One-year Survival Rate Research Articles

Developing “Off-the-Shelf” CLL1 CAR-DNT Therapeutics for the R/R Acute Myeloid Leukemia

Background: Acute myeloid leukemia (AML) is one of the most common and highly heterogeneous hematological malignancy. The prognosis is poor especially for the elderly patients. For Relapsed/Refractory(R/R) AML patients, the one-year overall survival rate is merely 20%. CAR-T cells have shown tremendous therapeutic benefits for ALL, DLBCL and MM. One of the limitations of current CAR-T therapies is the use of autologous T cells. This can be limiting due to the cost, complicated manufacturing process, rapid disease progression, and manufacturing failures etc. Therefore, there is a need to develop the ready-to-use allogeneic cell product. Double negative T (DNT) cells are the ideal candidate for AML cell therapy as they naturally kill AML cells, and have been successfully administered to AML patients with therapeutic benefit without causing GvHD. Relying on their own natural immune activated receptors, DNT cells could lyse a wide range of tumors independent of TAA expression, which have more advantages compared to the conventional CAR-T cells. In our study, we developed the allogeneic product of CAR-DNT cells targeting C-type lectin-like molecule-1 (CLL1), which is a promising target due to its over-expression in primary AML cells and leukemia stem cells, while absence on hematopoietic stem/progenitor cells. Methods: We developed a humanized single chain variable fragment (scFv) with specific recognition of human CLL1 antigen by screening from 62 murine-derived CLL1 antibodies. Then, we designed a second-generation CLL1 CAR structure containing 4-1BB-CD3ζ and transduced it into the DNT cells by lentivirus. To clarify the GvH and HvG reactions of DNT cells, we performed the mixed lymphocyte reaction experiments in vitro and compared DNT cells with TCR and B2M double knockout T(DKO) cells and TCR knockout T(TKO) cells. We evaluated the anti-tumor function of CLL1 CAR-DNT cells through killing experiments by different effector-to-target ratios and multiple stimulations with AML cell lines (THP1 and HL60). Furthermore, we speculated that the CAR structure plays a critical role in both tumoricidal function and persistence of CAR-DNT cells. We designed nearly 20 enhanced CAR structures based on the signaling pathway of DNT cells. These newly designed structures have been tested in vitro and will be confirmed in vivo. Results: The humanized anti-CLL1 scFv candidate H1-3Q2 demonstrated high specificity toward human CLL1 antigen at the Membrane Protein Array. H1-3Q2 based CAR-T cells showed good tumor suppression in vivo. However, due to the heterogenous expression of CLL1 in AML, CLL1 CAR-T cells may not be able to eliminate AML cancer cells completely. While DNT cells could naturally lyse tumor cells through the receptors like NKG2D and DNAM-1, providing them with lots of advantages. Moreover, DNT cells have the potential to be used as allogenic cell therapy product. Co-culturing allogenic PBMCs or umbilical cord blood with DNT cells for up to 72 hours resulted in little or no killing reaction, indicated a low risk of GvHD. Conversely, the PBMCs from three different donors were used to attack allogenic DNT cells or DKO/TKO T cells in vitro. The killing effect on DKO/TKO T cells gradually increased over time, while no effect on DNT cells was observed even after 192 hours. This suggested that DNT cells are not easily cleared by host immune cells. DNT cells could efficiently lyse various hematological and solid tumor cell lines, particularly showing high sensitivity towards AML cells. The introduction of the CAR moiety further enhanced the specificity of DNT cells. The in vitro killing results demonstrated that CLL1 CAR-DNT cells exhibited stronger and faster AML resistance compared with CAR-T cells, and even eliminated tumor cells that have lost TAA. However, CLL1 CAR-DNT cells showed limited proliferation in the multiple-stimulation assays. To address this, we designed enhanced CAR structures. Screening by multiple-challenge assays, the fifth-generation CAR exhibited outstanding proliferation and superior tumor lysis ability in vitro. Conclusions: Our findings demonstrate that CAR-DNT product is an ideal candidate for allogeneic adoptive immunotherapy and exhibits superior tumoricidal function. This study underscores the potential of the “off-the-shelf” CLL1 CAR-DNT cell product for treating R/R AML.

Herombopag, a Second Generation Thrombopoietin-Receptor Agonist, Stimulates Platelet Engraftment after Haploidentical Allogeneic Hematopoietic Stem Cell Transplantation

Introduction: The delayed platelet engraftment is a common complication in allogeneic hematopoietic stem cell transplantation (allo-HSCT), which elevates treatment-related mortality and impairs quality of life. Although some studies reported that platelet engraftment after allo-HSCT was promoted by thrombopoietin-receptor agonists (TPO-RAs), the recommended detailed TPO-RA administration is still lacking. This prospective, single-center, investigator-initiated pilot study aims to explore the efficacy and safety of herombopag, a second-generation TPO-RA, to stimulate platelet engraftment in haploidentical allo-HSCT (haplo-HSCT). Methods: A total of 36 patients (median age 38; range 15-59 years) with anaplastic anemia, myelodysplastic syndrome, acute leukemia, granulocytic sarcoma, or primary hemophagocytic lymphohistiocytosis were enrolled between November 2021 and June 2023. All patients received haplo-HSCT and post-transplant cyclophosphamide for acute graft-versus-host disease (aGVHD) prophylaxis. Patients received herombopag from day+5 post-HSCT until platelet>100,000/µL, disease progression, intolerable toxicity, or withdrawal of informed consent. The dose of herombopag was 5 mg/day initially and reduced to 2.5 mg/day when platelet>75,000/µL. Complete platelet engraftment (CPE) was defined as a platelet count exceeding 50,000/μl for seven consecutive days without transfusion. Partial platelet engraftment (PPE) was defined as a platelet count exceeding 20,000/μl for seven consecutive days without transfusion. The objective response included both CPE and PPE. The primary endpoint was the 21-day cumulative incidence and 28-day cumulative incidence of CPE and objective response after haplo-HSCT. The secondary endpoints were time to CPE, time to objective response, platelet transfusion units, aGVHD, relapse, non-relapse mortality, and safety. Results: The patients received herombopag treatment for a median of 15 days. The 21-day cumulative incidence of CPE was 55.6%, and that of objective response was 77.8%. The 28-day cumulative incidence of CPE was 69.4%, and that of objective response was 80.6%. The median time to objective response was 20.5 (95%CI 17-27) days. The median time to CPE was 23 (95%CI 10-33) days. The mean units of platelet transfusions required within 30 days after HSCT was 6.7. The median follow-up time was 12.1 months. The one-year overall survival rate was 85.3% (95%CI 72.8%-99.8%). Two patients died of aGVHD and two patients died of lung infection. Four Patients (11.1%) experienced molecular relapse. The cumulative incidence of grade III-IV aGVHD was 16.7%. Furthermore, cytomegalovirus reactivation occurred in 13 patients (36.1%). The most common herombopag-related adverse events were hypomagnesemia (61.1%), increased GGT (52.8%), increased ALT (38.9%), and increased bilirubin (19.4%). No grade III/IV adverse events were observed. Conclusion: Herombopag significantly stimulates platelet engraftment in haplo-HSCT patients and has a favorable safety profile. Further research with a larger sample size and longer follow-up period is required to confirm its optimal use.

Standard Risk Assessment Tools Fall Short to Assess Risk in Transplant Patients

Introduction: The HCT-CI (Hematopoietic Cell Transplantation-specific Comorbidity Index) predicts survival after HCT in patients with hematologic malignancies. HCT-CI ≥3 is associated with higher Non-Relapse Mortality (NRM) and lower overall survival in both allogeneic (allo) and autologous (auto)-HCT patients. The Disease Risk Index (DRI) Assessment Tool is a validated tool to categorize patients undergoing allo- transplant into risk categories based on disease status. It was developed to predict overall survival per disease status. This study was done to understand reasons for increased mortality in transplant patients at our center in 2021 compared to 2020 by comparing HCT-CI and DRI of transplant patients between the two years. Methods: The study was approved by our institution's IRB. A retrospective chart analysis of adult patients who underwent auto- or allo-HCT at Henry Ford Hospital in the years 2020 and 2021 was conducted. Relevant patient demographics, comorbidities, disease characteristics, and transplant-related data were collected. HCT-CI scores were calculated on all patients using the online calculator (https://www.mdcalc.com/calc/3980/hematopoietic-cell-transplantation-specific-comorbidity-index-hct-ci). Patients were also risk stratified based on the DRI Assessment Tool (https://cibmtr.org/CIBMTR/Resources/Research-Tools-Calculators/Disease-Risk-Index-DRI-Assignment-Tool). Data was reviewed and collected by investigators and compiled in a confidential platform. Results: A total of 166 patient records between 2020 and 2021 were reviewed. In 2020, 46 patients underwent auto-HCT and 28 underwent allo-HCT. In 2021, 58 patients underwent auto-HCT and 34 patients underwent allo-HCT. The one-year post transplant survival rates for patients are elucidated in Table 1. The median HCT-CI scores amongst the patients who underwent transplant was 3 in 2020 and 4 in 2021(refer Table 2). When assessing the Disease Risk Index, overall, more patients with higher disease risk were transplanted in 2021 compared to 2020 (refer Table 3). 16 patients (12 in 2021 and 4 in 2020) underwent transplant for diseases that are not included in the DRI assessment tool. Of these, 8 patients in 2021 underwent allo-HCT. These included aplastic anemia (AA), inherited bone marrow failure syndromes (BMF), solid tumors, primary CNS lymphomas, mycosis fungoides and hemophagocytic lymphohistiocytosis (HLH). Conclusion: The HCT-CI and the DRI are both tools used in transplant centers to risk stratify patients pre-transplant. The use of both tools can give a good sense of post-transplant outcomes, combining both individual patient characteristics as well as diseases specific variations. These data are also important for monitoring outcomes at transplant centers. In this study, patients who had an HCT-CI >/3 were similar in both years. The DRI however could not be ascertained in 16 patients, as these diseases are not currently included in the DRI. This makes outcome prediction for these particular patients suboptimal especially if they do not have as many comorbidities but still higher risk diseases. Furthermore, this precludes effective outcome monitoring in and amongst transplant centers. The combination of both the HCT-CI and the DRI would perform better if the DRI tool is revised to become more comprehensive or by creating a DRI that is specific for non-malignant disorders like AA, HLA and BMF. We intend to propose this to CIBMTR for further consideration.

Valve Hemodynamics by Valve Size and 1-Year Survival Following Implantation of the Portico Valve in the Multicenter CONFIDENCE Registry

BackgroundThe CONtrolled delivery For ImproveD outcomEs with cliNiCal Evidence registry was initiated to characterize the clinical safety and device performance from experienced transcatheter aortic valve implantation (TAVI) centers in Europe and Australia that use the Portico valve to treat patients with severe aortic stenosis. We herein report for the first time the valve performance at 30-day across all implanted valve sizes and the 1-year survival from this registry. MethodsThis was a prospective, multicenter, single-arm observational clinical investigation of patients clinically indicated for implantation of a Portico valve in experienced TAVI centers. Patients were treated with a commercially available valve (size 23, 25, 27, or 29 mm) using either the first-generation delivery system (DS) (n = 501) or the second-generation (FlexNav) DS (n = 500). Adverse events were adjudicated by an independent clinical events committee according to Valve Academic Research Consortium-2 criteria. Echocardiographic outcomes were assessed at 30 days by an independent core laboratory, and a survival check was performed at 1 year. ResultsWe enrolled 1001 patients (82.0 years, 62.5% female, 63.7% New York Heart Association functional class III/IV at baseline) from 27 clinical sites in 8 countries across Europe and one site in Australia. Implantation of a single valve was successful in 97.5% of subjects. Valve hemodynamics at 30 days were substantially improved relative to baseline, with large aortic valve areas and low mean gradients across all implanted valve sizes (aortic valve areas were 1.7 ± 0.4, 1.7 ± 0.5, 1.8 ± 0.5, and 2.0 ± 0.5 cm2, and mean gradients were 7.0 ± 2.7, 7.5 ± 4.7, 7.3 ± 3.3, and 6.4 ± 3.3 mmHg for 23, 25, 27, and 29 mm valve sizes, respectively). Across all implanted valve sizes, most patients (77.1%) had no patient-prosthesis mismatch. Death from any cause within 1 year occurred in 13.7% of the patients in the first-generation DS group as compared with 11.0% in the second-generation DS group (p = 0.2). ConclusionsThe Portico valve demonstrated excellent hemodynamic performance across all valve sizes in a large cohort of subjects implanted in experienced TAVI centers. One-year survival rates were favorable when using both the first-generation and second-generation (FlexNav) DSs in this high-risk cohort. ClinicalTrials.gov IdentifierNCT03752866.

The Prognosis of Advanced Non-Small Cell Lung Cancer Patients with Precision-Targeted Therapy Guided by NGS Testing or Routine Testing.

We aim to observe the potential survival benefits of driver gene-guided targeted therapy in advanced non-small cell lung cancer (NSCLC) patients compared to non-targeted therapy. Additionally, the study aims to assess whether Next-generation sequencing technology (NGS)-guided targeted therapy can provide survival advantages for advanced NSCLC patients compared to conventional Epidermal growth factor receptor (EGFR)/anaplastic lymphoma kinase (ALK) gene detection. Clinical data, genetic testing results, and treatment information of 1663 advanced lung cancer patients diagnosed by pathology from January 2013 to June 2019 in Jiangsu University Affiliated Lianyungang Hospital were collected. Propensity score matching survival analysis was used to evaluate the differences in overall survival(OS) between groups. In the unadjusted survival curve, targeted therapy patients had significantly longer median OS than non-targeted therapy patients (28.3 months vs 15.4 months, Hazard ratio (HR) = 0.5426, 95% confidence interval (CI) 0.4768-0.6176, P < 0.0001); the conclusion was the same after propensity score matching analysis, with targeted therapy group patients having significantly prolonged OS median (27.5 months vs 14.8 months, HR = 0.5572, 95% CI 0.4796-0.6474, P < 0.0001). In the unadjusted survival curve, the NGS group had a significantly prolonged median OS compared to the conventional gene detection group (23.4 months vs 21.2 months, HR = 1.243, 95% CI = 1.017-1.519, P = 0.0495). However, after propensity score matching analysis, no statistically significant difference existed in the median OS between the two patient groups (23.1 months vs 21.5 months, HR = 1.288, 95% CI = 0.9557-1.735, P = 0.0926). Further analysis demonstrated no advantage in the five-, three-, and two-year survival rates of the NGS group compared to conventional gene detection group patients. However, the one-year survival rate of the NGS group was significantly increased (83.2% vs 68.1%, HR = 0.4890, 95% CI = 0.3170-0.7544, P = 0.0015). Driver gene-guided targeted precision therapy significantly prolonged the median OS of advanced NSCLC patients compared to non-targeted therapy. NGS detection did not improve the median OS of advanced NSCLC patients compared to conventional EGFR/ALK gene detection but increased the one-year survival rate of patients.

PAEDIATRIC-01 SURGICAL OUTCOME OF MEDULLOBLASTOMA IN ETHIOPIA

Abstract OBJECTIVE Medulloblastoma is one of the commonest CNS[1] tumors in pediatric patients. This study tries to assess surgical treatment outcome and prognostic factors in patients diagnosed with medulloblastoma in Ethiopia, a LIC[2]. MATERIALS AND METHODS Retrospective study involving twenty-seven patients (21 pediatrics &amp; 6 adults) who underwent surgery for medulloblastoma (January 1, 2010-April 30, 2018), at two neurosurgical centers. Structured questionnaire was used to collect patients’ data &amp; surgical treatment outcome variables were assessed by suitable statistical tests. RESULTS 1-year and 6-month survival probability were 29% and 41 % respectively with a median survival of 107 days (95% CI: 49,166). Median survival was 66 days (95% CI: 27,105), with 6 months and one-year survival rate of 24 % (p=0.031) for pediatric patients. Majority (61.90%) of pediatric deaths were in the first two months of surgery. Six months &amp; one-year PFS[3] were around 83% and 44% respectively with median PFS of 9 months (95%CI: 7, 12). Younger age at presentation, postoperative open EVD[4], longer SICU[5] stay, lack of radiation treatment &amp; postoperative complications were negative outcome predictors. CONCLUSION Overall median and PFS of operated patients &amp;lt;15 years old is poor. Patients with negative outcome predictors have higher mortality&amp; poor postoperative functional status. Standardization of treatment with surgery &amp; CSI[6] ± chemotherapy yields longer survival rates in both pediatric and adult patients. [1] Central Nervous System [2] Low Income Country [3] Progression Free Survival [4] External Ventricular Drainage [5] Surgical Intensive Care Unit [6] Craniospinal Irradiation

Degradable Starch Microspheres Transarterial Chemoembolization with or without Lipiodol for Liver Metastases from Pancreatic Cancer: A Prospective Randomized Trial.

To evaluate and compare the outcome of patients with liver metastases from pancreatic cancer treated by transarterial chemoembolization (TACE) using two different protocols. In this prospective, randomized, single-center trial, patients were randomly assigned to receive TACE therapy either with degradable starch microspheres (DSM) alone or a combination of Lipiodol and DSM. From the initial 58 patients, 26 patients (13 DSM-TACE, 13 Lipiodol + DSM-TACE) who completed 3 TACE treatments at an interval of four weeks were considered for evaluation of tumor responses. Initial and final MRIs were used to evaluate local therapy response by RECIST 1.1; changes in diameter, volume, ADC value, and survival rate were statistically evaluated. The differences between the DSM-TACE and Lipiodol + DSM-TACE were identified for partial response (PR) as 15.4% versus 53.8%, stable disease (SD) as 69.2% versus 46.2%, progressive disease (PD) as 15.4% versus 0%, respectively (p = 0.068). Median overall survival times for DSM-TACE and Lipiodol + DSM-TACE were 20 months (95% CI, 18.1-21.9) and 23 months (95% CI, 13.8-32.2), respectively (p = 0.565). The one-year survival rates for DSM-TACE and Lipiodol + DSM-TACE were 85.4% and 60.4%, the two-year survival rates were 35.9% and 47.7%, and the three-year survival rates were 12% and 30.9%, respectively. The evaluated local therapy response by RECIST 1. was not significantly different between the two studied groups. A longer overall survival time was observed after Lipiodol + DSM-TACE therapy; however, it was not significantly different.

Survival Rate Estimation in Patients with Colorectal Cancer by applying Fuzzy Product Limit Estimator

Background: Survival rates are important to show the progress of the disease and the effect of treatments. The estimation of survival probabilities especially in presence of highly censored data is challenging. In this study, Fuzzy Product Limit Estimator (FPLE) is introduced to mitigate the challenge.&#x0D; Methods: In a longitudinal study, data of 173 CRC patients were analyzed. To estimate survival probabilities, mean and median survival time, Fuzzy Product Limit Estimator (FPLE), a data-driven method, was applied to the data. It provides a smooth survival probability curve and the continuation of the survival curve is not a concern in the case while the largest observed time is censored.&#x0D; Results: One-year survival rate for CRC patients was estimated to be 83% using FPLE and KM methods. The five-year survival rate was estimated to be 37% and 52% by the FPLE and KM methods, respectively. The largest observed time in data (71.96 months) was censored, so the survival rate after 71.96 months was not estimable by the KM method. But 10-year and 20-year survival rates were estimated by FPLE as 0.21 and 0.09. The mean (median) survival time was estimated 45.97 (65) and 82.69 (41.70) months by KM and FPLE methods, respectively. &#x0D; Conclusion: In presence of highly censored survival data, the FPLE method provides acceptable estimates of CRC patients' survival rate. Also, the continuation of the survival curve was estimated after the largest observed time. The smaller estimates by the FPLE at 5-year could be considered as warning that the actual survival rate is lower than that reported by the KM method.

The state of cancer care in Russia: breast cancer. Epidemiology and survival of patients. The impact of the SARS-CoV-2-beta-coronavirus epidemic (clinical and population study)

Background. Breast cancer is the main cause of morbidity and mortality of the female population among economically developed countries, including in Russia. Despite the continued increase in morbidity, mortality is decreasing, which is confirmed by a decrease in the index of accuracy (the ratio of the number of deaths to the sick). Calculations of survival at the population level (the most important criterion for evaluating the activities of the oncological service) in Russia are carried out only on the basis of databases of the population cancer registry of the North-Western Federal District. The accumulated 1.5 million primary cases of malignant tumors allowed for the in-depth development of data on rare tumor localities, including breast cancer among the male population.Aim. To study the impact of the coronavirus pandemic on the dynamics of the process of detection, mortality and survival of breast cancer patients in Russia and in the North-Western Federal District of the Russian Federation.Materials and methods. The material of the study is the reference books of the P. Hertzen Moscow Oncology Research Institute – branch of the National Medical Research Radiology Center, Ministry of Health of Russia, and the N.N. Petrov National Medical Research Oncology Center, Ministry of Health of Russia, and the database of the population cancer registry of the North-Western Federal District, clinical materials of the surgical department of breast tumors of theN.N. Petrov National Medical Research Oncology Center. More than 110 thousand primary cases of breast cancer were selected. Data processing was carried out by standard methods of oncology statistics recommended by the International Association of Cancer Registries (Eurocare program).Results. A significant impact of the coronavirus pandemic on the primary registration of breast cancer in Russia from 2019 to 2020 has been established, with some weakening of its impact in the subsequent period. The pandemic has had a significant impact on the quality of primary registration of patients. The value of the index of accuracy has been set back five years, but there is a sign of its improvement in 2021. The positive dynamics of one-year and five-year survival of patients with breast cancer is shown. The quality of registration of patients with breast cancer by detailed localization and histological structures of breast cancer was investigated. A significant decrease in the mortality of patients was noted when studying the patterns of dynamics in annual mortality over three follow-up periods.Conclusion. A steady increase in the incidence of breast cancer among women has been established, and the negative impact of the coronavirus pandemic has been noted. The mortality rate of the Russian population from breast cancer continues to decrease. The localization and histological structure of the incidence of breast cancer in women remains unchanged. The one-year and five-year survival rate of breast cancer patients continues to grow.

Stoma-free survival after anastomotic leak following rectal cancer resection: worldwide cohort of 2470 patients.

The optimal treatment of anastomotic leak after rectal cancer resection is unclear. This worldwide cohort study aimed to provide an overview of four treatment strategies applied. Patients from 216 centres and 45 countries with anastomotic leak after rectal cancer resection between 2014 and 2018 were included. Treatment was categorized as salvage surgery, faecal diversion with passive or active (vacuum) drainage, and no primary/secondary faecal diversion. The primary outcome was 1-year stoma-free survival. In addition, passive and active drainage were compared using propensity score matching (2 : 1). Of 2470 evaluable patients, 388 (16.0 per cent) underwent salvage surgery, 1524 (62.0 per cent) passive drainage, 278 (11.0 per cent) active drainage, and 280 (11.0 per cent) had no faecal diversion. One-year stoma-free survival rates were 13.7, 48.3, 48.2, and 65.4 per cent respectively. Propensity score matching resulted in 556 patients with passive and 278 with active drainage. There was no statistically significant difference between these groups in 1-year stoma-free survival (OR 0.95, 95 per cent c.i. 0.66 to 1.33), with a risk difference of -1.1 (95 per cent c.i. -9.0 to 7.0) per cent. After active drainage, more patients required secondary salvage surgery (OR 2.32, 1.49 to 3.59), prolonged hospital admission (an additional 6 (95 per cent c.i. 2 to 10) days), and ICU admission (OR 1.41, 1.02 to 1.94). Mean duration of leak healing did not differ significantly (an additional 12 (-28 to 52) days). Primary salvage surgery or omission of faecal diversion likely correspond to the most severe and least severe leaks respectively. In patients with diverted leaks, stoma-free survival did not differ statistically between passive and active drainage, although the increased risk of secondary salvage surgery and ICU admission suggests residual confounding.

Liver retransplantation in the modern concept of treatment of its terminal pathology (literature review)

The work is devoted to the analysis of modern literature data and approaches in performing repeated liver transplantation. The most frequent causes of liver graft loss are PNFT, HAT, recurrent initial disease and chronic rejection. The leading indication for retransplantation in children is HAT. The one-year survival rate after retransplantation is approximately 75%. Reducing the cost of organ retransplantation and the cost-effectiveness of the procedure are controversial issues. Mathematical modeling has identified several significant recipient and donor factors affecting the outcomes of retransplantation. Despite ethical and economic considerations, retransplantation is the only option for transplant patients whose grafts have failed to engraft. The decision to retransplant should be made with some caution, with full multi-type approach in large multidisciplinary transplant centers.

PD-1 Inhibitors combined with paclitaxel (Albumin-bound) and cisplatin for larynx preservation in locally advanced laryngeal and hypopharyngeal squamous cell carcinoma: a retrospective study.

laryngeal and hypopharyngeal squamous cell carcinoma (SCC) is a common head and neck cancer with significant impact on quality of life due to its crucial roles in vocalization, airway protection, and swallowing. This retrospective study aims to evaluate the efficacy and larynx organ preservation of neoadjuvant treatment with PD-1 inhibitors in combination with paclitaxel (Albumin-bound) and cisplatin for locally advanced laryngeal and hypopharyngeal SCC. Medical records of consecutive patients diagnosed with histologically or cytologically confirmed locally advanced SCC of the larynx and hypopharynx, who received PD-1 inhibitor therapy at a single tertiary care center, were reviewed from January 1, 2019, to December 15, 2022. The patients were treated with a combination of PD-1 inhibitors, paclitaxel (Albumin-bound) 260mg/m2, and cisplatin 60mg/m2 (TP) as their first-line therapy. Survival outcomes, laryngectomy-free survival (LFS) rates and response rates were assessed. The study cohort comprised 156 patients, predominantly male, with a median age of 60.4 years. The estimated one-year overall survival (OS) rate was 94.1%, two-year OS rate was 82.5%, one-year progression-free survival (PFS) rate was 80.4%, and two-year PFS rate was 66.3%. The one-year LFS was 86.4%, and the two-year LFS rate was 73.0%. The overall response rate after TP + PD-1 inhibitors therapy was 88.5%. Common treatment-associated adverse events included rash, thyroid function abnormalities, myelosuppression, and colitis. Neoadjuvant therapy with PD-1 inhibitors in combination with paclitaxel (Albumin-bound) and cisplatin showed promising efficacy and tolerability for larynx preservation in locally advanced laryngeal and hypopharyngeal SCC. The high response rates and favorable survival outcomes suggest this approach as a potential treatment option. Prospective randomized controlled trials are needed to further validate these findings and establish the role of immunotherapy in larynx preservation.

Novel therapies for graft versus host disease with a focus on cell therapies.

Graft versus host disease (GVHD) can occur at any period post allogeneic hematopoietic stem cell transplantation as a common clinical complication contributing to significant morbidity and mortality. Acute GVHD develops in approximately 30-50% of patients receiving transplants from matched related donors. High doses of steroids are used as first-line treatment, but are unsuccessful in around 40% of patients, resulting in the diagnosis of steroid-refractory acute GVHD. Consensus has yet to develop for the management of steroid-refractory acute GVHD, and prognosis at six months has been estimated at around 50%. Thus, it is critical to find effective treatments that increase survival of steroid-refractory acute GVHD. This article describes the currently known characteristics, pathophysiology, and treatments for GVHD, with a special focus on recent advances in cell therapies. In particular, a novel cell therapy using decidua stromal cells (DSCs) was recently shown to have promising results for acute GVHD, with improved effectiveness over previous treatments including mesenchymal stromal cells. At the Karolinska Institute, severe acute GVHD patients treated with placenta-derived DSCs supplemented with either 5% albumin or 10% AB plasma displayed a one-year survival rate of 76% and 47% respectively. Furthermore, patients with steroid-refractory acute GVHD, displayed survival rates of 73% with albumin and 31% with AB plasma-supplemented DSCs, compared to the 20% survival rate in the mesenchymal stromal cell control group. Adverse events and deaths were found to be attributed only to complications of hematopoietic stem cell transplant and GVHD, not to the study intervention. ASC Therapeutics, Inc, in collaboration with the Karolinska Institute, will soon initiate a phase 2 multicenter, open-label study to further assess the efficacy and safety of intravenous DSC treatment in sixty patients with Grade II-IV steroid-refractory acute GVHD. This novel cell therapy represents a promising treatment to combat the poor prognosis that steroid-refractory acute GVHD patients currently face.

Stereotactic Radiotherapy or Whole Brain Radiotherapy Combined with Pyrotinib and Capecitabine in HER2-Positive Advanced Breast Cancer Patients with Brain Metastases (BROPTIMA): A Prospective, Phase Ib/II Single-Arm Clinical Study

Approximately half of patients with advanced HER2-positive breast cancer (BC) will develop brain metastases (BM) over time. Local therapy including stereotactic radiotherapy (SRT) and whole brain radiotherapy (WBRT) is the main initial treatment in malignant tumor patients with BM. However, more than 50% patients after radiotherapy in one year suffered intracranial recurrence. Pyrotinib, a small molecule, irreversible, pan-ErbB receptor tyrosine kinase inhibitor (TKI), has a high potency for controlling BM and reducing the occurrence of brain metastases in advanced HER2-positive BC patients. We hypothesized that SRT or WBRT combined with pyrotinib and capecitabine could decrease intracranial progression in HER2 positive BC with newly diagnosed BM. In this prospective single-arm phase Ib/II trial (NCT04582968), eligible patients were assigned to either fractionated stereotactic radiotherapy (FSRT) or whole-brain radiation therapy (WBRT), combined with pyrotinib and capecitabine. The primary endpoint was one-year CNS progression-free survival (PFS) rate. Secondary endpoints included intracranial objective response rate (IC-ORR) according to RANO-BM criteria, progression-free survival (PFS), overall survival (OS) and evaluation of safety and neurocognitive function. From January 2020 to August 2022, 40 patients were enrolled. Twenty-nine patients were treated with FSRT in 8 Gy per fraction with 3 to 5 fractions and 11 were treated with WBRT in 3 Gy per fraction with 10 fractions, and then received chemotherapy in a time frame starting from 0 to 7 days after radiotherapy. At a median follow-up of 17.3 months, 1-year CNS-PFS rate was 74.9% (95% CI 61.9-90.7%) and median CNS-PFS was 18 months (95% CI, 15.5 to NA months). One-year PFS rate was 66.9% (53.1-84.2%) and median PFS time was 17.6 months (95% CI 12.8-34.1 months). The best intracranial response rate (IC-ORR: complete response and partial response) was 92.5% (37/40). The most common grade 3 or worse toxicity was diarrhea (7.5%) and asymptomatic radiation necrosis was detected in 4 of 67(6.0%) lesions treated with FSRT. No differences of neurocognitive function evaluated by MMSE (Mini-Mental State Exam) were observed between different groups at any time point. Radiotherapy combined with pyrotinib and capecitabine resulted in a promising efficacy that crossed the pre-specified boundary in patients with HER2-positive advanced breast cancer with brain metastases. This is the first prospective study showing the efficacy and safety of CNS radiotherapy concurrent with pyrotinib and capecitabine in patients with BM from HER2-positive breast cancer. Further investigation in a randomized controlled study is warranted.

Multi-Institutional Experience of Proton Therapy for Osteosarcoma in the Proton Collaborative Group (PCG) Prospective Registry

To report on the utilization of dose-escalated radiotherapy, acute toxicities, and survival following definitive proton therapy (PT) for osteosarcoma patients in a prospective multi-institutional study. Data on patients with osteosarcoma treated with definitive intent PT were queried from the Proton Collaborative Group (PCG) prospective registry. A similar query was performed on an institutional database with IRB approval. Overall survival rates were calculated by Kaplan-Meier. Toxicities were scored using CTCAE v4.0. Forty osteosarcoma patients across 9 institutions received definitive intent PT between 2011-2021 and met the eligibility criteria. Median age was 32 years (Range: 6-86 years). Median PT dose was 66.6 GyRBE (Range: 50.4-80.0 GyRBE); 38 patients received proton therapy alone, whereas 2 received combined proton/photon therapy. Seventeen (42.5%) patients received doses ≥70 GyRBE. Median follow-up was 3.1 years (Range: 0.9-10.5 years). One-year and three-year overall survival rates were 83.5% and 59.1%, respectively, with 14 deaths due to disease. Excluding skin desquamation and alopecia, 22 patients (55.0%) developed any acute grade 2+ toxicity, and 5 patients (12.5%) developed any grade 3 toxicities. No acute grade 4-5 toxicities were reported. The most frequent grade 2+ non-skin toxicities were fatigue (37.5%), anorexia/weight loss (17.5%), mucositis/esophagitis (22.5%), pain (20.0%), and nausea/vomiting (10.0%). The most frequent grade 3 toxicities were anorexia/weight loss (5.0%), mucositis/esophagitis (5.0%), and neurologic symptoms (5.0%). In this multi-institutional study, 42.5% of osteosarcoma patients treated with PT received doses between 70-80 Gy, with 12.5% experiencing any grade 3 toxicity. Long-term outcomes for disease control, late toxicity, and quality-of-life are needed to more fully assess the benefits and risks of dose-escalated radiotherapy in this radioresistant tumor. The authors plan to assess the outcomes of osteosarcoma patients treated with dose-escalated radiotherapy for unresectable or gross residual disease in future studies.

High-Dose-Rate Brachytherapy for Vaginal Rhabdomyosarcoma (RMS): Lessons Learned at a Single Institution

Botryoid RMS is a rare pediatric tumor most commonly arising within the vaginal wall of girls under age three. Most patients are successfully treated with low-risk chemotherapy protocols but local treatment is required to minimize risk of local relapse. Intravaginal brachytherapy is an effective local therapy that can minimize sequelae in these very young patients. We reviewed records of all patients with RMS who received intravaginal high-dose-rate brachytherapy from 2010-2022 at a single institution. All were treated with multiagent chemotherapy with or without minor surgical procedures, and had no gross disease prior to intravaginal brachytherapy. All patients underwent CT simulation under anesthesia and optimal-sized cylindrical applicators were chosen based on patient anatomy. Twelve girls, median age 23 months (range 3-33), were treated with daily anesthesia. All were Stage 1 and 92% had Group III disease. A single patient had Group IIA disease based on up-front resection. Early in the series, 5 patients received 21 Gy in 7 fractions according to COG protocol guidelines. Subsequent patients received higher doses of 28-30 Gy in 7-10 fractions. Custom sized cylinders were used with diameters ranging from 1.2-1.6 cm and dose was prescribed to a median depth of 3 mm. Median mean dose to the rectum, bladder, uterus, and bilateral ovaries was 8.7 Gy, 7.2 Gy, 6.9 Gy, and 5.0 Gy, respectively. Median follow-up was 4 years (range 1-10). No acute or late side effects have occurred. At follow-up, three girls were of pubescent age, all three exhibited signs of puberty and two had reached menarche. Three girls (25%) suffered local relapse at a median of 15 months (range 5-16 months) after brachytherapy. One-year and five-year local control rates were 92% (95% CI 54-99%) and 70% (95% CI 32-89%), respectively. All relapses were in patients receiving 21 Gy and two were beyond full dose coverage of brachytherapy at the introitus and in the uterus. Subsequent patients receiving higher doses and full coverage of the vagina have had no local failures. Two of three patients who failed were cured with salvage therapy resulting in one-year and five-year overall survival rates of 100% and 86% (95% CI 33-98%), respectively. Intravaginal high-dose-rate brachytherapy is an excellent option for local control of vaginal RMS with fewer long-term risks than external beam proton therapy or radical surgery. A dose of 28 Gy in 7 fractions prescribed to the entire vagina is necessary for optimal prevention of relapse. Longer follow-up is needed to confirm preservation of ovarian, reproductive, and sexual function.

Risk factors for myocardial injury during living donor liver transplantation in pediatric patients with biliary atresia.

Cold ischemia-reperfusion of the liver is an inevitable occurrence in liver transplantation that may also cause damage to the heart. Perioperative myocardial injury during liver transplantation can increase the incidence of postoperative mortality, but there is little research on the incidence of myocardial injury in children who undergo living donor liver transplantation (LDLT). Therefore, this study mainly explores the independent risk factors for myocardial injury in children who undergo LDLT. To analyze the data of children who underwent LDLT to determine the risk factors for intraoperative myocardial injury. We retrospectively analyzed the inpatient records of pediatric patients who underwent LDLT in Tianjin First Central Hospital from January 1, 2020, to January 31, 2022. Recipient-related data and donor-related data were collected. The patients were divided into a myocardial injury group and a nonmyocardial injury group according to the value of the serum cardiac troponin I at the end of surgery for analysis. Univariate analysis and multivariate logistic regression were used to evaluate the risk factors for myocardial injury during LDLT in pediatric patients. A total of 302 patients met the inclusion criteria. The myocardial injury group had 142 individuals (47%), and the nonmyocardial injury group included 160 patients (53%). Age, height, and weight were significantly lower in the myocardial injury group (P < 0.001). The pediatric end-stage liver disease (PELD) score, total bilirubin, and international standardized ratio were significantly higher in the myocardial injury group (P < 0.001). The mean arterial pressure, lactate, hemoglobin before reperfusion, duration of the anhepatic phase, cold ischemic time, incidence of postreperfusion syndrome (PRS), and fresh frozen plasma transfusion were significantly different between the two groups (P < 0.05). The postoperative intensive care unit stay and peak total bilirubin values in the first 5 d after LDLT were significantly higher in the myocardial injury group (P < 0.05). The pediatric patients with biliary atresia in the nonmyocardial injury group who underwent LDLT had a considerably higher one-year survival rate than those in the myocardial injury group (P = 0.015). Multivariate logistic regression revealed the following independent risk factors for myocardial injury: a high PELD score [odds ratio (OR) = 1.065, 95% confidence interval (CI): 1.013-1.121; P = 0.014], a long duration of the anhepatic phase (OR = 1.021, 95%CI: 1.003-1.040; P = 0.025), and the occurrence of intraoperative PRS (OR = 1.966, 95%CI: 1.111-3.480; P = 0.020). A high PELD score, a long anhepatic phase duration, and the occurrence of intraoperative PRS were independent risk factors for myocardial injury during LDLT in pediatric patients with biliary atresia.

Evaluation of Efficacy and Prognosis Analysis of Stage III-IV SMARCA4-deficient Non-small Cell Lung Cancer Treated by PD-1 Immune Checkpoint Inhibitors plus Chemotherapy and Chemotherapy

The SMARCA4 mutation has been shown to account for at least 10% of non-small cell lung cancer (NSCLC). In the present, conventional radiotherapy and targeted therapy are difficult to improve outcomes due to the highly aggressive and refractory nature of SMARCA4-deficient NSCLC (SMARCA4-DNSCLC) and the absence of sensitive site mutations for targeted drug therapy, and chemotherapy combined with or without immunotherapy is the main treatment. Effective SMARCA4-DNSCLC therapeutic options, however, are still debatable. Our study aimed to investigate the efficacy and prognosis of programmed cell death 1 (PD-1) immune checkpoint inhibitors (ICIs) in combination with chemotherapy and chemotherapy in patients with stage III-IV SMARCA4-DNSCLC. 46 patients with stage III-IV SMARCA4-DNSCLC were divided into two groups based on their treatment regimen: the chemotherapy group and the PD-1 ICIs plus chemotherapy group, and their clinical data were retrospectively analyzed. Efficacy assessment and survival analysis were performed in both groups, and the influencing factors for prognosis were explored for patients with SMARCA4-DNSCLC. Male smokers are more likely to develop SMARCA4-DNSCLC. There was no significant difference in the objective response rate (76.5% vs 69.0%, P=0.836) between chemotherapy and the PD-1 ICIs plus chemotherapy or the disease control rate (100.0% vs 89.7%, P=0.286). The one-year overall survival rate in the group with PD-1 ICIs plus chemotherapy was 62.7%, and that of the chemotherapy group was 46.0%. The difference in median progression-free survival (PFS) between the PD-1 ICIs plus chemotherapy group and the chemotherapy group was statistically significant (9.3 mon vs 6.1 mon, P=0.048). The results of Cox regression analysis showed that treatment regimen and smoking history were independent influencing factors of PFS in patients with stage III-IV SMARCA4-DNSCLC, and family history was an individual influencing factor of overall survival in patients with stage III-IV SMARCA4-DNSCLC. Treatment regimen may be a prognostic factor for patients with SMARCA4-DNSCLC, and patients with PD-1 ICIs plus chemotherapy may have a better prognosis.

Investigation of mortality rates and the factors affecting survival in out-of-hospital cardiac arrest patients

Background It is known that even if spontaneous circulation returns after cardiopulmonary resuscitation(CPR) in geriatric out-of-hospital cardiac arrests(OHCA), the overall one-year survival rate of these patients is very low. In our study, we aimed to investigate the factors affecting survival in OHCA cases. Methods OHCA patients over 18 years of age were examined in two different groups as 18–64 years old and over 65 years old. Demographic data, comorbidities, cardiac arrest rhythms and minutes, and the number of days they were hospitalized in the intensive care unit were recorded. Results The mean age was 65.9 ± 15.8 years and 39.9% (n = 110) of the patients were female. The number of intensive care unit stays was significantly higher in the over-65 age group (p = 0.011). The mortality rate and one-year survival rate were significantly lower in the over-65 age group (p < 0.001). Median CPR time was 21 min (IQR:14–32) in the entire patient population. The duration of CPR was 22 min (IQR:14–35) in patients with in-hospital mortality, and 15 min (IQR:13–25) in patients discharged from the hospital. In this comparison, the difference is statistically significant (p = 0.008). Conclusion In our study, it was determined that especially over 65 years of age, coronary artery disease, and post-arrest CPR duration were determinant and predictive factors in in-hospital and long-term survival.

Feline Oral Melanoma-A Retrospective Study in 20 Cats and Case Report.

This retrospective study reported the clinical presentation, histopathologic findings, treatment, results of clinical staging, necropsy findings, and survival times for 20 cats with oral melanoma. The median survival time was 102 days, with a one-year survival rate of 15% (n = 3). Metastatic disease was documented in 5 cases. Cats with metastatic disease, tumors within the oral cavity (in contrast to labial tumors), and those treated only palliatively after diagnosis had shorter survival times. One case was monitored from the time of presentation until euthanasia.