Induction Cycle Research Articles

MDB-43. SHARED DECISION-MAKING (SDM) REGARDING RADIATION-AVOIDING (RA) THERAPY IN YOUNG CHILDREN WITH MEDULLOBLASTOMA (MB)

Abstract BACKGROUND Standard treatment for MB in patients age ≥ 3 years includes craniospinal radiation with tumor bed boost and chemotherapy. Radiation carries substantial risk of long-term issues, particularly in the youngest patients: second malignancy, neurocognitive issues, vasculopathy and endocrinopathies. Numerous trials have attempted to decrease or avoid the use of radiation by intensifying chemotherapy, some using high dose chemotherapy with autologous hematopoietic stem cell rescue (HDC). One of the most successful RA protocols, Children’s Oncology Group ACNS0334 enrolled children age < 36 months and treated with 3 cycles of induction (+/- high dose methotrexate) and 3 cycles HDC without planned radiation. Since 2012, we offer SDM with caregivers regarding treatment of their children ages 3-7 years with MB. Caregivers may choose standard radiation and chemotherapy (SRC) or the RA treatment above. OBJECTIVE Describe patient and disease characteristics and outcomes in patients aged 3-7 years treated for MB with SDM regarding the use of radiation. METHODS Retrospective analysis of diagnosis, treatment and clinical outcomes in all children <8 y.o. who completed treatment for MB between 2012 and 2023. RESULTS There were 16 patients offered SDM (all gross total resection without metastases) 7 chose RA and 9 SRC. The SRC group was enriched with molecularly high-risk patients (4 MYC or MYCN amplification, 1 SHH with P53 mutation). In the RA group, relapse occurred in 14% (n=1 of 7). In the SRC group, 44% relapsed (n=4 of 9). One patient developed high-grade glioma in the radiation boost field 10 years later. There was 1 death in the RA group due to disease progression and 5 deaths in the SRC group, 1 due to second malignancy. CONCLUSIONS We report excellent survival with RA therapy for appropriately selected young children (age 3-7 years) when SDM is used with families to determine the best treatment for their child.

Radiation therapy (RT)-free pembrolizumab plus chemotherapy (P+C) for PD-L1 TPS ≥50% locally advanced non-small cell lung cancer (LA-NSCLC): Primary analysis from multicenter single arm phase II study (Evolution trial; WJOG11819L).

LBA8050 Background: Standard of care for unresectable LA-NSCLC is chemoradiation therapy (CRT) followed by durvalumab (D). Survival curves of P monotherapy/P+C for PD-L1 TPS ≥50% stage IV NSCLC suggested possible comparable survival to CRT for stage III patients (pts). Moreover, some studies of neoadjuvant C+immunotherapy (I) for stage III pts have demonstrated high pathological complete response and major pathological response rates, implying potentially outstanding efficacy of C+I for earlier stage. We thus hypothesized P+C without RT in PD-L1 ≥50% LA-NSCLC pts provides a comparable efficacy to CRT followed by D while avoiding CRT-induced severe toxicities. Methods: This is a phase II study conducted by West Japan Oncology Group. P with platinum plus pemetrexed (PEM) (non-squamous) or P with carboplatin plus nab-paclitaxel (squamous) was administered every 3 weeks without RT. After four cycles of induction P+C, P with PEM (non-squamous) or P alone (squamous) was continued until progression or 2 years. The primary endpoint was 2 year-PFS rate (threshold/expected: 20%/45%). Results: Between May 2020 and February 2022, 21 pts were enrolled. Median age was 73 (range, 53-89). Stage IIIA/B/C included 11 (52%)/7 (33%)/3 (14%), respectively. Histologic subtypes were 14 (67%) adenocarcinoma, 5 (24%) squamous cell carcinoma, and 2 (10%) others. Median follow-up period was 29.9 (range, 0.3-44.2) months. Median number of P administrations was 30 (range, 1-35). The primary endpoint was met with 2-year PFS rate of 67% (90% CI: 46-83%). At the time of data cut-off, 13 (62%) of 21 pts were still progression-free. Median PFS and OS were not reached. Two-year OS rate was 85%. Centrally reviewed tumor response: 8 (38%) CR; 9 (43%) PR; 3 (14%) SD; and 1 (5%) NE were confirmed, resulting in overall response rate (ORR) of 81% and disease control rate of 95%. ORRs/2-year PFS rates of PD-L1 TPS 50-79% and 80-100% were 67%/56% and 92%/75%, respectively. Non-hematological AEs ≥grade 3 were observed in 11 (52%) pts, including: 2 (10%) pneumonitis; 2 (10%) pneumonia; 1 (5%) diarrhea; 1 (5%) ALT elevation; and 1 (5%) acute heart failure. There was one (5%) grade 5 AE (pneumonia). Conclusions: RT-free P+C provided long-lasting responses in approximately two-thirds of pts. Higher PD-L1 TPS cases achieved higher RR, including some CRs and higher 2-year PFS rate. To confirm our hypothesis that RT-free P+C can be a less toxic curative option in selected LA-NSCLC pts with PD-L1 TPS ≥50%, further data is warranted. Clinical trial information: NCT04153734 .

Ramucirumab plus paclitaxel as switch maintenance versus continuation of oxaliplatin-based chemotherapy in patients (pts) with advanced HER2-negative gastric or gastroesophageal junction (GEJ) cancer: The ARMANI phase III trial.

LBA4002 Background: In pts with HER2-negative advanced gastric/GEJ cancer and PD-L1 low/absent expression, platinum/fluoropyrimidine doublets are a standard first-line therapy. In this patient population, the outcomes are unsatisfactory and second-line therapy is given in only 40% of clinical trial patients. Switch consolidation maintenance may prolong the benefit of the initial strategy and delay clinical deterioration. Despite ramucirumab failing to prolong both progression-free survival (PFS) and overall survival (OS) in the first-line setting, paclitaxel plus ramucirumab is a standard second-line therapy and warrants investigation as a post-induction strategy. Methods: Pts with HER2-negative advanced gastric/GEJ cancer without disease progression after 3 months of initial oxaliplatin-based chemotherapy, stratified by site of origin (GEJ vs gastric), prior gastrectomy and peritoneal disease, were randomized 1:1 to ramucirumab 8 mg/Kg on days 1,15 plus paclitaxel 80 mg/sqm on days 1,8,15 every 28 days (arm A) vs CAPOX/FOLFOX at the same doses used in the last induction cycle, for additional 3 mos followed by fluoropyrimidine monotherapy maintenance (arm B). The primary endpoint was PFS, OS was a key secondary endpoint; quality of life, safety, and biomarkers were evaluated. A sample size of 280 pts achieved a 90% power to detect as significant at a 5% level (2-sided log-rank test) a median PFS increase from 4 to 6 mos (target HR=0.67). HRs were estimated by Cox models adjusting for stratification factors. Restricted Mean Survival Time (RMST) analysis was conducted in case of violation of proportional hazards assumption. Results: From Jan 2017 to Oct 2023, 280 patients were randomly assigned (144 arm A/136 arm B). Baseline characteristics were: male sex 67/61%, median age 64/66 years, PS 0 74/65%, GEJ 26/26%, prior gastrectomy 28/23%, peritoneal metastases 53/42%. At a median follow-up of 43.7 months (IQR 22.0-57.9), median PFS was 6.6 vs. 3.5 mos in Arm A vs. B (HR=0.63, 95%CI 0.49-0.81; P<0.001). 24-mos RMST analysis showed a statistically significant 2.4-mos average increment (p=0.002). Median OS was 12.6 vs. 10.4 mos in Arm A vs. B (HR=0.75, 95%CI 0.58-0.97; P=0.030). The frequency of grade ≥3 adverse events was 40.4% vs. 20.7% in arms A vs. B, respectively, mainly neutropenia 25.5/9.6%; febrile neutropenia 2.1/0%; hypertension 6.4/0%; venous thromboembolism 2.1/0%; peripheral neuropathy 5.7/6.7%. No treatment-related deaths were reported. Conclusions: Switch maintenance with paclitaxel plus ramucirumab after 3 months of oxaliplatin-based doublets may be a new strategy in patients with HER2-negative metastatic gastric/GEJ cancer who are non-eligible for initial immune checkpoint inhibitor-based regimens according to specific guidelines and regulatory approvals. Clinical trial information: NCT02934464 .

Multi-institution real world analysis of patients with non-small cell lung cancer (NSCLC) treated with standard of care (SOC) neoadjuvant chemo-immunotherapy (chemoIO).

8049 Background: The approval of neoadjuvant chemoIO transformed the treatment paradigm for patients (pts) with early-stage, resectable NSCLC. Here we present a multi-institution, real world analysis of pts treated with neoadjuvant chemoIO as SOC. Methods: This was a retrospective analysis performed across 3 academic institutions. Pts were eligible if they received neoadjuvant chemoIO as SOC therapy for NSCLC with intent to proceed to surgery. Results: 107 pts were included. Median age was 69 (range, 45-84); 47% were male and 83% were white. 84% were former/current smokers with median 35 pack year history. ECOG scores of 0/1/2 at treatment start were 55%/44%/1%, respectively. Histologies were 65% adenocarcinoma, 27% squamous, and 7% other. PD-L1 scores (in 93% of pts) were ≥ 50% in 30%, and median TMB (in 73% of pts) was 8.2 (range, 0-56). Of tumors with next generation sequencing (81%), 45% had KRAS mutation and 18% had other oncogenic driver present. Pts were clinical stage IB (0.9%), IIA (6%), IIB (24%), IIIA (60%), or IIIB (8%); 47% had N2 disease and 3% had N3. 78% of pts underwent ≥ 3 cycles of chemoIO, with most pts receiving carboplatin (70%). 11 pts (10%) experienced grade ≥ 3 immune-related adverse events, 72% of which were pre-op. 82 pts (77%) proceeded to surgical resection. Of those who did not undergo surgery, 68% were stage III. The most common reason for no surgery was progression (PD)/unresectability (52%), followed by operability (36%) and pt decision (8%). 2 pts (2%) proceeded to surgery but had unresectable tumors. Median interval between last cycle of induction and surgery was 43 days (d) (range, 17-210); median length of stay was 4d (range, 1-21). 5 of 79 (6%) were readmitted within 30d. For pts without resection (27), 48% underwent chemoradiation (CRT), 26% RT alone, and 15% systemic therapy. 29 tumors (36%) demonstrated major pathologic response (MPR); of these, 16 (20%) had pathologic complete response (pCR). 2 pts had no decrement in viable tumor. Of 79 pts with adjuvant treatment data, 11% underwent RT alone, in combination with chemo, or in sequence with systemic therapy; 8% were recommended for RT but declined. 24% had systemic treatment including 14% IO, 6% targeted therapy, and 4% chemo. 18/107 pts (17%) had PD; 14/18 had stage III disease. PD occurred in 10/25 pts (40%) who did not have surgery; 6 of those had undergone definitive CRT or RT. PD occurred in 8/82 pts (10%) after surgery; of these, 5 had undergone adjuvant treatment at median 58d (range, 33-103). Conclusions: Real world analysis demonstrated older, frailer pts with more advanced disease than those enrolled on trial; lower chemoIO completion rates but comparable pCR and resection rates were seen. Further analyses will focus on outcomes of pts who did not undergo surgery.

Distinct tumor microbiome and metabolomic profiles to inform responses of patients with esophageal cancer to neoadjuvant chemoradiotherapy and immunotherapy.

4084 Background: Preclinical and clinical data indicate that neoadjuvant chemoradiotherapy (CRT) may prime an anti-tumor immunological response in esophageal cancer driven by intratumoral CD8+ T cells. However, responses to neoadjuvant therapy can vary widely across patients. The microbiome, a novel and potentially modifiable biomarker of immunotherapy response, may inform neoadjuvant response. Methods: Fecal and tumor samples were collected from patients with stage II-III resectable distal esophageal or gastroesophageal junction carcinoma treated with neoadjuvant immunotherapy followed by chemoradiotherapy (CRT) and immunotherapy (IO). Patients on arm A (n=15) received 2 cycles of induction with nivolumab plus 3 additional cycles with CRT. Patients on arm B (n=10) received nivolumab and relatlimab on a similar induction schedule, but concurrent IO and CRT resulted in immune related adverse events and a protocol amendment to CRT (NCT03044613). We examined fecal (n=19) and tumor (n=12) patient samples across both arms using 16S rRNA amplicon sequencing and high-resolution taxonomic assignment. Additionally, fecal samples were analyzed using an untargeted panel (General Metabolics) and pathway analysis was performed using Metaboanalyst (v6.0). Results: The fecal microbiome of patients with pathological complete response (pCR) grouped in distinct clusters compared to patients without pathological complete response (non-pCR) using Bray-Curtis (p < 0.001). Patients with >10% and <10% residual tumor grouped similarly but were significantly different from patients with 0% residual tumor (p < 0.001). On a linear discriminant axis, the top 10 abundant bacteria were significantly increased in pCR compared to non-pCR (p < 0.001). After FDR correction, six bacteria had significantly differing abundances. Bacteroides finegoldii, Paraprevotella clara, Ruminococcus callidus, and Roseburis inulinivorans were significantly enriched in pCR patients. Clostridiales and Bacteroides were significantly enriched in non-pCR patients. Fecal metabolomic analysis demonstrated six significant metabolites: in non-pCR, ropinirole, valine, phenylalanine, and isoleucine were enriched; in pCR, C16cer and D-urobilinogen were enriched (p < 0.05). Patients with improved neoadjuvant response had significantly higher abundances of Bacteroides and corresponding C16cer levels. Pathway analysis revealed significant involvement in aminoacyl-tRNA biosynthesis and sphingolipid metabolism. Conclusions: Patients with complete responses to combined CRT and IO for operable esophageal cancer had distinct fecal microbiome profiles as well as metabolomic pathways. These results may be useful to further characterize and predict patients who have improved responses to neoadjuvant therapy and serve as a basis for therapeutic intervention.

LUNAR-2: Pivotal, randomized, open-label study of tumor treating fields (TTFields, 150 kHz) concomitant with pembrolizumab and platinum based chemotherapy for the treatment of metastatic non-small cell lung cancer.

TPS8665 Background: Tumor Treating Fields (TTFields) are electric fields that disrupt processes critical for cancer cell viability. TTFields are delivered by a noninvasive portable device that has the European CE Mark and FDA approval for glioblastoma and mesothelioma. Preclinical non-small cell lung cancer (NSCLC) studies demonstrated that TTFields enhance the antitumor immune response, through disruption of mitosis and subsequent induction of immunogenic cell death. The pivotal, phase III LUNAR study (NCT02973789) in metastatic NSCLC progressing on/after platinum-based therapy demonstrated that TTFields with an immune checkpoint inhibitor (ICI) or docetaxel provided a statistically significant and clinically meaningful 3.3-month improvement in median overall survival (OS) vs an ICI or docetaxel alone, with no added systemic toxicities and no clinically significant difference on quality of life between groups. Despite advances in the treatment of NSCLC, survival rates for stage IV disease remain poor and there is a need for effective and tolerable treatments. Methods: LUNAR-2 (NCT06216301) is a pivotal, global, randomized, trial investigating the efficacy and safety of TTFields concomitant with pembrolizumab (P) and platinum-based chemotherapy (C) in patients (pts) with metastatic NSCLC, with a planned enrollment of 734 pts at 134 sites. Pts with NSCLC, radiologically evaluable disease in the thorax, ECOG PS of 0–1, and no prior treatment for metastatic disease are eligible. Pts will be stratified by histology, PD-L1 Tumor Proportion Score (TPS) and prior treatment with immunotherapy. Randomization is 1:1 to TTFields/P+C or P+C alone. Standard doses of P+C will be administered to both arms on day 1 of a 21-day cycle for 4 cycles of induction followed by up to 31 cycles of maintenance with TTFields/P or P alone. TTFields generated by the NovoTTF-200T System, will be delivered to the thorax ≥ 18 h/day until local disease progression per iRECIST. The primary endpoints are OS and progression-free survival (PFS) per RECIST v1.1 as assessed by a blinded independent central review (BICR). Secondary endpoints include OS and PFS according to histology or PD-L1 TPS, objective response rate, duration of response, and disease control rate, all per RECIST v1.1 as assessed by BICR and by investigator, comparing TTFields/P+C vs. P+C alone. Other secondary endpoints include PFS rates at 6, 12, 24 and 36 months per RECIST v1.1 as assessed by BICR, 1-, 2-, and 3-year survival rates and safety. Device Support Specialists will provide technical and lifestyle integration training for pts and caregivers throughout TTFields therapy. Pts usage is tracked by the device and is provided to pts and physicians to facilitate discussions to optimize outcomes by maximizing time on therapy. The trial is currently recruiting. Clinical trial information: NCT06216301 .

In vitro induction and selection of fluoroquinolone-resistant mutants in Elizabethkingia anophelis

For 29 parent strains, recognized by pulsed-field gel electrophoresis, the MICs multiplied significantly in the ciprofloxacin group than levofloxacin group, following the first and third induction cycle. Ser83Arg in GyrA was the most common site of mutations. No mutation in ParC nor ParE was identified in the selected mutants.

Glofitamab combined with poseltinib and lenalidomide for relapsed/refractory diffuse large B cell lymphoma: Interim analysis of GPL study.

7066 Background: Despite advanced treatments, including chimeric antigen receptor therapy (CAR-T), a significant proportion of patients succumb to relapsed and refractory diffuse large B cell lymphoma (R/R DLBCL). In vitro experiments suggest synergism between BTK inhibitor (BTKi) and T-cell engager, we initiated a multicenter trial of poseltinib and glofitamab in combination with lenalidomide in R/R DLBCL. Methods: This is a phase II, open label, single arm study aiming to enroll 76 participants with adult R/R DLBCL patients (NCT05335018). Patients refractory to frontline therapy or those who failed more than two lines of therapies were enrolled. Previous anti-CD19 CAR-T was allowed, while previous CD20 T-cell engager was not permitted. Participants received glofitamab (In cycle 1, dose is increased weekly from 2.5mg to 10mg, and after cycle 2, 30mg is administered on Day 1), lenalidomide (20mg daily from Day 1-14), and poseltinib (40mg twice daily from Day 1-21) (GPL) every 3 weeks for a total of 12 cycles(induction). Maintenance with poseltinib and lenalidomide for 17 cycles were given to patients after induction period. The primary endpoint is overall response rate (ORR), with secondary endpoints including duration of response (DoR), complete response rate (CRR), progression free survival (PFS), overall survival (OS), and incidence of treatment related adverse events. Results: No safety signals were observed in the safety cohort (n=6, 3+3 design). As of November 2023, 37 patients (median age 71) have been treated with GPL, with a median follow up duration of 3.6 months. In prior lines of therapy, 13 patients (35.1%) received treatment more than 2, and 26 patients (70.3%) were with Ann Arbor stage III/IV and 7 patients (18.9%) were refractory to frontline treatment. Previously, 3 patients (8.1%) received CAR-T. Out of 28 evaluable patients, ORR was 89.3%, with CRR of 42.9%. Six-month OS and PFS rate were 81% and 55%. DoR at 6 months was 66%. Neutropenia (45.9%) was the most common grade(gr) 3-4. Three patients (8.1%) died of gr5. There was 1 case (2.7%) of gr3 atrial fibrillation and gr1 bleeding. No incidence of gr3 or above liver/renal toxicity were observed. Overall, 3 patients (8.1%) discontinued GPL treatment due to toxicity, and cytokine release syndrome was observed in 7 patients (18.9%) and only 2 patients (5.4%) were gr3-4. Conclusions: Interim analysis indicates that the GPL regimen is an effective and safe regimen for R/R DLBCL patients. High response rates observed support further investigation of GPL for potential synergism between T-cell engagers and BTKi. This multicenter study is actively recruiting patients and is set to complete enrollment within this year. Clinical trial information: NCT05335018 . [Table: see text]

Phase 3 trial evaluating the efficacy and safety of odronextamab versus investigator’s choice in previously untreated follicular lymphoma (OLYMPIA-1).

TPS7096 Background: Follicular lymphoma (FL) is an incurable disease in which patients will relapse despite the effectiveness of first-line (1L) rituximab-based chemoimmunotherapy (CIT), indicating the need for alternative 1L treatments that can deepen and prolong response. Odronextamab, an off-the-shelf, CD20×CD3 bispecific antibody, showed compelling efficacy and generally manageable safety as a monotherapy at 3L+ for patients with relapsed/refractory (R/R) FL in the Phase 2 ELM-2 study (Villasboas, et al. ASH 2023). Objective and complete response (CR) rates were 80% and 73%, respectively, median duration of response was 22.6 months, median progression-free survival (PFS) was 20.7 months, and median overall survival was not reached. The rate of treatment-related adverse events leading to treatment discontinuation was 7.8%. The activity of odronextamab monotherapy in this heavily pretreated R/R FL population, including among patients with rituximab-refractory disease, provides a strong rationale for developing odronextamab as a chemotherapy-free option that can improve long-term outcomes in 1L. Methods: OLYMPIA-1 (NCT06091254) is a Phase 3, randomized, open-label, multicenter study of odronextamab versus investigator’s choice of CIT (R-CHOP, R-CVP, or R-bendamustine) in patients with previously untreated FL. The study consists of Part 1 (safety run-in), followed by Part 2 (randomization). In Part 1, patients will receive six 21-day cycles (induction) of intravenous odronextamab, administered in a step-up regimen during Cycle (C) 1 to mitigate the risk of cytokine release syndrome, followed by full dose starting from C2. Patients with CR or partial response at the end of induction will receive 12 doses of odronextamab maintenance given Q8W. In Part 2, patients will be randomized 1:1 to receive induction of six cycles of odronextamab followed by odronextamab maintenance, or CIT followed by rituximab maintenance. Key inclusion criteria: aged ≥18 years; CD20+ FL Grade 1–3a, stage II bulky or stage III/IV; measurable disease; and ECOG performance status 0–2. Patients with central nervous system lymphoma or histological Grade 3b are excluded. The Part 2 primary endpoint is CR at 30 months (CR30) as assessed by independent central review. Key secondary endpoints include PFS, event-free survival, investigator-assessed CR30, and patient-reported outcomes. Biomarkers (including minimal residual disease by ctDNA) will be evaluated as exploratory endpoints. This trial is currently recruiting and is expected to enroll ~12–32 patients in Part 1 and ~446 patients in Part 2 at ~200 global sites. Clinical trial information: NCT06091254 .

Phase 3 trial evaluating the efficacy and safety of odronextamab plus chemotherapy versus rituximab plus chemotherapy in previously untreated follicular lymphoma (OLYMPIA-2).

TPS7099 Background: Odronextamab, an off-the-shelf, CD20×CD3 bispecific antibody, has shown compelling efficacy and generally manageable safety as monotherapy in patients with heavily pretreated relapsed/refractory (R/R) follicular lymphoma (FL), including those with rituximab-refractory disease (Villasboas et al. ASH 2023). In the Phase 2 ELM-2 study, odronextamab demonstrated objective and complete response (CR) rates of 80% and 73%, respectively, and median duration of response of 22.6 months; median overall survival was not reached. Treatment-related adverse events led to treatment discontinuation in 7.8% of patients. These encouraging results support an investigation into whether odronextamab plus chemotherapy is superior to the current FL first-line standard of care of rituximab plus chemotherapy. This study will also evaluate whether odronextamab maintenance is required to achieve progression-free survival (PFS), given the risks associated with sustained B-cell depletion. Methods: OLYMPIA-2 (NCT06097364) is a Phase 3, randomized, open-label, multicenter study of odronextamab plus chemotherapy (Odro-CHOP/Odro-CVP) versus R-CHOP/R-CVP in patients with previously untreated FL. The study consists of Part 1A (dose escalation), Part 1B (dose optimization), and Part 2 (randomization). In Part 1, patients will receive six 21-day cycles (induction) of Odro-CHOP, in which intravenous odronextamab will be administered in a step-up regimen starting on Cycle (C) 1 Day (D) 8 to mitigate the risk of cytokine release syndrome, followed by full dose starting from C2D8. Patients with CR or partial response at the end of induction will receive 12 doses of odronextamab maintenance given Q8W. In Part 2, patients will be randomized 1:1:1 to receive induction of 6 cycles of Odro-CHOP/Odro-CVP with no maintenance (Arm A), Odro-CHOP/Odro-CVP followed by odronextamab maintenance (Arm B), or R-CHOP/R-CVP followed by rituximab maintenance (Arm C). Key inclusion criteria: aged ≥18 years; CD20+ FL Grade 1–3a, stage II bulky or stage III/IV; measurable disease; and ECOG performance status 0–2. Part 1: patients with FL that is R/R (Part 1A only) or previously untreated with Follicular Lymphoma International Prognostic Index-1 (FLIPI-1) score 3–5. Part 2: previously untreated patients with FLIPI-1 score 0–5. Patients with central nervous system lymphoma or histological Grade 3b are excluded. The Part 2 primary endpoint is CR rate at 30 months (CR30) by independent central review. Key secondary endpoints include PFS, event-free survival, investigator-assessed CR30, and patient-reported outcomes. Biomarkers (including minimal residual disease by ctDNA) will be evaluated as exploratory endpoints. This trial is currently recruiting and is expected to enroll up to 64 patients in Part 1 and ~669 patients in Part 2 at ~200 global sites. Clinical trial information: NCT06097364 .

Comparison of Adding Sildenafil Versus Estradiol to Clomiphene Citrate on the Applebaum Score and Pregnancy Rate in Patients With Unexplained Infertility: A Double-Blind Randomized Controlled Trial.

Both sildenafil and estradiol are seen to improve endometrial thickness in patients with infertility who are undergoing clomiphene induction cycles. However, the correlation between endometrial thickness and pregnancy rate is debatable. This study investigated the effect of adding oral sildenafil to clomiphene citrate (CC), compared to adding estradiol valerate, on the uterine biophysical profile (Applebaum score) and pregnancy rate. This was a double-blinded, randomized controlled trial conducted in Kisangani inthe Democratic Republic of the Congo from October 1, 2021, to October 31, 2023. Patients with unexplained infertility were randomly assigned to one of two groups: the interventional, which was given CC (2 x 50 mg/day from day 3 to day 7 of the menstrual cycle)+ sildenafil (2 x 25 mg/day orally from day 8 to day 12)or (ii) the control group, which was given CC (similar dosage as the intervention group) + EV (2 x 2 mg/day orally from day 8 to day 12), for a maximum of three cycles. Applebaum scores and clinical pregnancy rates were measured. Patients in the sildenafil and EV groups were similar in mean age (29.04 versus 28.89 years).Of the 74 patients enrolled in each group, 71 in the sildenafil group and 72 in the EV group received treatment and were followed to completion. The Applebaum scores were significantly higher in the sildenafil group than in the EV group (17.05 versus 15.14, respectively, P=0.000).In the sildenafil group, the clinical pregnancy rate was also significantly higher, at 28.92% versus 20.83% in the EV group (P=0.04). As compared to EV, the oral addition of sildenafil to CC is associated with a good Applebaum score and a high rate of clinical pregnancy in patients with unexplained infertility.

Gradual ER calcium depletion induces a progressive and reversible UPR signaling.

The unfolded protein response (UPR) is a widespread signal transduction pathway triggered by endoplasmic reticulum (ER) stress. Because calcium (Ca2+) is a key factor in the maintenance of ER homeostasis, massive Ca2+ depletion of the ER is a potent inducer of ER stress. Although moderate changes in ER Ca2+ drive the ubiquitous Ca2+ signaling pathways, a possible incremental relationship between UPR activation and Ca2+ changes has yet to be described. Here, we determine the sensitivity and time-dependency of activation of the three ER stress sensors, inositol-requiring protein 1 alpha (IRE1α), protein kinase R-like ER kinase (PERK), and activating transcription factor 6 alpha (ATF6α) in response to controlled changes in the concentration of ER Ca2+ in human cultured cells. Combining Ca2+ imaging, fluorescence recovery after photobleaching experiments, biochemical analyses, and mathematical modeling, we uncover a nonlinear rate of activation of the IRE1α branch of UPR, as compared to the PERK and ATF6α branches that become activated gradually with time and are sensitive to more important ER Ca2+ depletions. However, the three arms are all activated within a 1 h timescale. The model predicted the deactivation of PERK and IRE1α upon refilling the ER with Ca2+. Accordingly, we showed that ER Ca2+ replenishment leads to the complete reversion of IRE1α and PERK phosphorylation in less than 15 min, thus revealing the highly plastic character of the activation of the upstream UPR sensors. In conclusion, our results reveal a dynamic and dose-sensitive Ca2+-dependent activation/deactivation cycle of UPR induction, which could tightly control cell fate upon acute and/or chronic stress.

Extended versus conventional letrozole regimen in patients with polycystic ovary syndrome undergoing their first ovulation induction cycle: a prospective randomized controlled trial.

Can an extended letrozole (LE) regimen result in a higher ovulatory rate than a conventional regimen in patients with polycystic ovary syndrome (PCOS) undergoing their first ovulation induction cycle? There was no statistical difference in ovulation rate between patients with PCOS using the extended LE regimen and those using the conventional LE regimen. LE has become the first-line agent for ovulation induction. However, there is still a proportion of non-responsive cycles in patients with PCOS undergoing ovulation induction therapy with LE alone, and the extended LE regimen has been demonstrated to be a feasible method for inducing ovulation in these non-responders. Nevertheless, whether the extended regimen could be applied to all patients with PCOS as a first choice for the induction of ovulation remains to be explored. This was a prospective randomized controlled trial that included 148 female patients with PCOS who underwent their first ovulation induction cycle with LE from January 2021 to October 2022. Participants were randomly assigned to receive an extended (5 mg LE daily for 7 days) or conventional regimen (5 mg LE daily for 5 days) for one treatment cycle. The ovulation rate was the primary outcome. Secondary outcomes included the clinical pregnancy rate, the number of preovulatory follicles, and the rate of multiple pregnancies. The ovulation rate among patients receiving an extended LE regimen was slightly higher than the rate with a conventional LE regimen, but the difference did not reach statistical significance in either the intention-to-treat analysis (90.54% [67/74] vs 79.73% [59/74], P = 0.065; relative risk [95% CI]: 0.881 [0.768-1.009]) or the per-protocol analysis (90.54% [67/74] vs 84.29% [59/70], P = 0.257; relative risk [95% CI]: 0.931 [0.821-1.055]). The number of preovulatory follicles was nearly identical in the two groups (1.39 ± 0.62 vs 1.37 ± 0.59, P = 0.956), and no cases of ovarian hyperstimulation syndrome were observed. With regards to the endometrial parameters, the mean endometrium thickness was slightly thicker with the conventional LE regimen compared to that with the extended LE regimen, though with no statistical difference (9.27 ± 1.72 mm vs 9.57 ± 2.28 mm, P = 0.792). In the per-protocol analysis, the rates of clinical pregnancy (20.27% [15/74] vs 14.29% [10/70], P = 0.343; relative risk [95% CI]: 0.705 [0.34-1.463]) and live birth (13.51% [10/74] vs 11.43% [8/70], P = 0.705; relative risk [95% CI]: 0.846 [0.354-2.019]) did not differ significantly between treatment groups. Moreover, all conceptions were singletons without neonatal defects. The major concerns regarding this study are its single-center and open-label nature. Additionally, the limited number of lean patients with PCOS with a mean body mass index of 23-25 kg/m2 enrolled in our trial also restricted the generalizability of our findings. A change from the standard strategy of ovulation induction in patients with PCOS is not advisable, because a statistically superior effect of the extended LE regimen over a conventional regimen was not detected. The extended LE regimen could be applied with caution in a specific population who failed to respond to a conventional regimen rather than all the patients with PCOS during ovulation induction. Additional prospective trials with larger sample sizes and different PCOS subgroups are needed to assess the ovulatory effects of various LE treatment durations. This study was funded by the Shanghai First Maternity and Infant Hospital, affiliated with Tongji University School of Medicine (grant numbers: 2023B03 to Y.F., 2023B18 to X.Z., and 2020RC02 to Y.F.). The authors report no conflicts of interest. Chinese Clinical Trial Registry (ChiCTR2100042082). 13 January 2021. 21 January 2021.

Effective Radiosensitization of HNSCC Cell Lines by DNA-PKcs Inhibitor AZD7648 and PARP Inhibitors Talazoparib and Niraparib.

(1) Head and neck squamous cell carcinoma (HNSCC) is common, while treatment is difficult, and mortality is high. Kinase inhibitors are promising to enhance the effects of radiotherapy. We compared the effects of the PARP inhibitors talazoparib and niraparib and that of the DNA-PKcs inhibitor AZD7648, combined with ionizing radiation. (2) Seven HNSCC cell lines, including Cal33, CLS-354, Detroit 562, HSC4, RPMI2650 (HPV-negative), UD-SCC-2 and UM-SCC-47 (HPV-positive), and two healthy fibroblast cell lines, SBLF8 and SBLF9, were studied. Flow cytometry was used to analyze apoptosis and necrosis induction (AnnexinV/7AAD) and cell cycle distribution (Hoechst). Cell inactivation was studied by the colony-forming assay. (3) AZD7648 had the strongest effects, radiosensitizing all HNSCC cell lines, almost always in a supra-additive manner. Talazoparib and niraparib were effective in both HPV-positive cell lines but only consistently in one and two HPV-negative cell lines, respectively. Healthy fibroblasts were not affected by any combined treatment in apoptosis and necrosis induction or G2/M-phase arrest. AZD7648 alone was not toxic to healthy fibroblasts, while the combination with ionizing radiation reduced clonogenicity. (4) In conclusion, talazoparib, niraparib and, most potently, AZD7648 could improve radiation therapy in HNSCC. Healthy fibroblasts tolerated AZD7648 alone extremely well, but irradiation-induced effects might occur. Our results justify in vivo studies.

Synthesis of novel carbazole hydrazine-carbothioamide scaffold as potent antioxidant, anticancer and antimicrobial agents

BackgroundCarbazole-based molecules containing thiosemicarbazide functional groups are recognized for their diverse biological activities, particularly in enhancing therapeutic anticancer effects through inhibiting crucial pathways. These derivatives also exhibit noteworthy antioxidant properties.ObjectivesThis study aims to synthesize, characterize, and evaluate the antioxidant and anticancer activities of 18 novel carbazole derivatives.MethodsThe radical scavenging capabilities of the compounds were assessed using the 2,2-diphenyl-1-picrylhydrazyl assay. Antiproliferative activities were evaluated on MCF-7 cancer cell lines through viability assays. Additionally, the modulation of the PI3K/Akt/mTOR pathway, apoptosis/necrosis induction, and cell cycle analysis were conducted for the most promising anticancer agents.Resultsnine compounds showed potent antioxidant activities with IC50 values lower than the positive control acarbose, with compounds 4 h and 4y exhibiting the highest potency (IC50 values of 0.73 and 0.38 µM, respectively). Furthermore, compounds 4o and 4r displayed significant anticancer effects, with IC50 values of 2.02 and 4.99 µM, respectively. Compound 4o, in particular, exhibited promising activity by targeting the PI3K/Akt/mTOR signaling pathway, inhibiting tumor survival, inducing apoptosis, and causing cell cycle arrest in MCF-7 cell lines. Furthermore, compound 4o was showed significant antimicrobial activities against S. aureus and E. coli, and antifungal effect against C. albicans. Its potential to overcome drug resistance through this pathway inhibition highlights its promise as an anticancer agent. Molecular docking simulations supported these findings, revealing favorable binding profiles and interactions within the active sites of the enzymes PI3K, AKT1, and mTOR. Moreover, assessing the druggability of the newly synthesized thiosemicarbazide derivatives demonstrated optimal physicochemical properties, further endorsing their potential as drug candidates.

Comparison of the pregnancy outcomes of progestin-primed vs. antagonist ovarian stimulation in patients with poor ovarian response: a retrospective study

Objectives Progestin-primed ovarian stimulation (PPOS) is an efficient controlled ovarian stimulation (COS) method. The study explored the pregnancy outcomes between PPOS and antagonist ovarian stimulation protocol (GnRH-ant) in infertile patients with poor ovarian response (POR). Methods This retrospective study included patients with POR who underwent COS at the Reproductive Medical Center of Shanxi Maternal and Child Health Hospital from January 2021 to April 2022. The cycles were grouped as the GnRH-ant group and the PPOS group. The primary outcome was the clinical pregnancy rate; the secondary outcomes included the biochemical pregnancy abortion rate and live birth rate. Results Frozen embryo transfer was used in all cycles in this study. The cycles were divided into the GnRH-ant (n = 236 cycles) and PPOS (n = 273 cycles) groups. Age, BMI, type of infertility, infertility duration, FSH, LH, PRL, E2, T, P, and the number of cycles in the hospital were similar between the two groups (all p > 0.05). No statistically significant differences were observed in the clinical pregnancy rate (primary outcome, 32.71% vs. 43.90%, p = 0.082), total Gn dose, total Gn days, ART mode (IVF or ICSI), AFC, MII follicles, 2PN embryos, fertility, cycle cancelation rate, biochemical pregnancy rate, abortion rate, or live birth rate between the two groups (all p > 0.05). The PPOS group exhibited a higher rate of high-quality embryos than the GnRH-ant group (50.12% vs. 42.90%, p = 0.045). Conclusions The PPOS protocol was comparable to the GnRH-ant protocol regarding induction parameters and cycle cancelation, biochemical pregnancy, clinical pregnancy, and abortion rates but might be associated with a higher proportion of high-quality embryos.

P53 activation enhances the sensitivity of non-small cell lung cancer to the combination of SH003 and docetaxel by inhibiting de novo pyrimidine synthesis

BackgroundIdentifying molecular biomarkers for predicting responses to anti-cancer drugs can enhance treatment precision and minimize side effects. This study investigated the novel cancer-targeting mechanism of combining SH003, an herbal medicine, with docetaxel in non-small cell lung cancer (NSCLC) cells. Also, the present study aimed to identify the genetic characteristics of cancer cells susceptible to this combination.MethodsCell viability was analyzed by WST-8 assay. Apoptosis induction, BrdU incorporation, and cell cycle analysis were performed using flow cytometry. Metabolites were measured by LC–MS/MS analysis. Real-time PCR and western blotting evaluated RNA and protein expression. DNA damage was quantified through immunofluorescence. cBioPortal and GEPIA data were utilized to explore the mutual co-occurrence of TP53 and UMPS and UMPS gene expression in NSCLC.ResultsThe combination treatment suppressed de novo pyrimidine nucleotide biosynthesis by reducing the expression of related enzymes. This blockade of pyrimidine metabolism led to DNA damage and subsequent apoptosis, revealing a novel mechanism for inducing lung cancer cell death with this combination. However, some lung cancer cells exhibited distinct responses to the combination treatment that inhibited pyrimidine metabolism. The differences in sensitivity in lung cancer cells were determined by the TP53 gene status. TP53 wild-type lung cancer cells were effectively inhibited by the combination treatment through p53 activation, while TP53 mutant- or null-type cells exhibited lower sensitivity.ConclusionsThis study, for the first time, established a link between cancer cell genetic features and treatment response to simultaneous SH003 and docetaxel treatment. It highlights the significance of p53 as a predictive factor for susceptibility to this combination treatment. These findings also suggest that p53 status could serve as a crucial criterion in selecting appropriate therapeutic strategies for targeting pyrimidine metabolism in lung cancer.

RETRACTION: A randomized trial of local endometrial injury during ovulation induction cycles.

Helmy, M. E. E., Maher, M. A., Elkouly, N. I., Ramzy, M. (2017) A randomized trial of local endometrial injury during ovulation induction cycles. International Journal of Gynecology & Obstetrics, 138: 47-52. https://doi.org/10.1002/ijgo.12178. The above article, published online on 11 April 2017 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor-in-Chief, Professor Michael Geary, the International Federation of Gynecology and Obstetrics, and John Wiley and Sons Ltd. Concerns were raised by a third party about inconsistencies in the data of this article and the authors were asked to provide an explanation. The authors responded to the journal's inquiry, but could not share original data. Following the authors response, an independent review concluded that the sample size calculations were not reproducible, that the analysis of live births was misreported, and that, due to the absence of original data, the journal was not able to reproduce the calculations for relative risks reported in the manuscript. The journal has determined that these errors fundamentally compromise the conclusions of the article and that they could not be addressed by a correction. As such, the journal is issuing this retraction. The authors disagree with this retraction.

Low Estradiol Level and Endometrial Thickness on the Day of Endometrial Transformation Influence Clinical Pregnancy After Intrauterine Insemination.

The causes of pregnancy failure after intrauterine insemination (IUI) are controversial. The purpose of this study was to investigate the influencing factors on clinical pregnancy after IUI. This study retrospectively analyzed 1464 cycles of IUI performed at the Meizhou People's Hospital between March 2014 and June 2023. The χ2 test and logistic regression analysis was applied to assess the associations between the some factors (maternal age, paternal age, cycle type (natural cycle or ovulation induction cycle), hormone level on the day of endometrial transformation (estradiol (E2), luteinizing hormone (LH), and progesterone (P)), endometrial thickness on the day of endometrial transformation, and forward motile sperm concentration after treatment) and pregnancy failure. Among the 1464 IUI cycles in this study, 268 cycles of assisted reproduction resulted in clinical pregnancy, with a clinical pregnancy rate of 18.3%. During the cycles with clinical pregnancy, there were 25 (12.9%) preterm births and 169 (87.1%) full-term births. The E2 level on the day of endometrial transformation in clinical pregnancy group was higher than that in the pregnancy failure group (658.79±656.02 vs 561.21±558.83 pg/mL)(P=0.025). The clinical pregnancy group had a higher percentage of endometrial thickness between 8 and 13mm on the day of endometrial transformation than the pregnancy failure group (83.2% vs 75.0%)(P=0.002). The results of regressions analysis showed that low E2 level on the day of endometrial transformation (<238.3 pg/mL vs ≥238.3 pg/mL: OR 1.493, 95% CI: 1.086-2.052, P=0.014), and endometrial thickness <8mm on the day of endometrial transformation (<8mm vs 8-13mm: OR 1.886, 95% CI: 1.284-2.771, P=0.001) may increase risk of pregnancy failure performed IUI. Low estradiol level, and endometrial thickness on the day of endometrial transformation may increase risk of pregnancy failure performed intrauterine insemination.

A phase 1/2 study of NS-87/CPX-351 (cytarabine and daunorubicin liposome) in Japanese patients with high-risk acute myeloid leukemia

ObjectivesNS-87/CPX-351 is a dual-drug liposomal encapsulation of cytarabine and daunorubicin. NS-87/CPX-351 exerts antileukemic action by maintaining a synergistic molar ratio of cytarabine to daunorubicin of 5:1 within the liposome while in circulation. Patients with high-risk acute myeloid leukemia (AML), which includes therapy-related AML and AML with myelodysplasia-related changes (AML-MRC), have poorer outcomes than those with other AML.MethodologyThis open-label phase 1/2 (P1/2) study was conducted in 47 Japanese patients aged 60–75 years with newly diagnosed high-risk AML to evaluate the pharmacokinetics, safety, and efficacy of NS-87/CPX-351.ResultsIn the 6 patients enrolled in the P1 portion, no dose-limiting toxicities (DLTs) were reported, and 100 units/m2 during the induction cycle was found to be acceptable. Cytarabine and daunorubicin had a long half-life in the terminal phase (32.8 and 28.7 h, respectively). In the 35 patients enrolled in the P2 portion, composite complete remission (CRc; defined as complete remission [CR] or CR with incomplete hematologic recovery [CRi]) was achieved in 60.0% (90% CI: 44.7–74.0) of the patients. Adverse events due to NS-87/CPX-351 were well tolerated.OutcomesNS-87/CPX-351 can be considered as a frontline treatment option for Japanese patients with high-risk AML.