patients died during admission. In these patients, weights were not maintained before ICU transfer. (OR = 0.4072 (0.0207-8.0136) (p = 0.55)). Conclusions: Fluid overload and sepsis are significant concerns in the treatment of MM. Our findings suggest that maintaining euvolemia can effectively manage patients on the floor and limit and in some cases prevent ICU transfers. Although there are limitations to our study due to its retrospective, single-center nature, the cost-effectiveness and noninvasive means of maintaining euvolemic status support its potential application to standard treatment protocols. Further prospective studies are warranted to validate these findings. [Table: see text]

Evolving patterns of transplant strategies for mantle cell lymphoma in the era of BTK inhibitors and CAR-T therapy.

e19012 Background: Mantle cell lymphoma is an aggressive lymphoma with poor survival after chemotherapy alone. Both autologous (auto) and allogeneic (allo) transplants have improved outcomes over the years, but transplant strategies most beneficial for MCL are not clearly defined. Recently, BTK inhibitors and chimeric antigen therapies (CAR T) therapy approach has changed the landscape of Mantle cell Lymphoma. Methods: Patient Population:A total of 71 patients underwent transplant for diagnosis of MCL at Penn State Cancer Institute, between March 1993 and March 2023. Median follow up was 3.1 years (32 days-9883 days) after transplant. Patient Characteristics: A total of 71 patients (62 M: 9 F) underwent transplants, including autologous (n=30), allogeneic (n=32), and CAR T (n=9). Since 2020, 19 transplants were performed: CAR T (n=9) auto transplants (n=9) and allogeneic transplants (n=1). Relapsed and refractory MCL (n=4) patients received CAR T whereas patients achieving CR 1 (n=8) and PR1 (n=1) received auto transplants. Most patients were Caucasian (n= 68), with few Hispanic (1), African American (1), or Asian (1). Results: Median age at the time of transplant was 61 (37-70) years for autologous, 56 (33-67) years for allogenic and 63 (55 -75) years for CAR T respectively. Disease status at transplant was CR 52.1% (n=37), primary induction failure or relapsed/refractory 36.6% (n=26), PR 11.3% (n=8). High LDH was seen at the time of transplant in 16.9% (n=12) patients and normal in 83.1%(n=59) patients. Blastoid morphology was seen in only 13.8% (n=4) autologous, 37.9% (n=11) allogenic and 33.3% (n=3) CAR T patients. Outcomes: Overall survival (OS) at 1 year and 3 years was 93.3% and 85.9% for autologous (auto) transplants, 62.5% and 52.9% for Allogeneic (allo) transplants, 88.9% and 76.2% for CAR-T therapy respectively (P = 0.007). Progression free survival at 1 year and 3 years was 86.3% and 75.0% for auto transplants; 50.0% and 43.3% for allo Transplants; 66.7% and 66.7% for CART Therapy (P = 0.03). Primary cause of death was Treatment Related Mortality (TRM) (n= 9) (GVHD=4; Pulmonary=3; MOF=2) and disease progression (n=10); unknown (n=4); other (n=1). Primary cause of death for CAR T therapy was grade IV ICANS and disease progression. Conclusions: Recently CAR T therapies have changed the landscape of MCL treatment algorithm in both Blastoid and non-Blastoid histology MCL patients. But in the era of CAR T therapy and BTK inhibitors for MCL, achieving CR at the time of transplant predicts improved long-term outcomes. Randomized studies or larger retrospective CIBMTR data analysis may be important to answer best transplant strategy for MCL patients. [Table: see text]

The timing of checkpoint inhibition in relation to stem cell transplantation increases the risk of inflammatory adverse events.

e14706 Background: Stem cell transplantation (SCT) and immune checkpoint inhibitors (ICIs) are both used to treat hematological malignancies. There may sometimes be an overlap in the patient’s exposure to both treatments. Theoretically, ICIs potentiate the graft-versus-tumor effect following SCT but may increase the risk of inflammatory adverse events (AEs). Conversely, immunosuppression following SCT may decrease the risk of immune-mediated AEs. We aim to explore the effect of immunotherapy on the risk and severity of inflammatory AEs following SCT. Methods: We performed a single-center, retrospective chart review including all patients with a hematological malignancy who were treated with immunotherapy and received SCT. Patients who did not receive immunosuppressive regimens after their transplant (e.g., autologous transplants) were excluded. Patients were divided into 2 groups based on the timing of ICI: pre-SCT ICI (group 1) and post-SCT ICI (group 2). We gathered clinical data including patient demographics, post-SCT immunosuppressive regimens, and pre- and post-SCT inflammatory AEs. Results: 63 patients were included. Around 82% of patients in group 1 experienced a post-transplant AE compared to 50% in group 2 ( p = 0.014). These AEs occurred earlier in group 1 patients (median 57 days in group 1 vs. 195 in group 2; p = 0.007). Roughly 80% of the inflammatory conditions involved the gastrointestinal system. Severity and complication rates did not differ between groups, but gastrointestinal inflammation in group 1 was more likely to require immunosuppressive medication (75.7% and 37.8% requiring corticosteroids and selective immunosuppressive therapy, respectively, in group 1 patients vs. 33.3% and 0% in group 2 patients; p &lt; 0.05). Conclusions: To our knowledge, our study is one of few exploring the impact of ICI timing in relation to SCT on the risk of post-SCT inflammatory AEs. Administration of immunotherapy prior to SCT may predispose patients to inflammatory AEs after SCT, which may occur earlier and last longer than if ICIs are started after SCT. Future studies are needed to further explore this phenomenon. [Table: see text]

Paradigm Shifts in Hodgkin Lymphoma Treatment: From Frontline Therapies to Relapsed Disease.

Combination chemotherapy with or without radiation has served as the primary therapeutic option for classic Hodgkin lymphoma (cHL), leading to durable remission in a majority of patients with early- and advanced-stage cHL. Patients with relapsed/refractory (RR) cHL could still be cured with salvage chemotherapy and autologous stem-cell transplantation. Brentuximab vedotin (BV) and the anti-PD-1-blocking antibodies, nivolumab and pembrolizumab, are highly effective treatments for cHL and have revolutionized the management of the disease. Recent studies incorporating BV and PD-1 blockade into salvage therapy for RR cHL and into frontline treatment regimens have changed the cHL treatment paradigm. The novel agents are also useful in the treatment of older patients who have poor outcomes with traditional therapy. This manuscript will review current strategies for approaching the management of previously untreated, RR, and challenging populations with cHL, including how to incorporate the novel agents.