Comparison of Cisplatin Monotherapy and PLADO in the Management in Children with Standard-Risk Hepatoblastoma in a Resource-Challenged Nation.

Background: Recent SIOPEL studies have shown cisplatin monotherapy to be equally effective in management of Standard risk Hepatoblastoma (SRHB)as compared to PLADO. Aims and Objectives: To study the chemotherapy, response and outcomes in children with SRHB. Material and Methods: A retrospective study was conducted and all children with SRHB who presented to us from June 2007 to December 2017 were included. All patients with standard risk hepatoblastoma who had received at least 2 cycles of chemotherapy were included. Data regarding the demographics, PRETEXT stage, chemotherapy, response to chemotherapy and outcomes were recorded. Kaplan Meier survival analysis was performed to calculate 5 year overall survival (OS) and event free survival (EFS). Results: Thirty two children were included in the study. The disease was PRETEXT I in 5 (15.6%), II in 9 (28.1%) and 18 (56.2%). Nineteen children (59.4%) received Cisplatin monotherapy and of these 6 patients (all PREXT III) had poor response and the chemotherapy was upgraded to PLADO. The remaining 13 (40.6%) received upfront PLADO chemotherapy. Only 31 patients could be operated. Tumor recurred in 5 patients, 2 who had upfront PLADO and 3 patients had been upgraded to PLADO. The 5 year OS and EFS was 100% in the monotherapy group (n=13), 92% and 69% in the upfront PLADO group (n=13), and 62% and 22% in the upgraded to PLADO group (n=6). Patients with PRETEXT III disease in whom chemotherapy was upgraded to PLADO had significantly lower survival (p=0.036) compared to those who received upfront PLADO chemotherapy. Conclusion: Two thirds of patients with PRETEXT stage III who received cisplatin monotherapy showed poor response and were upgraded to PLADO chemotherapy. These patients had a significantly poorer outcome compared to the rest of the cohort. PRETEXT stage III standard-risk hepatoblastoma may benefit from PLADO chemotherapy instead of cisplatin monotherapy.

Increasing kidney grafts for transplantation.

INTRODUCTION: The current pool of organs available for transplantation does not cover requirements, for this reason non-standard risk donors need to be incorporated into the pool. In this way, donors with small renal tumour are considered for transplantation after bench tumour excision. The aim of our study was to analyse our experience in using these grafts for transplantation. MATERIALS AND METHODS: Retrospective analysis from our prospective accrued database of donors with incidental renal mass used for kidney transplantation between January 2007 and August 2018. RESULTS: Twenty kidney transplantations were performed, thirteen cases received the affected kidney (after tumour removal) and seven the contralateral kidney; from six living and eleven deceased donors. Donor and recipient median age was 58 years (range 22-82) and 56.5 years (range 38-74), respectively. Mean tumour diameter was 12.7 mm (SD 9.5). Tumours resulted in two benign lesions and fifteen renal cell carcinoma. Surgical margins were negative. Two cases presented with bleeding after reperfusion was solved without repercussion. One case presented with immediate vein thrombosis. None of them present delayed graft function. After a 69 month follow-up none of the donors or the recipients presented tumour recurrence. CONCLUSIONS: Kidneys with small incidental tumours seem to be a good option for kidney transplantation in selected patients after bench surgery excision with good functional and oncologic results. More studies and longer follow-up are needed to confirm these results.

Standard risk assessment forms help reduce preventable harm in older adult inpatients: A retrospective chart review study.

AIMS: To examine nurse documentation of assessments using standard risk assessment forms in older inpatients, and to determine the value of such assessment. DESIGN: Cross-sectional retrospective chart review. METHODS: This retrospective review of risk evaluation documentation in patients' medical records focused on skin, continence, medical complications, nutrition, cognition, mobility, medications and pain. RESULTS: A total of 1000 medical records from Taiwan hospitals were reviewed from January 2016 to December 2017, and 379 from Australian hospitals were reviewed from March 2011 to February 2012. Taiwanese patients with documented assessment of skin (aOR =2.94, 95%CI =1.88-4.54), nutrition (aOR =3.22, 95%CI =1.08-9.59), cognition (aOR =2.61, 95%CI =1.32-5.16) and pain (aOR =5.01, 95%CI=1.63-15.38) had significantly higher odds of developing new problems; while Australian patients with documented assessments of continence (aOR =11.55, 95%CI =1.48-90.45) and nutrition (aOR =12.90, 95%CI =1.67-99.06) had significantly higher odds of developing new problems. DISCUSSION: Nursing assessments and interventions documented in standard risk assessment forms help clinical nurses detect new preventable problems and prevent harm in older hospital inpatients across geographic locations and hospital types. Standard nursing forms can be used in clinical practice to guide proactive care by nurses to prevent harm during hospitalisation. IMPACT: Older inpatients are at risk of preventable harm and new health problems. The present study found that incorporating eight factors sensitive to nursing care into standard risk assessment forms can help reduce preventable harm in older inpatients. In addition, these forms guide assessment and intervention effectively in different countries.

Effect of Interleukin-2 Receptor Antibody Induction Therapy on Survival in Renal Transplant Patients Receiving Tacrolimus.

BACKGROUND: This study aims to assess outcomes of interleukin-2 (IL-2) receptor blocker induction therapy on allograft and patients' outcomes in standard risk recipients in the tacrolimus era, analysing data form the British Renal Transplant Registry. METHODS: The study population involved all standard-risk renal transplant patients from 2000 till 2015 who were registered in the UK transplant registry and followed up till May 2018. Standard risk transplants were defined as patients with <2DR mismatch, calculated reaction frequency <20%, live donors or donors after brain death and patients with no previous renal transplantation transplant. We used inverse probability weights to adjust different covariates between the groups. Cox regression analysis for adjusted data and treatment effects model were used to assess outcomes. RESULTS: In all, 3,597 renal transplant patients were included in the study. Two groups were identified; induction group (n = 2,858) which included patients who received IL-2 receptor blocker induction therapy and the no-induction group (n = 739). There was no significant difference between both groups in terms of estimated glomerular filtration rate (eGFR) rate at 1-year post-transplant (correlation co-efficient = 1.224, 95% CI ranges from -0.347 to 2.796). Average eGFR was 59.922 mL/min/1.73 m2 in the induction group (SD 29.171) and 64.557 mL/min/1.73 m2 in the no-induction groups (SD 46.763). There was no significant difference between both groups regarding graft survival at 5 years post-transplant (hazard ratio [HR] 0.944, 95% CI ranges from 0.599 to 1.485, p = 0.804), patient survival at 5 years post-transplant (HR 0.809, 95% CI ranges from 0.477 to1.372, p = 0.433). CONCLUSION: In the standard risk renal transplant population, the IL2 receptor blocker induction regimen does not affect eGFR at 1 year or renal and graft outcomes at 5 years.

Haploidentical transplantation compared with matched sibling and unrelated donor transplantation for adults with standard-risk acute lymphoblastic leukaemia in first complete remission.

We retrospectively investigated outcomes of haploidentical donor (HID) transplant for adults with standard-risk acute lymphoblastic leukaemia (ALL) in first complete remission (CR1) compared with human leucocyte antigen (HLA)-matched sibling donor (MSD) and HLA-matched unrelated donor (MUD) transplants. A total of 348 adult patients were enrolled, including 127 HID, 144 MSD and 77 MUD recipients. The cumulative incidence of grade II-IV acute graft-versus-host disease (aGVHD) was 39·5%, 24·0% and 40·3% for HID, MSD and MUD, respectively (P = 0·020). However, there was no difference in grade III-IV aGVHD (11·4%, 7·7%, 13·5%, respectively, P = 0·468). The 5-year cumulative transplant-related mortality was 16·4%, 11·6% and 19·6% (P = 0·162), the 5-year relapse rate post-transplantation was 14·8%, 21·1% and 16·7% (P = 0·231), the 5-year overall survival was 70·1%, 73·7% and 69·8% (P = 0·525), and the 5-year disease-free survival was 68·7%, 67·3% and 63·7%, respectively (P = 0·606). Furthermore, the 3-year GVHD-free, relapse-free survival was not different (50·8%, 54·9% and 52·2%, respectively, P = 0·847). Our results indicate that the outcomes of HID transplants are equivalent to those of MSD and MUD, and that HID transplantation is a valid alternative for standard-risk adults with ALL in CR1 who lack matched donors.

Predictors of inferior clinical outcome in patients with standard-risk multiple myeloma.

INTRODUCTION: Outcome of patients with standard-risk (SR) multiple myeloma (MM) has improved; however, subsets of patients do worse than expected. We sought to identify the factors associated with inferior outcome. METHODS: We evaluated 51 patients with SR MM that received upfront autologous hematopoietic stem cell transplantation (auto-HCT) after induction and had a progression-free survival (PFS) of ≤18 months. RESULTS: The median age of patients was 61 yr. Forty-one (80%) patients received induction with immunomodulatory drugs, proteosome inhibitors, or combination of both. The overall response rate (ORR) after auto-HCT was 96% (stringent complete response 23%, complete response 10%, very good partial response 22%, and partial response 39%). The median PFS was 7.8, and median overall survival (OS) was 56.3 months. On univariate analysis, concurrent light-chain amyloidosis (AL) was associated with inferior PFS [hematological response (HR); 2.51, 95% CI; 0.64-10.58, P = 0.03] and occurrence of soft tissue plasmacytoma was associated with a significantly shorter OS (HR: 3.05, 95% CI: 0.57-16.29, P = 0.02). CONCLUSION: Our analysis suggests that concurrent AL and soft tissue plasmacytoma were associated with shorter PFS and OS, respectively. Heterogeneity in clinical outcome of SR MM merits better tools for prognostication, such as gene expression profiling and minimal residual disease assessment to identify high-risk patients.

Treatment for childhood acute lymphoblastic leukemia in Taiwan: Taiwan Pediatric Oncology Group ALL-2002 study emphasizing optimal reinduction therapy and central nervous system preventive therapy without cranial radiation.

BACKGROUND: Reinduction therapy has improved the outcomes in children with acute lymphoblastic leukemia (ALL). We sought to determine the optimal course(s) of reinduction therapy for standard-risk (SR, or "low-risk" in other groups) patients. Also, we evaluated outcomes using triple intrathecal therapy without cranial radiation (CrRT) for central nervous system (CNS) preventive therapy. PROCEDURE: From 2002 to 2012, all newly diagnosed children with ALL in Taiwan were enrolled in Taiwan Pediatric Oncology Group ALL-2002 protocol. SR patients were randomized to receive single or double reinduction courses. The patients enrolled before 2009 received CrRT, while those enrolled later did not. The Kaplan-Meier method was used to estimate survival rates and the difference between two groups was compared by the two-sided log-rank test. RESULTS: In 1,366 eligible patients, the 5-year overall survival (OS) was 81.6 ± 1.1% (standard error) and 5-year event-free survival (EFS) was 74.3 ± 1.2%. In SR patients, the 5-year OS for one and two reinduction courses was 91.6 ± 2.1% and 93.7 ± 1.8%, respectively, and the 5-year EFS was 85.2 ± 2.7% and 89.8 ± 2.3%, respectively. There were no significant differences in survival between these two groups. Patients with MLL or BCR-ABL1 had the worst outcomes: 5-year EFS was 23.4 and 31.8% and 5-year OS was 28.6 and 44.7%, respectively. There was no significant difference in CNS relapse or survival between the era with or without CrRT. CONCLUSIONS: For SR patients, one-course reinduction was adequate. Triple intrathecal therapy alone successfully prevented CNS relapse.

Donor Killer Immunoglobulin-Like Receptor Profile Bx1 Imparts a Negative Effect and Centromeric B-Specific Gene Motifs Render a Positive Effect on Standard-Risk Acute Myeloid Leukemia/Myelodysplastic Syndrome Patient Survival after Unrelated Donor Hematopoietic Stem Cell Transplantation.

Donor killer immunoglobulin-like receptor (KIR) group B profiles (Bx) and homozygous of centromeric motif B (Cen-B/B) are the most preferable KIR gene content motifs for hematopoietic stem cell transplantation (HSCT). The risk of transplant from Bx1 donors and the benefit of the presence of Cen-B (regardless of number) were observed for standard-risk acute myeloid leukemia/myelodysplastic syndrome (AML/MDS) patients in this 4-year retrospective study. A total of 210 Chinese patients who underwent unrelated donor HSCT were investigated. Donor KIR profile Bx was associated with significantly improved overall survival (OS; P = .026) and relapse-free survival (RFS; P = .021) and reduced nonrelapse mortality (NRM; P = .017) in AML/MDS patients. A significantly lower survival rate was observed for transplants from Bx1 donors compared with Bx2, Bx3, and Bx4 donors for patients in first complete remission (n = 82; OS: P = .024; RFS: P = .021). Transplant from donors with Cen-B resulted in improved OS (HR = .256; 95% CI, .084 to .774; P = .016) and RFS (HR = .252; 95% CI, .084 to .758; P = .014) in AML/MDS patients at standard risk. However, this particular effect did not increase with a higher number of Cen-B motifs (cB/B versus cA/B; OS: P = .755; RFS: P = .768). No effect was observed on high-risk AML/MDS, acute lymphoblastic leukemia/non-Hodgkin lymphoma, and chronic myelogenous leukemia patients. Avoiding the selection of HSCT donors of KIR profile Bx1 is strongly advisable for standard-risk AML/MDS patients. The presence of the Cen-B motif rather than its number was more important in donor selection for the Chinese population.

Superior survival of unmanipulated haploidentical hematopoietic stem cell transplantation compared with chemotherapy alone used as post-remission therapy in adults with standard-risk acute lymphoblastic leukemia in first complete remission.

We wanted to compare the efficacy of haploidentical hematopoietic stem cell transplantation (HSCT) with chemotherapy alone in adults with standard-risk acute lymphoblastic leukemia (ALL) in first complete remission (CR1). One hundred thirty-eight consecutive adult patients with standard-risk ALL in CR1 were retrospectively investigated. Of these patients, 59 received chemotherapy alone (group A) and 79 received unmanipulated haploidentical HSCT (group B). Cumulative incidence of relapse at 5 years in group A was significantly higher than that in group B (66.3% versus 29.9%, P < .0001). Overall and disease-free survival in group A were significantly inferior to group B (P < .0001). Moreover, multivariate analyses demonstrated that central nervous system leukemia (P = .002), T cell immunophenotype (P = .044), expression of E2A-PBX1 (P = .007), and positive minimal residual disease after the first cycle of consolidation (P = .004) were correlated with relapse. Patients with 1 of 4 risk factors were assigned to the high-risk group. Otherwise, patients without risk factors were assigned to the low-risk group. In the high-risk group, HSCT had lower relapse rates and superior DFS compared with chemotherapy (P < .05), but in the low-risk group, there were no differences between HSCT and chemotherapy (P > .05). This study is the first to demonstrate that compared with chemotherapy alone, haploidentical HSCT is a better postremission therapy in adults with standard-risk ALL in CR1. Moreover, based on the 4 risk factors, the establishment of risk stratification could identify the subgroup of patients with a higher risk of relapse in adults with standard-risk ALL in CR1. Furthermore, risk stratification-directed postremission therapies using haploidentical HSCT or chemotherapy alone not only reduce relapse rate but also avoid unnecessary treatment-related mortality and improve survival.

Efficacy and Safety of High-Dose Chemotherapy with Treosulfan and Melphalan in Multiple Myeloma.

(1) Background: Upfront treatment consolidation with high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT) has relevantly contributed to achieving durable remissions following induction treatment in multiple myeloma (MM) patients. The optimization of HDCT regimens can, therefore, essentially contribute to improving the depth and duration of tumor remissions. To date, melphalan at 200 mg/m2 is the standard HDCT regimen for fit MM patients. In our previous work, we showed promising efficacy and safety results for treosulfan (14 g/m2) and melphalan (200 mg/m2) (TreoMel) in acute myeloid leukemia (AML) patients receiving ASCT. Based on these data, TreoMel became the standard of care for fit MM patients at our institution. (2) Methods: We identified 115 consecutive MM patients who underwent consolidation with TreoMel between 01/2020 and 08/2022 at the University Hospital of Bern. We analyzed the safety and efficacy data, as well as the treosulfan pharmacokinetics, correlating them with tumor responses. (3) Results: A complete response (CR) rate of 84% was achieved, which is comparable to the CR rate reported for the quadruplet combination. The median PFS was 30 months (95% CI: 20.4-not reached), and the 31-month OS rate was 83%. The median area under the curve (AUC) for treosulfan was 952.5 mg*h/L (range: 527.4-1781.4), and the median peak level was 332.3 mg/L (range: 168-554). The treosulfan pharmacokinetics showed no significant correlation with MM responses after HDCT and ASCT. However, female patients had a significantly higher AUC (p = 0.007) and peak value (p = 0.001), and the higher values were associated with longer hospitalizations. (4) Conclusions: Treatment consolidation with TreoMel HDCT demonstrated a promising efficacy and safety profile in our cohort of MM patients and deserves further investigation in prospective studies.

JACLS ALL-02 SR protocol reduced-intensity chemotherapy produces excellent outcomes in patients with low-risk childhood acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. As overall cure rates of childhood ALL have improved, reduction of overall treatment intensity while still ensuring excellent outcomes is imperative for low-risk patients. We report the outcomes of patients treated following the standard-risk protocol from the prospective Japan Association of Childhood Leukemia Study (JACLS) ALL-02 study, which was conducted between 2002 and 2008 for patients with newly diagnosed ALL aged 1-18 years. Of 1138 patients with B-cell precursor ALL, 388 (34.1%) were allocated to this protocol. Excellent outcomes were achieved despite the overall treatment intensity being lower than that of most contemporary protocols: 4 years event-free survival (EFS) was 92.3% and 4 years overall survival 98.2%. Patients with high hyperdiploidy (HHD) involving triple trisomy (trisomy of chromosomes 4, 10, and 17) or ETV6-RUNX1 had even better outcomes (4 years EFS 97.6% and 100%, respectively). Unique characteristics of this protocol include a selection of low-risk patients with a low initial WBC count and good early treatment response and reduction of cumulative doses of chemotherapeutic agents while maintaining dose density. In Japan, we are currently investigating the feasibility of this protocol while incorporating minimal residual disease into the patient stratification strategy.

BoBafit : A copy number clustering tool designed to refit and recalibrate the baseline region of tumors' profiles.

Human cancer arises from a population of cells that have acquired a wide range of genetic alterations, most of which are targets of therapeutic treatments or are used as prognostic factors for patient's risk stratification. Among these, copy number alterations (CNAs) are quite frequent. Currently, several molecular biology technologies, such as microarrays, NGS and single-cell approaches are used to define the genomic profile of tumor samples. Output data need to be analyzed with bioinformatic approaches and particularly by employing computational algorithms. Molecular biology tools estimate the baseline region by comparing either the mean probe signals, or the number of reads to the reference genome. However, when tumors display complex karyotypes, this type of approach could fail the baseline region estimation and consequently cause errors in the CNAs call. To overcome this issue, we designed an R-package, BoBafit , able to check and, eventually, to adjust the baseline region, according to both the tumor-specific alterations' context and the sample-specific clustered genomic lesions. Several databases have been chosen to set up and validate the designed package, thus demonstrating the potential of BoBafit to adjust copy number (CN) data from different tumors and analysis techniques. Relevantly, the analysis highlighted that up to 25% of samples need a baseline region adjustment and a redefinition of CNAs calls, thus causing a change in the prognostic risk classification of the patients. We support the implementation of BoBafit within CN analysis bioinformatics pipelines to ensure a correct patient's stratification in risk categories, regardless of the tumor type.

Long-term outcomes of modified BFM-95 regimen in adults with newly diagnosed standard-risk acute lymphoblastic leukemia: a retrospective single-center study.

The standard treatment for adult acute lymphoblastic leukemia (ALL) is undefined. Patients with newly diagnosed standard-risk ALL at a single institution were retrospectively analyzed. From 2010 to 2017, 46 patients were treated using the modified Berlin-Frankfurt-Münster (BFM)-ALL-95 regimen. Hematologic and molecular complete remission (CR) rates of 91.3% and 76.1% were achieved. The 5-year event-free survival (EFS) and overall survival (OS) rates for all patients in the cohort were 58.0% (95% confidence interval, 42.1-73.9%) and 66.7% (95% CI, 51.4-82.0%), respectively. No patient presented with central nervous system involvement after CR in this study. This condition could be related to four doses of high-dose methotrexate (MTX) every 3 months during the maintenance phase. Multivariate analysis revealed that minimal residual disease positive and time interval between induction IA and Protocol M of more than 70 days were independent adverse factors for EFS and OS. One or more instances of grade 4 myelosuppression occurred during induction therapy. Nonhematological side effects were mild. No toxicity-related deaths were observed in the entire cohort. The data indicated that the modified regimen is well tolerated and can produce the promising outcomes in Chinese adults with standard-risk ALL.