Outcomes from hematopoietic stem cell transplantation following treosulfan-based conditioning: A clinical and pharmacokinetic analysis.

BACKGROUND: The aims of this study are to report our experience with treosulfan-based conditioning regimens for patients with non-malignant hematologic conditions, correlating clinical outcomes at different time points post-transplant with treosulfan exposure (AUC). METHODS: This study was a single-center observational study investigating overall survival (OS), disease-free survival (DFS), and event-free survival (EFS) end-points post-transplant. The consequences of treosulfan AUC with respect to toxicity, correction of underlying disease, and long-term chimerism were also explored using pharmacokinetic analysis. RESULTS: Forty-six patients received 49 transplants with treosulfan and fludarabine-based conditioning between 2005 and 2023. Twenty-four patients also received thiotepa. Donor chimerism was assessed on either whole blood or sorted cell lines at different time points post-transplant. Thirty-nine patients received treosulfan pharmacokinetic assessment to evaluate cumulative AUC, with five infants receiving real-time assessment to facilitate daily dose adjustment. OS, DFS, and EFS were 87%, 81%, and 69%, respectively. Median follow-up was 32.1 months (range 0.82-160 months) following transplant. Lower EFS was associated with patient age (<1 year; p = .057) and lower cumulative treosulfan dose (<42 g/m2; p = .003). Stable donor chimerism in B-cell, NK-cell, and granulocyte lineages at 1-year post-transplant were more prevalent in patients receiving thiotepa conditioning. Two infants required daily dose adjustment to treosulfan to avoid high AUC. CONCLUSIONS: Excellent clinical outcomes and stable chimerism were observed in this patient series. The addition of thiotepa conferred no significant toxicity and trended toward sustained ongoing donor engraftment. Correlating treosulfan AUC with long-term patient outcomes is required.

Combination low-dose cyclophosphamide with check-point blockade and ionizing radiation promote an abscopal effect in mouse models of melanoma.

PURPOSE: The complex strategy of hypo-fractionated radiotherapy (HFRT) in combination with an immune checkpoint inhibitor (ICI) can stimulate a potential systemic antitumor response; however, the abscopal effect is always precluded by the tumor microenvironment, which may limit sufficient T-cell infiltration of distant nonirradiated tumors for certain kinds of inhibitory factors, such as regulatory T-cells (Tregs). Additionally, low-dose cyclophosphamide (LD-CYC) can specifically kill regulatory Tregs and strongly synergize antigen-specific immune responses, which could promote an abscopal effect. MATERIALS AND METHODS: We explored whether a triple regimen consisting of HFRT, ICI, and LD-CYC could achieve a better systemic antitumor response in bilateral mouse tumor models. RESULT: Our data demonstrate that LD-CYC combined with HFRT and antiprogrammed cell death ligand 1 (PDL-1) therapy could enhance the abscopal effect than only HFRT/antiPDL-1 or HFRT alone. Surprisingly, repeat CYC doses cannot further restrain tumor proliferation but can prolong murine overall survival, as revealed by the major pathologic responses. These results are associated with increased CD8 + effector T-cell infiltration, although LD-CYC did not upregulate PDL-1 expression in the tumor. CONCLUSIONS: Compared with traditional strategies, for the first time, we demonstrated that a triple treatment strategy remarkably increased the number of radiation-induced tumor-infiltrating CD8 + T-cells, effectively decreasing infiltrating Tregs, and promoting an abscopal effect. Thus, we describe a novel and effective therapeutic approach by combining multiple strategies to target several tumor-mediated immune inhibitory mechanisms.

Temozolomide nano-in-nanofiber delivery system with sustained release and enhanced cellular uptake by U87MG cells.

OBJECTIVE: The study was aimed at formulating temozolomide (TMZ) loaded gelatin nanoparticles (GNPs) encapsulated into polyvinyl alcohol (PVA) nanofibers (TMZ-GNPs-PVA NFs) as the nano-in-nanofiber delivery system. The secondary objective was to explore the sustained releasing ability of this system and to assess its enhanced cellular uptake against U87MG glioma cells in vitro. SIGNIFICANCE: Nano-in-nanofibers are the emerging drug delivery systems for treating a wide range of diseases including cancers as they overcome the challenges experienced by nanoparticles and nanofibers alone. METHODS: The drug-loaded GNPs were formulated by one-step desolvation method. The Design of Experiments (DoE) was used to optimize nanoparticle size and entrapment efficiency. The optimized drug-loaded nanoparticles were then encapsulated within nanofibers using blend electrospinning technique. The U87MG glioma cells were used to investigate the uptake of the formulation. RESULTS: A 32 factorial design was used to optimize the mean particle size (145.7 nm) and entrapment efficiency (87.6%) of the TMZ-loaded GNPs which were subsequently ingrained into PVA nanofibers by electrospinning technique. The delivery system achieved a sustained drug release for up to seven days (in vitro). The SEM results ensured that the expected nano-in-nanofiber delivery system was achieved. The uptake of TMZ-GNPs-PVA NFs by cells was increased by a factor of 1.964 compared to that of the pure drug. CONCLUSION: The nano-in-nanofiber drug delivery system is a potentially useful therapeutic strategy for the management of glioblastoma multiforme.

Single-Agent Trabectedin Versus Physician's Choice Chemotherapy in Patients With Recurrent Ovarian Cancer With BRCA-Mutated and/or BRCAness Phenotype: A Randomized Phase III Trial.

PURPOSE: Literature evidence suggests that trabectedin monotherapy is effective in patients with recurrent ovarian cancer (OC) presenting BRCA mutation and/or BRCAness phenotype. METHODS: A prospective, open-label, randomized phase III MITO-23 trial evaluated the activity and safety of trabectedin 1.3 mg/m2 given once every 3 weeks (arm A) in BRCA 1/2 mutation carriers or patients with BRCAness phenotype (ie, patients who responded to ≥two previous platinum-based treatments) with recurrent OC, primary peritoneal carcinoma, or fallopian tube cancer in comparison with physician's choice chemotherapy in the control arm (arm B; pegylated liposomal doxorubicin, topotecan, gemcitabine, once-weekly paclitaxel, or carboplatin). The primary end point was overall survival (OS) evaluated in the intention-to-treat population. RESULTS: Overall, 244 patients from 21 MITO centers were randomly assigned (arm A = 122/arm B = 122). More than 70% of patients received ≥three previous chemotherapy lines and 35.7% had received a poly (ADP-ribose) polymerase inhibitor (PARPi) before enrollment. Median OS was not significantly different between the arms: arm A: 15.8 versus arm B: 17.9 months (P = .304). Median progression-free survival was 4.9 months in arm A versus 4.4 months in arm B (P = .897). Among 208 patients evaluable for efficacy, the objective response rate was 17.1% in arm A and 21.4% in arm B, with comparable median duration of response (5.62 v 5.66 months, respectively). No superior effect was observed for trabectedin in the prespecified subgroup analyses according to BRCA mutational status, chemotherapy type, and pretreatment with a PARPi and/or platinum-free interval. Trabectedin showed a higher frequency of grade ≥3 adverse events (AEs), serious AEs, and serious adverse drug reactions compared with control chemotherapy. CONCLUSION: Trabectedin did not improve median OS and showed a worse safety profile in comparison with physician's choice control chemotherapy.

Effectiveness and Safety of Trabectedin and Radiotherapy for Patients With Myxoid Liposarcoma: A Nonrandomized Clinical Trial.

Importance: Preclinical data about the synergistic activity of radiotherapy (RT) and trabectedin have been reported. The combination of trabectedin and RT in treating myxoid liposarcomas appears worth exploring. Objective: To explore the effectiveness and safety of trabectedin combined with RT. Design, Setting, and Participants: This international, open-label, phase 2 nonrandomized clinical trial including 46 patients with myxoid liposarcoma was conducted in 4 centers in Spain, 1 in Italy, and 2 in France from July 1, 2016, to September 30, 2019. Eligible patients had to have a histologic, centrally reviewed diagnosis of localized resectable myxoid liposarcoma arising from an extremity or the trunk wall. Interventions: Trabectedin was administered at the recommended dose stemming from the phase 1 trial (1.5 mg/m2), with intravenous infusion during 24 hours every 21 days for a total of 3 cycles. Radiotherapy was started after completion of the first trabectedin infusion (cycle 1, day 2). Patients received 25 fractions of radiation for a total of 45 Gy. Surgery was planned 3 to 4 weeks after the administration of the last preoperative cycle and not until 4 weeks after the end of preoperative RT. Pathologic specimens were mapped in tumor sections to estimate the histologic changes and the percentage of viable tumor after neoadjuvant treatment. Main Outcomes and Measures: The primary objective of the phase 2 part of the study was overall response. Secondary objectives were effectiveness measured by relapse-free survival and activity measured by functional imaging and pathologic response. Results: A total of 46 patients were enrolled. Four patients were not evaluable. The median age was 43 years (range, 18-77 years), and 31 patients were male (67%). Overall, 9 of 41 patients (22%) achieved a partial response with neoadjuvant treatment with trabectedin and RT, with 5 of 39 patients (13%) achieving a complete pathologic response and 20 of 39 patients (51%) having 10% or less of a viable remaining tumor. Partial responses according to Choi criteria were observed in 24 of 29 evaluable patients (83%), and no patient had disease progression. Treatment was well tolerated. Conclusions and Relevance: Although the primary end point of this phase 2 nonrandomized clinical trial was not met (Response Evaluation Criteria in Solid Tumors response in ≥70% of patients), results suggest this combination was well tolerated and effective in terms of pathologic response. Thus, trabectedin plus RT might be a treatment option regarding tolerability; further evidence should be generated in this setting.

Exploring temozolomide encapsulated PEGylated liposomes and lyotropic liquid crystals for effective treatment of glioblastoma: in-vitro, cell line, and pharmacokinetic studies.

Temozolomide (TMZ) is one of the best choices for treating glioblastoma. However, due to the short plasma half-life, only 20-30 % brain bioavailability can be achieved using traditional formulations. In the present study, PEGylated liposomes and lyotropic liquid crystals (LLCs) were developed and investigated to prolong the plasma circulation time of TMZ. Industrially feasible membrane extrusion and modified hot melt emulsification techniques were utilized during the formulation. Liposomes and LLCs in the particle size range of 80-120 nm were obtained with up to 50 % entrapment efficiency. The nanocarriers were found to show a prolonged release of up to 72 h. The cytotoxicity studies in glioblastoma cell lines revealed a âˆ¼1.6-fold increased cytotoxicity compared to free TMZ. PEGylated liposomes and PEGylated LLCs were found to show a 3.47 and 3.18-fold less cell uptake in macrophage cell lines than uncoated liposomes and LLCs, respectively. A 1.25 and 2-fold increase in the plasma t1/2 was observed with PEGylated liposomes and PEGylated LLCs, respectively, compared to the TMZ when administered intravenously. Extending plasma circulation time of TMZ led to significant increase in brain bioavailability. Overall, the observed improved pharmacokinetics and biodistribution of TMZ revealed the potential of these PEGylated nanocarriers in the efficient treatment of glioblastoma.

Clinical Efficacy of Bendamustine Plus Rituximab (BR) for B-cell Relevant Indolent Non-Hodgkin's Lymphoma and Role of ß2-MG in Predicting the Efficacy of BR Regimen: A Real-World Retrospective Study in China.

BACKGROUND: Domestic bendamustine has been approved for appearing on the market in China in the past two years. The report on bendamustine plus rituximab (BR) in the treatment of Chinese B-cell-associated indolent non-Hodgkin's lymphoma (iNHL) has not yet been published. This study probed into clinical efficacy of the BR regimen for B-cell-associated iNHL in China as well as the value of ß2-microglobulin (ß2-MG) as a prognostic factor. METHODS: We retrospectively analyzed clinical data of 73 B-cell-associated iNHL patients who received BR treatment in The First Affiliated Hospital, College of Medicine, Zhejiang University from January 2020 to January 2021, including clinical characteristics, therapies, therapeutic efficacy, and prognosis-related factors. Thirty-three patients (45.2%) did not receive any other treatment before the BR regimen, and other patients received CHOP, R-CHOP, and other regimens in the past. The cutoff date for follow-up was May 2021. Clinical characteristics of patients were analyzed. The clinical efficacy of the BR regimen was evaluated. Differences of ß2-MG expression before and after treatment were analyzed between the CR+PR group and the SD+PD group. Main outcomes were progression-free survival (PFS) and overall survival (OS). A multivariate Cox regression model was taken to analyze prognostic factors relative to survival rate of patients, and adverse events (AEs) during treatment. RESULTS: The objective response rate (ORR) of B-cell-associated iNHL patients who received BR regimen as first-/multiline treatment was 79.5%, with complete response (CR) of 37.0%, partial response (PR) of 42.5%, median PFS of 12.1 months (95% confidence interval (CI): 10.9-13.2), and median OS of 15.5 months (95% CI: 14.8-16.1). Before treatment, there was no statistical significance in the ß2-MG level between the CR+PR group and the SD+PD group (p > 0.05). After treatment, the ß2-MG level in the CR group was noticeably lower than that in the SD+PD group (p < 0.05). The ß2-MG level in the CR+PR group decreased conspicuously after treatment (p < 0.05). The ß2-MG level in the SD+PD group after treatment was not notably different from that before treatment (p > 0.05). According to the median expression level of ß2-MG before treatment, patients were divided into two groups. The average PFS of the low expression group was 12.69 ± 0.77 months, which was longer than the high expression group (10.13 ± 0.74 months), but the difference between the groups was not statistically significant (p > 0.05). Multivariate Cox regression analysis showed that B-cell-associated iNHL subtype was the independent prognostic marker most likely to affect PFS of patients (p = 0.051). Incidence of any grade of AEs in all patients was 32.9% (24/73). CONCLUSION: B-cell-associated iNHL patients who received BR regimen had favorable clinical efficacy and were tolerable to AEs. Though the ß2-MG level in this study could not be used to predict clinical outcome, a lower level before treatment seemed to be implicated in better survival outcomes of patients. Our research also unraveled that B-cell-associated iNHL subtype may be a key factor to patient's prognosis. Overall, this study offers some important insights into clinical application of the BR regimen for Chinese B-cell-associated iNHL patients.

Comparing paclitaxel-platinum with ifosfamide-platinum as the front-line chemotherapy for patients with advanced-stage uterine carcinosarcoma.

BACKGROUND: Uterine carcinosarcoma (UCS) is a rare but highly lethal disease. Adjuvant chemotherapy is highly recommended for advanced UCS. To date, the standard chemotherapy regimen is still uncertain, although two regimens as paclitaxel-platinum (PP) and ifosfamide-platinum (IP) regimens are most commonly used. The aims of the current study attempt to compare both regimens in the management of advanced UCS patients. METHODS: We evaluated advanced UCS patients who were treated either with PP or with IP after primary cytoreductive surgery in single institute retrospectively. The clinical-pathological parameters, recurrence, and survival were recorded. RESULTS: A total of 16 patients were analyzed. Twelve patients received adjuvant PP therapy, and the remaining four patients received IP therapy. The median follow-up time was 28 months, ranging from 3.8 months to 121 months. Disease-related death occurred in 10 patients (62.5%). The median progression-free survival was 4.9 months, ranging from 3.8 months to 36.5 months in IP, and 23.1 months, ranging from 9.3 months to 121 months in PP, with statistically significant difference (p = 0.04). The median overall survival was 9.5 months (ranging from 3.8 months to 36.5 months) and 28.7 months (ranging from 10.3 months to 121 months) in IP and PP, respectively, without statistically significant difference (p = 0.06). Presence of pelvic and para-aortic lymphadenopathy and deep myometrial invasion (>1/2) were associated with worse prognosis by univariate analysis. No prognostic factor could be identified using multivariate analysis model. CONCLUSION: In the current study, due to extremely little number of subjects enrolled, the advantage of using paclitaxel-platinum regimen in the management of advanced UCS was still unclear, although a certain trend of favoring was supposed. We are looking forward to seeing more studies to identify the approximate regimen in the management of this highly lethal disease.

An expanded-access clinical study of thiotepa (DSP-1958) high-dose chemotherapy before autologous hematopoietic stem cell transplantation in patients with malignant lymphoma.

Thiotepa, an antineoplastic ethylenimine alkylating agent that can penetrate the central nervous system, was recently approved in Japan as high-dose chemotherapy prior to autologous hematopoietic stem cell transplantation (HSCT) for patients with malignant lymphoma. To further evaluate the safety and efficacy of thiotepa, a multicenter, open-label, non-comparative, expanded access program was undertaken in Japan, including a larger population of Asian patients with malignant lymphoma. Intravenous thiotepa (200 mg/m2/day) was administered over 2 h on days -4 and -3 before scheduled HSCT, plus intravenous busulfan (0.8 mg/kg) over 2 h every 6 h on days -8, -7, -6 and -5. In the safety analysis population (N = 51), 25 patients (49.0%) had primary central nervous system lymphomas. The most common treatment-emergent adverse event was febrile neutropenia (49/51 [96.1%]). No unexpected safety events were observed, and no event resulted in death or treatment modification. Forty-seven patients (92.2%) had engraftment (neutrophil count ≥ 500/mm3 for three consecutive days after bone-marrow suppression and HSCT). The survival rate at day 100 post-transplantation was 100%. These data confirm the safety of thiotepa prior to autologous HSCT for patients with malignant lymphoma.Trial registration: JapicCTI-173654.

Enhanced cytotoxic activity of beta carotene conjugated liposomes towards breast cancer cell line: comparative studies with cyclophosphamide.

This work aims to evaluate cyclophosphamide (Cyclo) cytotoxic efficacy combined with liposomes in the presence or absence of beta carotene (beta) by detecting the effects of these compounds on the breast cancer cell line (MCF-7) DNA damage. The IC50 value for beta in cytotoxic assay with MCF-7 treated cells was 21.15 µg/ml, while with liposomal beta (LipoBeta) being 121 µg/ml. The free Cyclo IC50 value was 719.86 µg/ml, its liposomal form (LipoCyclo) was 172 µg/ml. The results indicated that in contrast with Cyclo and control values, all comet assay parameters for the LipoBeta were significantly increased (P < 0.05). In MCF-7 cells treated with beta, the findings show a higher intensity of comet tail than those treated with LipoBeta. The presence of several double-strand breaks suggests this high intensity relative to the head. The molecular combination between Cyclo and liposomes in the presence or absence of beta was characterized. Dynamic light scattering measurements confirmed the mono-dispersity of all samples. The incorporation of Cyclo or beta into liposomes exhibited a slight shift to higher temperature compared to the main peak of empty liposomes that exists at 101.5°C which creates a conformational disorder within the phospholipids. The FTIR study showed structural alterations in vesicles after liposome encapsulation.

Triolein emulsion enhances temozolomide brain delivery: an experimental study in rats.

PURPOSE: To evaluate the enhancement of temozolomide (TMZ) delivery in the rat brain using a triolein emulsion. MATERIALS AND METHODS: Rats were divided into the five groups as following: group 1 (negative control), group 2 (treated with triolein emulsion and TMZ 20 mg/kg), and group 3 (TMZ 20 mg/kg treatment without triolein), group 4 (treated with triolein emulsion and TMZ 10 mg/kg), and group 5 (TMZ 10 mg/kg treatment without triolein). Triolein emulsion was infused into the right common carotid artery. One hour later, the TMZ concentration was evaluated quantitatively and qualitatively using high-performance liquid chromatography (HPLC-MS) and desorption electrospray ionization mass spectrometry (DESI-MS) imaging, respectively. The concentration ratios of the ipsilateral to contralateral hemisphere in each group were determined and the statistical analysis was conducted using an unpaired t-test. RESULTS: Quantitatively, the TMZ concentration ratio of the ipsilateral to the control hemisphere was 2.41 and 1.13 in groups 2 and 3, and were 2.49 and 1.14 in groups 4 and 5, respectively. Thus, the TMZ signal intensities of TMZ in group 2 and 4 were statistically high in the ipsilateral hemispheres. Qualitatively, the signal intensity of TMZ was remarkably high in the ipsilateral hemisphere in group 2 and 4. CONCLUSIONS: The triolein emulsion efficiently opened the blood-brain barrier and could provide a potential new strategy to enhance the therapeutic effect of TMZ. HPLC-MS and DESI-MS imaging were shown to be suitable for analyses of enhancement of brain TMZ concentrations.

First-principles studies on two-dimensional B3O3 adsorbent as a potential drug delivery platform for TEPA anticancer drug.

The remarkable properties of pristine B3O3 nanosheet as a nanocarrier for adsorption and desorption of TEPA anticancer drug for designing potential drug delivery platform were investigated using periodic DFT calculations. We studied the adsorption energy of all stable complexes formed between the drug molecule and B3O3 in gas and aqueous phases along with electronic structure analysis of complexes. Different adsorption configurations were studied for drug/B3O3 complexes, including the interaction of the C atom of the triangular ring, O atom in the TEPA drug with the B atom in B3O3, and indirect drug interaction the middle of the R1 ring cavity of the B3O3 nanosheet. The take-up of TEPA prompts a substantial change of 68.13% in the band gap (Eg) of the B3O3 nanosheet in the most stable complex. The present study results affirmed the application of B3O3 nanosheet as a potential vehicle for TEPA drugs in the treatment of cancerous tissues.

Cell membrane coating integrity affects the internalization mechanism of biomimetic nanoparticles.

Cell membrane coated nanoparticles (NPs) have recently been recognized as attractive nanomedical tools because of their unique properties such as immune escape, long blood circulation time, specific molecular recognition and cell targeting. However, the integrity of the cell membrane coating on NPs, a key metrics related to the quality of these biomimetic-systems and their resulting biomedical function, has remained largely unexplored. Here, we report a fluorescence quenching assay to probe the integrity of cell membrane coating. In contradiction to the common assumption of perfect coating, we uncover that up to 90% of the biomimetic NPs are only partially coated. Using in vitro homologous targeting studies, we demonstrate that partially coated NPs could still be internalized by the target cells. By combining molecular simulations with experimental analysis, we further identify an endocytic entry mechanism for these NPs. We unravel that NPs with a high coating degree (≥50%) enter the cells individually, whereas the NPs with a low coating degree (<50%) need to aggregate together before internalization. This quantitative method and the fundamental understanding of how cell membrane coated NPs enter the cells will enhance the rational designing of biomimetic nanosystems and pave the way for more effective cancer nanomedicine.

Cell survival after DNA damage in the comet assay.

The comet assay is widely used in basic research, genotoxicity testing, and human biomonitoring. However, interpretation of the comet assay data might benefit from a better understanding of the future fate of a cell with DNA damage. DNA damage is in principle repairable, or if extensive, can lead to cell death. Here, we have correlated the maximally induced DNA damage with three test substances in TK6 cells with the survival of the cells. For this, we selected hydrogen peroxide (H2O2) as an oxidizing agent, methyl methanesulfonate (MMS) as an alkylating agent and etoposide as a topoisomerase II inhibitor. We measured cell viability, cell proliferation, apoptosis, and micronucleus frequency on the following day, in the same cell culture, which had been analyzed in the comet assay. After treatment, a concentration dependent increase in DNA damage and in the percentage of non-vital and apoptotic cells was found for each substance. Values greater than 20-30% DNA in tail caused the death of more than 50% of the cells, with etoposide causing slightly more cell death than H2O2 or MMS. Despite that, cells seemed to repair of at least some DNA damage within few hours after substance removal. Overall, the reduction of DNA damage over time is due to both DNA repair and death of heavily damaged cells. We recommend that in experiments with induction of DNA damage of more than 20% DNA in tail, survival data for the cells are provided.

A natural protein based platform for the delivery of Temozolomide acid to glioma cells.

Glioblastoma is one of the most difficult to treat cancers with poor prognosis and survival of around one year from diagnosis. Effective treatments are desperately needed. This work aims to prepare temozolomide acid (TMZA) loaded albumin nanoparticles, for the first time, to target glioblastoma (GL261) and brain cancer stem cells (BL6). TMZA was loaded into human serum albumin nanoparticles (HSA NPs) using the desolvation method. A response surface 3-level factorial design was used to study the effect of different formulation parameters on the drug loading and particle size of NPs. The optimum conditions were found to be: 4 mg TMZA with 0.05% sodium cholate. This yielded NPs with particle size and drug loading of 111.7 nm and 5.5% respectively. The selected formula was found to have good shelf life and serum stability but with a relatively fast drug release pattern. The optimized NPs showed excellent cellular uptake with âˆ¼ 50 and 100% of cells were positive for NP uptake after 24 h incubation with both GL261 and BL6 glioblastoma cell lines, respectively. The selected formula showed high cytotoxicity with Ì´ 20% cell viability at 1 mM TMZA after 72 h incubation time. Finally, the fluorescently labelled NPs showed co-localization with the bioluminescent syngeneic BL6 intra-cranial tumour mouse model after intravenous administration.

A randomized phase III study of short-course radiotherapy combined with Temozolomide in elderly patients with newly diagnosed glioblastoma; Japan clinical oncology group study JCOG1910 (AgedGlio-PIII).

BACKGROUND: The current standard treatment for elderly patients with newly diagnosed glioblastoma is surgery followed by short-course radiotherapy with temozolomide. In recent studies, 40 Gy in 15 fractions vs. 60 Gy in 30 fractions, 34 Gy in 10 fractions vs. 60 Gy in 30 fractions, and 40 Gy in 15 fractions vs. 25 Gy in 5 fractions have been reported as non-inferior. The addition of temozolomide increased the survival benefit of radiotherapy with 40 Gy in 15 fractions. However, the optimal regimen for radiotherapy plus concomitant temozolomide remains unresolved. METHODS: This multi-institutional randomized phase III trial was commenced to confirm the non-inferiority of radiotherapy comprising 25 Gy in 5 fractions with concomitant (150 mg/m2/day, 5 days) and adjuvant temozolomide over 40 Gy in 15 fractions with concomitant (75 mg/m2/day, every day from first to last day of radiation) and adjuvant temozolomide in terms of overall survival (OS) in elderly patients with newly diagnosed glioblastoma. A total of 270 patients will be accrued from 51 Japanese institutions in 4 years and follow-up will last 2 years. Patients 71 years of age or older, or 71-75 years old with resection of less than 90% of the contrast-enhanced region, will be registered and randomly assigned to each group with 1:1 allocation. The primary endpoint is OS, and the secondary endpoints are progression-free survival, frequency of adverse events, proportion of Karnofsky performance status preservation, and proportion of health-related quality of life preservation. The Japan Clinical Oncology Group Protocol Review Committee approved this study protocol in April 2020. Ethics approval was granted by the National Cancer Center Hospital Certified Review Board. Patient enrollment began in August 2020. DISCUSSION: If the primary endpoint is met, short-course radiotherapy comprising 25 Gy in 5 fractions with concomitant and adjuvant temozolomide will be a standard of care for elderly patients with newly diagnosed glioblastoma. TRIAL REGISTRATION: Registry number: jRCTs031200099 . Date of Registration: 27/Aug/2020. Date of First Participant Enrollment: 4/Sep/2020.

Bendamustine Plus Rituximab as Salvage Treatment for Patients with Relapsed or Refractory Low-grade B-cell Lymphoma and Mantle Cell Lymphoma: A Single-Center Retrospective Study.

Bendamustine plus rituximab (B-R) is an effective therapy for relapsed or refractory (r/r) low-grade B-cell lymphoma (LGBCL) and mantle cell lymphoma (MCL); however, clinical data from Japanese patients treated with B-R therapy are limited. We retrospectively evaluated the efficacy and safety of B-R therapy in 42 patients who received B-R therapy at our hospital for r/r LGBCL and MCL. All patients received intravenous (IV) ritux-imab 375 mg/m2 on day 1 and IV bendamustine 90 mg/m2 on days 2 and 3 every 28 days for up to 6 cycles. The common histologic subtypes were follicular lymphoma (n = 29, 70%), marginal zone lymphoma (n = 6, 14%), and MCL (n = 5, 12%). The overall response rate was 93%, with 62% complete response and complete response unconfirmed. The median progression-free survival (PFS) was 38 months (95% confidence interval [CI], 24.6 to not reached [NR]), and the median overall survival (OS) was 80 months (95% CI, 60.7 to NR). Patients receiving a cumulative dose of bendamustine ≥ 720 mg/m2 showed a significantly longer PFS and OS. Grade 3/4 adverse events (≥ 10%) included neutropenia (55%), lymphopenia (69%), and nausea (24%). B-R therapy was effective and well tolerated, and the cumulative dose of bendamustine was associated with a favorable outcome.

Serum anti-Müllerian hormone as a marker of ovarian reserve after cancer treatment and/or hematopoietic stem cell transplantation in childhood: proposal for a systematic approach to gonadal assessment.

OBJECTIVE: Female patients treated with alkylating agents in childhood are at risk for ovarian impairment. We aimed at describing the pattern of residual ovarian function in a cohort of survivors of hematological malignancies and/or hematopoietic stem cell transplantation (HSCT) and assessing the relationship between cyclophosphamide equivalent dose (CED) and anti-Müllerian hormone (AMH). DESIGN AND METHODS: Gonadal health was clinically and biochemically assessed in 124 post-menarchal survivors who underwent treatment for pediatric hematological malignancies and/or HSCT between 1992 and 2019. RESULTS: Overt 'premature ovarian insufficiency' (POI) was detected in 72.1 and 3.7% of transplanted and non-transplanted patients, respectively; milder 'diminished ovarian reserve' (DOR) in 16.3 and 22.2%. In non-transplanted patients, increasing CED values were associated with lower AMH-SDS (P = 0.04), with the threshold of 7200 g/m2 being the best discriminator between DOR/POI and normal ovarian function (AUC: 0.75 on ROC analysis) and with an observed decrease of 0.14 AMH-SDS for each CED increase of 1 g/m2. In addition, age at diagnosis ≥10 years played a detrimental role on ovarian reserve (P = 0.003). In the HSCT group, irradiation was associated with a statistically significant reduction in AMH-SDS (P = 0.04). CONCLUSIONS: In non-transplanted patients, CED ≥ 7200 mg/m2 was associated with a DOR, while younger age at diagnosis played a protective role on ovarian reserve. As a result of the data collected, we propose a systematic algorithm to assess iatrogenic gonadal impairment in young female patients exposed to chemo-radiotherapy in childhood for hematological disorders.

Replication of Oncology Randomized Trial Results using Swedish Registry Real World-Data: A Feasibility Study.

Nationwide healthcare registries are potential important real-world data (RWD) sources for assessing drug effectiveness in oncology. However, it is unclear whether registry-derived RWD are suitable for clinical development. In this study, we replicate results from the comparator arm of two previously published oncology randomized controlled trials (RCTs) using RWD from Swedish nationwide healthcare registries. For replication 1, the RCT included 553 patients and the RWD included 283 patients treated with sorafenib for advanced hepatocellular cancer. The median overall survival (OS) was 11.2 (95% confidence interval (CI): 10.1-13.2) months in the RCT and 8.2 (95% CI: 7.0-9.9) months in the RWD, unadjusted hazard ratio (HR) 0.75 (95% CI: 0.63-0.88). For time-to-treatment discontinuation (TTD), the HR was 1.00 (95% CI: 0.87-1.16). For replication 2, the RCT included 154 patients and the RWD included 704 patients treated with melphalan, prednisone, and thalidomide for untreated multiple myeloma. The median OS was 52.6 (95% CI: 40-not applicable) months in the RCT and 36.9 (95% CI: 33.8-40.5) months in the RWD, unadjusted HR 0.67 (95% CI: 0.51-0.87). For TTD, the HR was 0.89 (95% CI: 0.74-1.06). The results were similar when applying various propensity-based confounding adjustments. In conclusion, OS was shorter in the RWD, whereas TTD was similar. Importantly, the data necessary (ex: eligibility criteria and baseline confounders) for replicating RCTs was mostly not available and these results further underscore the importance of developing frameworks for capturing relevant patient-level RWD for clinical and regulatory decision making in oncology.