Significant Difference In PFS Research Articles

Post-Transplant Cyclophosphamide-Based Graft-Versus-Host Disease Prophylaxis in HLA-Matched and Haploidentical Donor Transplants for Patients with Hodgkin disease: A Comparative Study of the LWP EBMT

INTRODUCTION Post-transplant cyclophosphamide (PTCy) has proven to be a highly effective strategy in preventing graft-versus-host disease (GVHD) in haploidentical (haplo) hematopoietic stem cell transplantation (HSCT), but it is being increasingly used in HLA-matched transplants. The outcomes of haplo HSCT with PTCY in various hematologic malignancies, particularly in relapsed/refractory Hodgkin disease (HD), have shown promising results, challenging those obtained in transplant patients from HLA-matched donors without PTCy. However, there is limited information on the impact of donor types on the outcomes of patients with HD undergoing allogenic HSCT when using homogeneous GVHD prophylaxis with PTCy. To address this knowledge gap, we have conducted an extensive study using the Lymphoma Working Party of the European Society for Blood and Marrow Transplantation (LWP-EBMT) registry. The aim of this study was to compare the outcomes of patients with HD undergoing HSCT from both HLA-matched donors, which include matched sibling donors (MSD) and matched unrelated donors (MUD), and haplo donors, using PTCy as GVHD prophylaxis approach in all cohorts. PATIENTS AND METHODS Inclusion criteria All adults (≥ 18 years) patients diagnosed with HD who underwent their first HSCT between January 2010 and December 2020 from either a MSD, MUD or haplo, and whose data were reported to the EBMT registry were included. For the purposes of this study, only transplants who received PTCy-based as GVHD prophylaxis were considered. Statistical Analysis The study utilized statistical methods such as Kaplan-Meier estimation, Log-Rank test, competing risks analysis, and Cox proportional hazards regression. The analyses included OS, PFS, NRM, aGVHD, cGVHD, and graft failure. The statistical software R and packages were used. RESULTS Patient and Transplantation Characteristics Patient, disease and transplant-related characteristics of the 860 patients are summarized in Table 1. Engraftment The cumulative incidence (Cum Inc) of neutrophil recovery at day 30 was 95% (95% CI, 93-96) in the HLA-matched group and 96% (95% CI, 91-98) in the haplo cohort (p=0.18). The 60-day Cum Inc of platelet recovery in similar order was 94% (95% CI, 88-97) and 86% (95% CI, 83-88) (p<0.001). GVHD The Cum Inc of acute GVHD grade II-IV at 100 days in the HLA-matched and the haplo cohorts was 24% (95% CI, 17-31) and 34% (95% CI, 30-37), respectively (p=0.01), whereas for grade III-IV it was 8% (95% CI, 4-13) and 10% (95% CI, 8-13), (p=0.44). In multivariable analysis (table 2), haplo was associated with an increased risk of acute GVHD grades II-IV, when compared with HLA-matched (HR 0.65; 95% CI, 0.46-0.93; p=0.01). Other variables are shown in table 2. The 2-year Cum Inc of chronic GVHD in the HLA-matched and haplo cohorts was 26% (95% CI, 19-33) and 27% (95% CI, 24-31), respectively (p=0.75). Other variables are shown in table 2. NRM and relapse The Cum Inc of NRM at 2 years was 10% (95% CI; 6-16) for HLA-matched and 18% (95% CI; 15-21) for haplo (p=0.02). In multivariable analysis (table 2), haplo was associated with an increased risk of NRM, when compared to HLA-matched (HR 0.5; 95% CI, 0.28-0.89; p=0.01). Other variables are shown in table 2. The Cum Inc of relapse at 2 years was 22% (95% CI; 15-29) for HLA-matched and 24% (95% CI; 20-27) for haplo (p=0.81). Other variables are shown in table 2. Survival The 2-year OS for the HLA-matched and haplo cohorts was 82% (95% CI; 75-88) and 70% (95% CI; 67-74), respectively (p=0.002). In multivariable analysis (table 2), compared to HLA-matched, haplo (HR, 0.51; 95% CI, 0.34-0.77; p=0.001) was associated with worse survival. Other variables are shown in table 2. The 2-year PFS was similar between HLA-matched and haplo (66%; 95% CI, 58-74; and 58%; 95% CI, 54-62, respectively; p=0.17). Other variables are shown in table 2. Comparison of outcomes for MSD and MUD With regards to the donor type, most posttransplant outcomes did not exhibit significant differences, except for a higher incidence of grades II-IV acute GVHD in the MUD group (33%; 95% CI, 32-44) compared to the MSD group (17%; 95% CI, 10-25) (p=0.01). CONCLUSION Our study shows that in patients with HD undergoing HSCT with PTCy for GVHD prophylaxis, no significant differences in 2-year PFS were observed between HLA-matched and haplo. A higher risk of acute GVHD and NRM is associated with haplo, leading to lower OS compared to HLA-matched transplantation.

CTNI-46. UPFRONT VERSUS DEFERRED TREATMENT IN LOWER GRADE IDH-MUTANT GLIOMAS: A SINGLE-CENTER RETROSPECTIVE ANALYSIS

Abstract BACKGROUND IDH-mutant gliomas are a diverse group of gliomas possessing a mutation in the isocitrate dehydrogenase enzyme. The treatment for both oligodendroglioma (1p/19q co-deleted) and astrocytoma includes resection followed by radiation therapy and chemotherapy. However, there is debate over the optimal timing of adjuvant treatment after surgery. An initial observation approach is sometimes pursued, particularly after gross total resection in young adults. We sought to examine the impact of timing of treatment in order to inform clinical decision-making. METHODS We identified 286 biopsied or resected glial tumors treated at MD Anderson Cancer Center from July 2015 to June 2022. Tumors were categorized using available molecular data based on the WHO 2021 diagnostic criteria. Progression-free survival was analyzed using Kaplan-Meier estimates. RESULTS Of 286 tumors, 232 had identified IDH-mutation, of which 89 were 1p/19q co-deleted and 143 were non-co-deleted. Of oligodendroglioma patients, 71 received either upfront chemotherapy, radiation or both and 18 received treatment upon progression; of astrocytoma patients, 96 were treated upfront and 47 received treatment at progression. Among oligodendroglioma patients, there were no significant differences in PFS between treatment timing groups (75.6 vs 66.7 months, P = 0.18). There was additionally no difference between oligodendroglioma patients treated initially with PC or PCV regimens vs temozolomide (not reached vs 75.4 months, P = 0.24). Among astrocytoma patients, upfront treatment was associated with longer PFS (93.8 vs 45.2 months, P < 0.01). Patients with low-risk grade 2 gliomas (age <40 and gross total resection) also showed longer PFS with upfront treatment (138.0 vs 45.2 months, P = 0.03). CONCLUSION Overall, the results in this molecularly defined cohort suggest a progression-free survival benefit from upfront treatment in IDH-mutant lower grade gliomas, including in low-risk gliomas. The optimal timing and nature of adjuvant treatment for lower grade gliomas remains a matter of debate.

PATH-28. OUTCOME IMPACT OF THE CDKN2A/B HEMI-ZYGOUS DELETION IN IDH-MUTANT ASTROCYTOMA

Abstract Homozygous deletion of CDKN2A/B is a strong adverse prognostic factor in IDH-mutant astrocytomas. However, the impact of hemizygous deletions is unknown. We investigated the impact of CDKN2A/B hemizygous deletions on prognosis. We enrolled 52 adult patients with IDH-mutant astrocytomas between December 2002 and November 2021. CDKN2A/B deletion was evaluated with multiplex ligation-dependent probe amplification (MLPA) with threshold correction using a digital PCR-based IDH-mutant allele frequency. Immunohistochemical analysis of p16/MTAP was performed in CDKN2A/B deletion cases. Of the 52 cases, nine and three were classified as hemizygous and homozygous deletions, respectively. The OS was shorter in the order of homozygous deletion, hemizygous deletion, and copy-neutral groups (median OS:38.5, 59.5, and 93.1 months, respectively). Multivariate analysis revealed hazard ratios of 9.30 (p = 0.0191) and 2.44 (p = 0.0943) for homozygous and hemizygous deletions, respectively. Regarding PFS, in astrocytoma, the time to recurrence tended to be shorter in the order of homozygous deletion, hemizygous deletion, and copy-neutral, with a median PFS of 20.9, 38.9, and 53.0 months, respectively. There was no significant difference in PFS between the hemizygous deletion and copy-neutral groups (p = 0.4030). Malignant transformation was confirmed in 1 of 1 homozygous deletion, 2 of 3 hemizygous deletions, and 5 of 16 copy-neutrals. No significant difference was observed between the hemizygous deletion and copy-neutral groups; however, hemizygous deletion tended to require less time for malignant transformation than copy-neutral group (p = 0.1112). Immunohistochemistry revealed p16-negative and MTAP retention in cases with a hemizygous deletion, whereas homozygous deletions had p16-negative and MTAP loss. In conclusion, CDKN2A/B hemizygous deletions exerted a negative impact on OS in astrocytomas. Immunohistochemistry of p16/MTAP can be utilized to validate hemizygous or homozygous deletions in combination with conventional molecular diagnosis.

EPID-15. SEX-SPECIFIC DIFFERENCES IN GLIOBLASTOMA IN THE RESPOND CONSORTIUM

Abstract AIM The goal of this study was to understand sex-specific differences in the molecular, clinical and radiological tumor parameters and survival outcomes of Glioblastoma (GBM) patients within the international GBM dataset, known as the ReSPOND (Radiomic Signatures for PrecisiON Diagnostics) consortium. METHODS Sex-based differences were retrospectively studied in 1922 GBM patients from the ReSPOND consortium which includes information from over 14 institutions across 3 continents. The parameters include age, Methylguanine-DNA Methyltransferase (MGMT) promoter methylation status, isocitrate dehydrogenase 1 (IDH1) mutation status, Karnofsky performance status (KPS), extent of resection (EOR), tumor epicenter, volumes, laterality and spatial extent. Non-parametric tests, log-rank test and cox-proportional hazard analysis were performed to understand sex-based differences in tumor parameters, survival rates and hazard ratios. Spatial atlases were generated to understand radiological parameters such as tumor spatial extent. RESULTS GBM in was diagnosed at a median age of 62.6 years in females compared to 61 years in males (p = 0.001). Additionally, 44% females compared to 37% males (p = 0.04) had methylated MGMT and 79% females compared to 73% males (p = 0.004) had IDH1 wildtype. The tumor volumes were smaller in females (necrotic core, edema, and enhancing tumor) compared to males. Females exhibited a higher prevalence of right hemisphere (39.6%) and right temporal lobe tumors (19.7%), while males showed a higher prevalence of left hemisphere (40.3%) left temporal lobe tumors (23.7%). No significant sex-based differences in OS and PFS was observed in overall sample, although longer PFS was observed in elderly (above 60 years) female patients. CONCLUSION This is a first international large cohort study looking at sex-based differences in GBM patients using the ReSPOND consortium data. Several sex-specific differences in the distribution of various tumor phenotypes were noted, however sex was not a contributing factor in OS and PFS.

Ibrutinib and Rituximab Versus Fludarabine, Cyclophosphamide, and Rituximab for Patients in NCRI FLAIR Study with Previously Untreated CLL: Assessment of Mutational Landscape of Patients at Baseline and Prognostic Impact

Introduction: Recent studies using next generation sequencing have revealed recurrent mutated genes in CLL are associated with clinical outcome. We assessed the baseline mutational profile of 771 patients from FLAIR treated with either fludarabine, cyclophosphamide and rituximab (FCR) or ibrutinib and rituximab (IR). The prognostic impact of individual gene mutations on disease progression was investigated. Method: FLAIR is a phase III, multicentre, randomised, controlled, open, parallel group trial for previously untreated CLL requiring therapy according to IWCLL criteria. Patients with >20% chromosome 17p deletion were excluded. Patients were randomised to FCR or IR. Somatic hypermutation (SHM) status was determined by PCR amplification of IGHV-IGHD-IGHJ gene rearrangements using IGHV leader/FR1 primers. Bidirectional Sanger sequencing was analysed using IMGT V-Quest and the ARResT/AssignSubsets tool. Extracted DNA was sequenced using an Illumina MiSeq and analysed using an in-house pipeline. Amplicon based targeted sequencing of 33 recurrently mutated genes in lymphoid malignancies were performed in parallel. Detected variants were reported down to minimum variant allele fractions of 3-5% and coverage of 100X. Low level variants were confirmed by repeat sequencing. Results: 771 patients were randomly assigned to receive FCR (385) or IR (386). IGHV gene SHM status was available for 728/771 (94.4%): 388 (53.3%) IGHV unmutated (>98% of nucleotide identity to germline), 294 (40.4%) IGHV mutated and 46 (6.3%) stereotyped subset #2 (n=28 IGHV mutated, n=18 IGHV unmutated). Gene mutations were assessed in 767/771 (99.5%) patients at baseline and mutations (>1) were detected in 480/767 (62.6%). Mutation frequencies ranged from 0.1-18.8% with mutations in SF3B1 (18.8%), ATM (14.5%), NOTCH1 (10.0%), MYD88 (6.1%), POT1 (5.7%), TP53 (5.0%), BRAF (4.4%) and RPS15 (4.0%) being the most frequent. No detectable mutations at baseline were found in 287/767 (37.4%) and there was no significant difference in PFS or OS compared to patients with >1 mutation. A significantly shorter PFS and OS was observed for TP53 mutated patients compared to wildtype (HR 2.23 [95% CI 1.31-3.79]; p=0.003 and HR 2.43 [95% CI 1.04-5.66]; p=0.039 respectively). When further subdivided by treatment, a trend for shorter PFS was observed in TP53 mutated patients in both arms compared to wildtype, but significance was only achieved for FCR (HR 2.48 [95% CI 1.25-4.91]; p=0.009) and not IR (HR 2.27 [95% CI 0.97-5.30]; p=0.059). A significantly shorter PFS was observed for FCR compared to IR in patients with ATM mutations at baseline (HR 0.35 [95% CI 0.16-0.80]; p=0.012) and RSP15 (HR 0.19 [95% CI 0.04-0.96]; p=0.044). A trend for shorter PFS was also observed in NOTCH1 mutated patients treated with FCR however, this was not found to be significant when compared to wildtype or NOTCH1 mutated IR patients. CREBBP mutation at baseline (n=19; 2.5%) was associated with shorter PFS (HR 2.63 [95% CI 1.29-5.35]; p=0.008) and OS (HR 4.37 [95% CI 1.75-10.94]; p=0.002) compared to wild type (Fig). When further subdivided by treatment arm, shorter PFS and OS was also observed for CREBBP mutated patients treated with FCR compared to wildtype (n=11; HR 4.37 [95% CI 1.75-10.94]; p=0.002 and HR 10.14 [95% CI 3.83-26.83]; p<0.001 respectively). A similar trend was not observed with IR (n=8; PFS HR 0.79 [CI 0.11-5.74]; p=0.819 and OS HR NE [95% CI NE-NE]; p=0.988). CREBBP mutated patients treated with FCR had a shorter PFS compared to IR (HR 0.1 [95% CI 0.01-0.86]; p=0.036). The PFS and OS for IGHV subset #2 was similar to IGHV mutated patients (Fig). In FCR treated patients there was no difference between mutated (n=13) and unmutated subset #2 (n=7) but with IR there was a trend that IGHV mutated subset #2 patients (n=15) had better PFS and OS than their IGHV unmutated counterparts. Conclusions: Our study confirms that TP53 mutations result in shorter PFS and OS in CLL. We demonstrate improved PFS when patients with ATM or RPS15 mutations are treated with IR compared to FCR. Mutations in the CREBBP gene have recently been described as a novel candidate driver in CLL. We report a significant improvement in disease progression in CREBBP mutated patients treated with IR when compared to FCR. In contrast to previous studies in frontline CLL IGHV subset #2 patients had a similar outcome to good risk IGHV mutated patients.

Allogeneic Hematopoietic Stem Cell Transplantation in Advanced Systemic Mastocytosis

Purpose Advanced systemic mastocytosis (AdvSM) is driven by the KIT D816V mutation in >90% of patients (pts.). Depending on subtype, median survival is between 1.5 and 4 years. Despite recent advances on responses and survival due to the availability of effective KIT inhibitors, allogeneic hematopoietic stem cell transplantation (alloHSCT) remains the only curative treatment option. Data on optimal timing, conditioning regimens, and pre- as well as post-alloHSCT treatments for maintenance or relapse are however scarce. Current recommendations mainly refer to a retrospective analysis published almost 10 years ago (Ustun et al., JCO 32, 2014). With the advent of new therapies and improved transplant procedures, more recently collected data on alloHSCT in AdvSM are needed for actual assessment of optimal treatment strategies. Patients & Methods This retrospective analysis identified 71 pts. with AdvSM who underwent alloHSCT at 20 German centers between 1999 and 2021. Data were collected via the 'German Stem Cell Transplantation Registry (DRST)' and the 'German Registry on Disorders of Eosinophils and Mast Cells (GREM)'. Additional baseline characteristics and response status prior to, during and post alloHSCT were provided by the participating centers. Results At time of alloHSCT, median age was 59 years (range 21-84); 55/71 (77%) pts. were male. Median time between diagnosis of AdvSM and alloHSCT was 1.2 years (range 0.1-16.7). Pts. were grouped into (i) aggressive systemic mastocytosis (ASM, n=6) and SM with an associated hematological neoplasm (SM-AHN, n=24), totaling 30/71 (42%) ASM/SM-AHN pts., (ii) SM with an associated acute myeloid leukemia (SM-AML; 28/71, 39%) and (iii) mast cell leukemia ± AHN (MCL±AHN; 13/71, 18%). The median follow-up time after alloHSCT was 1.4 years (range 0-20.4). PFS and OS were 52% (SD ± 6.1%) and 62% (SD ± 5.9%) at 1 year, and 39% (SD ± 6.3%) and 50% (SD ± 6.2%) at 3 years. Discrimination between the three cohorts allowed a three-tier risk stratification (median PFS, 4.5 vs. 0.7 vs. 0.3 years, P<0.001; median OS, 9.0 vs. 3.3 vs. 0.9 years, P=0.007, Figure 1). Overall non-relapse mortality rate was 30% (21/71) including infectious complications in 8/21 (38%), GvHD in 1/21 (5%), cardiotoxicity in 1/21 (5%) and ‘combinations/not further specified’ in 11/21 (52%) pts. The 100-day non-relapse mortality was 8% (6/71; ASM/SM-AHN, 0/30; SM-AML, 4/28, 14%; MCL±AHN, 2/13, 15%). OS was associated with response status of SM (17/41, 41%; median OS 4.6 vs. 1.1 years, P=0.029) or AHN (26/43, 60%, median OS not reached vs. 0.4 years, P=0.003) prior to alloHSCT ( Figure 2). Univariable analyses revealed absence of a KIT D816V mutation (HR 2.9 [1.2-6.5], P<0.001) and a complex karyotype (HR 4.2 [1.8-10.0], P=0.016) as adverse prognostic factors regarding OS. PFS was significantly impacted by diagnosis of MCL±AHN (HR 3.5 [1.7-7.5], P<0.001), absence of a KIT D816V mutation (HR 2.5 [1.2-5.4], presence of a complex karyotype (HR 4.2 [1.8-10.0], P=0.016), P=0.021) and absence of the use of tyrosine kinase inhibitors prior to alloHSCT (HR 0.461 [0.249-0.854], P=0.014). In contrast, HLA match (complete vs. incomplete), type of conditioning (myeloablative vs. dose-reduced intensity), use of total body irradiation (≥8 Gy yes vs. no) or the transplantation at high volume centers (≥7 patients yes vs. no) were not associated with significant differences in PFS or OS. During or after alloHSCT, 30/71 (42%) pts. showed either refractory (9/71, 13%) or relapsed (21/71, 29%) disease (R/R), being highest among MCL±AHN pts. (11/13, 85%; ASM/SM-AHN, 9/30, 30%; SM-AML, 10/28, 36%; P=0.002). R/R SM was predominantly observed in MCL±AHN (10/11, 91%) while R/R AHN was higher in SM-AML patients (6/10, 60%) and ASM/SM-AHN (5/9, 56%). The median time to relapse was 0.6 years (range 0.1-4.5). Post alloHSCT, a response to various treatment regimens was achieved in 13/30 (43%) pts. (ASM/SM-AHN, 3/9, 33%; SM-AML, 5/10, 50%; MCL±AHN, 5/11, 45%) with highest response rates in 9 pts. receiving midostaurin and/or avapritinib (7/9, 78%). Conclusions In pts. with AdvSM eligible for alloHSCT, i) baseline characteristics affect outcome of alloHSCT more than specific transplant procedures, ii) alloHSCT should not be performed in pts. without response prior to alloHSCT and iii) post-alloHSCT strategies such as preemptive or residual disease guided maintenance therapy should be considered to improve post-alloHSCT outcome.

Orelabrutinib Monotherapy in Patients with Relapsed or Refractory Waldenström's Macroglobulinemia in a Single-Arm, Multicenter, Open-Label, Phase 2 Study: Long Term Follow-up Results

Background Orelabrutinib is a novel, small molecule, selective irreversible Bruton tyrosine kinase inhibitor, approved in China for the treatment of patients with relapsed/refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), mantle cell lymphoma (MCL), and marginal zone lymphoma (MZL). The previous publication of this study reported that orelabrutinib is highly active in R/R Waldenström's macroglobulinemia (WM), with a well-tolerated safety profile (EClinicalMedicine. 2022;52:101682). We present here the long-term results of this study. Methods This is a prospective, multicenter study of orelabrutinib in patients with WM who had at least one prior line of treatment (ClinicalTrials NO. : NCT04440059). Orelabrutinib was administered orally at a daily dose of 150 mg until disease progression or unacceptable toxicity. Genotyping using MYD88 L265P and CRCR4 S338X mutation were performed with qPCR assay. The primary endpoint was major response rate (MRR) assessed by the Independent Review Committee (IRC) according to IWWM-6 (Br J Haematol. 2013; 160: 171-176). Results Between August 2019 and December 2020, 66 R/R WM patients were assessed for eligibility. Forty-seven eligible patients were evaluated for efficacy at a median follow-up of 31.9 months (interquartile range: 28.0，36.5). As assessed by IRC, the MRR was 80.9%, and the overall response rate was 91.5%. The PFS rates was estimated as 72.1% at 36 months and the median PFS has not been reached. There is no significant difference in PFS across various MYD88 L265P and CRCR4 S338X genotype (P=0.69; Figure 1). The 30-months PFS rate in MYD88 L265P/CXCR4 NEG, MYD88 L265P/CXCR4 S338X, and MYD88 NEG/CXCR4 NEG were 86.2%, 75% and 75%, respectively. Most adverse events were Grades 1 or 2 (63.8%). The common grade 3 or higher adverse events occurred were neutropenia (10.6%), thrombocytopenia (8.5%), and pneumonia (6.4%). Treatment related serious adverse events were reported in 8.5% patients. Adverse events leading to discontinuation occurred in 4 patients (8.5%). One treatment-related death was reported (hepatitis B reactivation). Conclusions Results with longer follow-up continue to show that orelabrutinib has high, deep and durable response in patients with R/R WM. Data support the safety of long-term orelabrutinib treatment in R/R WM, with no new safety signals identified.

Identifying the Optimal Conditioning Intensity of Hematopoietic Stem Cell Transplantation in Patients with Acute Myeloid Leukemia in Complete Remission

Background Allogeneic hematopoietic stem cell transplantation (HSCT) as consolidation therapy is considered a curative option for acute myeloid leukemia (AML) in complete remission (CR) to prevent relapse. Many studies have investigated the optimal conditioning intensity, comparing reduced-intensity conditioning regimen (RIC) and myeloablative conditioning regimen (MAC) for patients with AML in CR. However, inconsistent results have been observed, possibly due to selection biases and significant heterogeneous treatment effects when focusing on average treatment effect. Some studies have attempted to assess treatment effects in specific subgroups, highlighting the heterogeneity conditioning intensity's impact. However, these analyses typically examined one factor at a time, overlooking potential multiple-factor combinations that might contribute to such heterogeneity.To address these limitations and surpass conventional comparison studies and subgroup analyses, machine-learning methods for group identification have been developed. In this study, we aimed to identify patient groups in which MAC or RIC had a superior PFS in patients with AML in CR using a machine-learning approach. Methods Our study included 3273 patients aged 40-69 years with AML in CR from the TRUMP2. These patients were divided into training (N=2020) and validation cohorts (N=1253). In the training cohort, we employed a group identification model to identify patient subsets. Preprocessing of variables was performed to ensure the ease of use in clinical practice. We modeled the magnitude of interaction between treatment and covariates without the main effect of covariates, thus leading to the construction of a scoring system that measures the individualized-treatment effect. The objective variable was set as 1-year PFS, and the interaction effects between treatment and covariates were estimated using a regression model with propensity score weight and LASSO regularization. The sum of the interaction term between treatment and covariates was defined as the “Conditioning Intensity Score”. Patients were categorized into high-score and low-score groups using a cut-off level of median in patients who received RIC. Subsequently, in the validation cohort, we estimated the average treatment effect of RIC compared to MAC for each group with hazard ratios (HR) using inverse treatment probability weight analysis. Results In the training cohort, the median age was 55 years (IQR, 48-61 years), with 1110 (55%) male patients. Among them, 666 (33%) received RIC, while the others underwent MAC. Conditioning Intensity Model was developed and consistent with followings; age over 49 (1.4 points), age over 49 and male (0.8 points), age over 49 and poor karyotype (0.5 point), age over 49 and cord blood transplantation (0.9 points), poor karyotype (-1.6 points), poor karyotype and primary induction failure (8.0 points), poor karyotype and bone marrow transplantation (-5.3 points), cord blood transplantation and hematopoietic cell transplant comorbidity index over 2 (2.1 points) and cord blood transplantation and extra bone marrow involvement (-8.6 points). The cut-off level was set as 2.2. The weighted HR of RIC on 1-year PFS was 0.56 (95%CI; 0.40-0.79, p < 0.001) in the high-score group and 1.23 (95%CI: 0.97- 1.57, p=0.094) in the low-score group. In the entire validation cohort, there were no significant differences in PFS between the RIC and MAC (67.7% [95% CI: 62.1-70.3%] in the RIC group vs. 70.3% [95% CI: 67.2-73.1%] in the MAC group, P=0.318). Patients were divided into two groups based on Conditioning Intensity Score. In the high-score group, the 1-year PFS was 73.9% (95% CI: 65.0-80.9%) in the RIC group vs. 66.2% (95% CI: 58.3-73.0%) in the MAC group ( P=0.181), with a weighted HR of 0.69 (95% CI: 0.43-1.11) for PFS in the RIC group compared to that the MAC group ( P=0.125) (Figure left). Conversely, in the low-score group, the 1-year PFS was 63.7% (95% CI: 56.3-70.2%) in the RIC group vs. 71.2% (95% CI: 67.8-74.2%) in the MAC group ( P=0.031), with a weighted HR of 1.35 (95% CI: 0.96-1.89) in the RIC group compared to the MAC group (log-rank P=0.086) (Figure right). Conclusion In conclusion, we have demonstrated the feasibility of utilizing a machine learning method for subgroup identification of conditioning regimens in patients with AML in CR. This established model holds promise for designing patient-specific regimens.

Correlation of Flow Cytometric BCL2 and MCL1 Expression with Cytogenetic Characteristics and Outcome in Multiple Myeloma

Introduction: Clonal plasma cells mediate apoptosis resistance through increased expression of anti-apoptotic proteins which increase survival and mediate resistance to intrinsic mitochondrial pathway. The key anti-apoptotic members are BCL-2, MCL-1, BCL-XL, BCL-B and BCL-W. High BCL2 expression or t(11;14) is shown to be predictive of response to Venetoclax in Multiple Myeloma (MM). Venetoclax may only be effective in a subset of patients, namely those who have relatively high BCL2 and low MCL1. Resistance to Venetoclax can be mediated by mutation in BCL2 or gain in copy number of MCL1, which maps to 1q21. The relationship between cytogenetic abnormalities and expression of BCL2 and MCL1 is not clear except for an occasional study which has shown MM with CCDN1 translocation has high BCL2 and low MCL1 expression and MM with MMSET and MAF translocation has high MCL1 and low BCL2 expression. Also, previous studies have used either immunohistochemistry or real time quantitative PCR for studying BCL2 and MCL1 expression, both of which are met with challenges in interpretation. We aimed to correlate the intracellular expression of BCL2 and MCL1 by flow-cytometry (FCM) with cytogenetic characteristics and outcome. Methodology: FCM was performed in bone-marrow of 143 consecutive MM cases with ≥10% plasma cells (PCs) and 20 bone marrow samples with non-clonal PCs by lyse-stain-wash method followed by intracellular staining of BCL2 (Alexa Fluor 647 conjugated anti-human BCL2 antibody) and MCL-1 (PE-conjugated anti-human MCL1 antibody). The sequential gating strategy used in the analysis of intracellular BCL2 and MCL1 expression in PCs and T lymphocytes is shown in Figure 1. The percentage of PCs positive for BCL2 and MCL1 compared to the tube without these antibodies [Fluorescence Minus One (FMO) cutoff threshold], the mean fluorescence intensity (MFI) expression of BCL2 and MCL1 in PCs and T cells, and the ratio of expression of BCL2 and MCL1 on PCs and T cells (BCL2 PC/T, MCL1 PC/T), MFI BCL-2 PC/MFI MCL1 PC were studied and further correlated with 5-7 panel FISH cytogenetics by using Kruskal Wallis test or Mann-Whitney U test. The overall survival/OS and progression-free survival/PFS was calculated using Kaplan-Meir Survival Curve analysis. Result and discussion: During the study, FCM was performed in 143 MM patients (103 Newly Diagnosed MM and 40 Relapsed Refractory MM). The cytogenetic findings includes IGH:: FGFR3 (n=29), IGH:: CCND1 (n=8), IGH:: MAF (n=3), gain1q21 (n=76), 1q21-amplification (n=30), 1p32-deletion (n=17) and TP53-deletion (n=21). A median of 38,779 PCs was acquired by FCM. The BCL2 and MCL1 expression was seen in 4-100% (median-96.9%) and 0-100% (median-78.8%) of clonal PCs, respectively. The median BCL2 MFI and MCL1 MFI were 43,289 and 6,481 respectively. The median BCL2 PC/T, MCL1 PC/T and BCL2 PC/MCL1 PC in clonal PCs were 1.90, 4.35, and 07.1, respectively, whereas in non-clonal PCs they were 0.87, 3.02 and 3.21, respectively.BCL2 PC/T, MCL1 PC/T and BCL2 PC/MCL1 P were significantly higher in clonal PCs than non-clonal PCs, with a p-value of 0.002, 0.001, and 0.009, respectively. The median MCL1 MFI was significantly lower (3,825 vs. 6,559; p=0.020) and median BCL2 PC/MCL-1 PC (12 vs 6.7; p=0.012) was significantly higher in IGH:: CCND1 compared to others; while an opposite pattern was seen in gain1q21 (7,420 vs 5,525; p=0.032 and 5.5 vs 8.6; p=0.046). The dim expression (<25-percentile) of BCL2 and MCL1 was noted in 25% (n=36) MM cases. Survival analysis did not yield a significant difference in OS or PFS between patients with dim, moderate or strong expression of BCL2 or MCL1. Conclusions: Our study demonstrates an objective assessment of BCL2 and MCL1 expression by FCM. BCL2 PC/T,MCL1 PC/T and BCL2 PC /MCL1 PC were significantly higher in myeloma cells compared to non-clonal PCs. Low MCL1 expression or high BCL2/MCL1 ratio was associated with IGH:: CCND1; while strong MCL1 and low BCL2/MCL1 ratio was most frequent in 1q21 amplification. We identified dim-expression (< 25-percentile) of BCL2 or MCL1 in 25% of cases of MM, where the benefit of anti-BCL2/MCL1 targeted therapy needs to be studied. Routine testing of BCL2 and MCL1 expression by FCM may be beneficial before starting Venetoclax/similar targeted therapy.

Predictive value of Dmax and %ΔSUVmax of 18F-FDG PET/CT for the prognosis of patients with diffuse large B-cell lymphoma

PurposeTo investigate the prognosis value of a combined model based on 18F-fluoro-deoxyglucose positron emission tomography-computed tomography (18F-FDG PET-CT) baseline and interim parameters in patients with diffuse large B-cell lymphoma (DLBCL).MethodsWe retrospectively analyzed the PET metabolic parameters and clinical data of 154 DLBCL patients between December 2015 and October 2020. All of these patients underwent 18F-FDG PET/CT scan before treatment and after three or four courses of chemotherapy. The optimal cut-off values for quantitative variables were determined by the receiver operating characteristic (ROC) curve. The baseline and interim PET/CT parameters, which respectively included maximum standardized uptake value (SUVmax0), total metabolic tumor volume (TMTV0), standardized total metabolic tumor volume (STMTV0), and the distance between the two furthest lesions (Dmax) and total tumor lesion glycolysis (TTLG1), SUVmax1, TMTV1, and the rate of change of SUVmax (%ΔSUVmax), and clinical characteristics were analyzed by chi-squared test, Kaplan-Meier survival curve, and Cox regression analysis.ResultsOf 154 patients, 35 exhibited disease progression or recurrence. ROC analysis revealed that baseline 18F-FDG PET/CT metabolic parameters, including maximum standardized uptake value (SUVmax0), total metabolic tumor volume (TMTV0), standardized total metabolic tumor volume (STMTV0), and the distance between the two furthest lesions (Dmax), along with interim 18F-FDG PET/CT metabolic parameters such as total tumor lesion glycolysis (TTLG1), SUVmax1, TMTV1, and the rate of change of SUVmax (%ΔSUVmax), were predictive of relapse or progression in DLBCL patients (P < 0.05). The chi-squared test showed that TMTV0, STMTV0, Dmax, SUVmax1, TMTV1, TTLG1, %ΔSUVmax, Deauville score, IPI, Ann Arbor stage, and LDH were associated with patient prognosis (P < 0.05). Multivariate Cox regression analysis showed that Dmax (P = 0.021) and %ΔSUVmax (P = 0.030) were independent predictors of prognosis in DLBCL patients. There were statistically significant differences in PFS among the three groups with high, intermediate, and low risk according to the combination model (P < 0.001). The combination model presented higher predictive efficacy than single indicators.ConclusionThe combined model of baseline parameter Dmax and intermediate parameter %ΔSUVmax of 18F-FDG PET/CT improved the predictive efficacy of PFS and contributed to the risk stratification of patients, providing a reference for clinical individualization and precision treatment.

Impact of BMI on the survival outcomes of non-small cell lung cancer patients treated with immune checkpoint inhibitors: a meta-analysis

ObjectivesICIs have become the standard treatment for advanced NSCLC patients. Currently, PD-L1 is the most widely useful biomarker to predict ICI efficacy, but the sensitivity and specificity are limited. Therefore, the useful predictive biomarkers of ICI efficacy is urgently needed. BMI is an internationally used measure of body health. Obesity may affect ICI efficacy by changing T cell functions. This meta-analysis aimed to clarify the relationship between BMI and survival outcomes of NSCLC patients treated with ICIs.MethodsA systematic review was conducted to identify studies that assessed the association between BMI and survival outcomes in patients treated with ICIs. OS was the primary endpoint, and PFS was the secondary endpoint. Random-effect models or fixed-effect models were utilized to combine study effects according to the Cochran Q and I2 tests.ResultsNine studies, including 4602 NSCLC patients treated with ICIs, that met the inclusion criteria were selected for this meta-analysis. There was no significant difference in PFS (HR 0.885; 95% CI 0.777–1.009, p = 0.068) or OS (HR 0.947; 95% CI 0.789–1.137, p = 0.560) between the low BMI group and the high BMI group. However, in the subgroup analysis, compared with normal-weight patients, overweight and obese patients achieved prolonged PFS (HR 0.862; 95% CI 0.760–0.978, p = 0.021) and OS (HR 0.818; 95% CI 0.741–0.902, p<0.0001).ConclusionOverweight and obese NSCLC patients tend to achieve prolonged survival time with ICI regimens. Further prospective studies are needed to strengthen the association between ICI outcomes and BMI levels.

Treatment options for stage III-N2 pulmonary lymphoepithelioma-like carcinoma: A retrospective cohort study

Background and purposePulmonary lymphoepithelioma-like carcinoma (PLELC) is a rare form of non-small cell lung carcinoma (NSCLC) that shares similarities with nasopharyngeal carcinoma. The optimal treatment for stage III-N2 PLELC remains controversial. Methods and materialsWe conducted a retrospective analysis from stage III-N2 PLELC patients between 2009 and 2022 in our center. The patients were categorized into three groups: Group 1 (G1, definitive chemoradiotherapy), Group 2 (G2, radical surgery plus adjuvant chemoradiotherapy), and Group 3 (G3, radical surgery plus adjuvant chemotherapy). ResultsA total of 103 patients were included in the study, with 34, 25, and 44 patients in G1, G2, and G3, respectively. The median follow-up time was 47.4 months. The overall median PFS was 66.6 months, with 3-year PFS and 3-year OS rates of 66.0% and 92.4%, respectively, for all patients. Multivariate analysis revealed no significant difference in PFS between G1 and G2 (p = 0.354), while both groups exhibited significantly longer PFS than G3 (p < 0.001; p = 0.039). Similarly, no significant difference in OS was observed between G1 and G2 (p = 0.649), but both tended to demonstrate improved OS compared to G3 (p = 0.081; p = 0.092). Only one case of grade 3 radiation esophagitis was observed in G1, and no grade 3 or higher radiation pneumonitis were reported. ConclusionsPatients with stage III-N2 PLELC have a favorable prognosis, with radiotherapy playing a crucial role in treatment. Both definitive chemoradiotherapy and radical surgery followed by chemoradiotherapy demonstrate favorable efficacy and manageable toxicity.

A Retrospective Study of Anlotinib Combined with Anti-PD-1 Inhibitors in the 2nd or Later-Line Treatment of Advanced Solid Tumors.

To investigate the clinical efficacy and safety of anlotinib combined with anti-PD-1 inhibitors in the 2nd or later-line treatment of advanced solid tumors. A total of 63 patients with advanced solid tumors who had failed or could not endure the adverse reactions after receiving first-line or more systematic treatment in the Second Affiliated Hospital of Harbin Medical University from March 2019 to April 2023 were treated with anlotinib Hydrochloride capsule combined with anti-PD-1 inhibitors. The efficacy and adverse reactions were evaluated according to RECIST1.1 and NCICTC4.0 standards. The percentage of overall response rate of 63 patients during the combination administration indicated that complete response was 1.6% (n=1), partial response was 23.8% (n=15), stable disease was 39.7% (n=25) and progressive disease was 34.9% (n=22), yielding objective response rate (ORR) of 25.4% and disease control rate (DCR) of 65.1%. Furthermore, the median PFS of 63 patients with advanced solid tumors was 7 months and the median OS was not reached, and the median follow-up time is 4.5 months. In subgroup analysis, there was no significant difference in PFS between first-line, second-line, third-line and above (p=0.631); there was no significant difference in PFS between PD-1 positive patients and PD-1 negative patients (p=0.094); there was no significant difference in PFS between patients who had previously used anti-PD-1 inhibitors and patients who had not used before (p=0.204). The most common adverse reactions were hypertension, hand-foot syndrome, and fatigue, with an incidence of 28.4% (18/63), 25.6% (14/63), and 25.6% (14/63), respectively. Most of the adverse reactions were grade 1-2, and there were no grade 4 adverse reactions. Anlotinib combined with anti-PD-1 inhibitors demonstrated promising efficacy and tolerable safety for patients with advanced solid tumors in the 2nd or later-line treatment.

Outcomes of relapsed clinical stage I versus de novo metastatic testicular cancer patients: an analysis of the IGCCCG Update database

BackgroundActive surveillance after orchiectomy is the preferred management in clinical stage I (CSI) germ-cell tumours (GCT) associated with a 15 to 30% relapse rate.Patients and methodsIn the IGCCCG Update database, we compared the outcomes of gonadal disseminated GCT relapsing from initial CSI to outcomes of patients with de novo metastatic GCT.ResultsA total of 1014 seminoma (Sem) [298 (29.4%) relapsed from CSI, 716 (70.6%) de novo] and 3103 non-seminoma (NSem) [626 (20.2%) relapsed from CSI, 2477 (79.8%) de novo] were identified. Among Sem, no statistically significant differences in PFS and OS were found between patients relapsing from CSI and de novo metastatic disease [5-year progression-free survival (5y-PFS) 87.6% versus 88.5%; 5-year overall survival (5y-OS) 93.2% versus 96.1%). Among NSem, PFS and OS were higher overall in relapsing CSI patients (5y-PFS 84.6% versus 80.0%; 5y-OS 93.3% versus 88.7%), but there were no differences within the same IGCCCG prognostic groups (HR = 0.89; 95% CI: 0.70–1.12). Relapses in the intermediate or poor prognostic groups occurred in 11/298 (4%) Sem and 112/626 (18%) NSem.ConclusionRelapsing CSI GCT patients expect similar survival compared to de novo metastatic patients of the same ICCCCG prognostic group. Intermediate and poor prognosis relapses from initial CSI expose patients to unnecessary toxicity from more intensive treatments.

A Randomized Controlled Phase Ⅱ Study of Nab-Paclitaxel vs. Paclitaxel plus Cisplatin in Concomitant Chemoradiotherapy for Locally Advanced Non-Small Cell Lung Cancer

To evaluate the efficacy and safety of concomitant chemoradiotherapy with nab-paclitaxel and cisplatin in patients with locally advanced non-small cell lung cancer (NSCLC). This study (NCT04284215) is a prospective, phase II, randomized controlled study, and the patients are enrolled in a ratio of 1:1 in the study with patients treat-naïve locally advanced stage III non-small cell lung cancer.in comparison with paclitaxel plus cisplatin, the regimen of nab-paclitaxel plus cisplatin was use in the treatment of DT:69 Gy/46f.Nab-paclitaxel 40mg/m2/week (4-6 weeks in total) and cisplatin 75mg/m2 for 2 cycles. paclitaxel 175mg/m2 d1, cisplatin 75mg/m2 for 2 cycles. The primary endpoints are ORR and treatment-induced toxicity of concurrent chemoradiotherapy, and the secondary endpoints are PFS and OS. A total of 68 patients (1:1) were randomized from March 3, 2019 to August 23, 2021.Sixty-five patients received concomitant chemoradiotherapy according to the study protocol, including 32 patients in the nab-paclitaxel group and 33 patients in the paclitaxel group. There was no significant difference in ORR between the two groups (84.4% vs. 73.7%, p = 0.411).There was no difference in median PFS between the two groups (14 months (95% CI 14.60-22.93) vs. 12 months (95% CI 13.15-22.74), P = 0.521).The incidence of grade III-IV leukopenia and neutropenia, fatigue, nausea, vomiting and other toxic and adverse reactions in the nab-paclitaxel group were significantly lower than those in the paclitaxel group (P<0.006, P<0.000, 0.016, 0.021, 0.019) CONCLUSION: Compared with paclitaxel plus cisplatin regimen, the combination of nab-paclitaxel plus cisplatin regimen has no significant difference in ORR and PFS, but significantly reduces the incidence of grade III-IV granulocytopenia and gastrointestinal reactions.

Neoadjuvant immunochemotherapy with pembrolizumab plus chemotherapy in resectable non-small cell lung cancer

BackgroundNeoadjuvant immunotherapy, the focus of current research and treatment modality for long-term survival, has become one of the main options in supporting primary treatment interventions in early NSCLC. MethodsThis was a retrospective analysis of patients with locally resectable NSCLC who received the neoadjuvant drug pembrolizumab combined with chemotherapy and underwent surgical resection. Pathological responses, PFS and OS in the whole sample and subgroups were analyzed. ResultsOf the 61 patients included in this retrospective analysis, 31 (50.82%) achieved a pCR, and 38 (62.30%) obtained an MPR. Patients with a pCR had significantly higher OS than the non-pCR group (HR = 0.093, P = 0.0227); patients with an MPR also had significantly elevated OS compared with the non-MPR group (HR = 0.05357, P = 0.0169). Patients with lymph node metastasis after surgery had significantly reduced OS (HR = 0.01607, p = 0.0004) and PFS (HR = 0.08757, p = 0.0004) than those without lymph node metastasis. There was no significant difference in OS and PFS between squamous cell carcinomas (SCC) group and adenocarcinomas (AD) group. No significant differences in OS and PFS were found between patients administered 2 and 3 cycles of neoadjuvant therapy before surgery, between those administered ≤5 and > 5 cycles of adjuvant therapy post-surgery, and between patients with TPS <50% and ≥50% (all P > 0.05). ConclusionNeoadjuvant immunochemotherapy with pembrolizumab plus chemotherapy in non-small cell lung cancer is safe and tolerable. Both pCR and MPR were closely associated with OS and PFS, reflecting a good response of tumor tissues to drug therapy. Lymph node metastasis after surgery was a poor prognostic factor, reducing OS and PFS.

Abstract B022: Clinical outcomes in NF2-mutated RCC treated with contemporary immunotherapy regimens

Abstract Background: Neurofibromin-2 (NF2) encodes the cell scaffolding protein merlin, which is involved in the Hippo tumor suppressor pathway. Somatic loss of function NF2 alterations in renal cell carcinoma (RCC) are associated with poor prognosis and can also molecularly define a subset of unclassified renal cell carcinomas without a standard of care treatment. While immuno-oncology (IO) combination regimens such as ipilimumab/nivolumab (IO/IO) or PD-1 inhibitor with a VEGFR-targeted therapy (IO/VEGFR) are the standard of care for clear cell RCC, efficacy of IO-based regimens for NF2 mutated RCC remains unknown. We report the first comparison of clinical responses to IO/IO, IO/VEGFR, or other systemic therapies for NF2-mutated RCC. Methods: NF2-mutated RCC patients receiving systemic therapy at Memorial Sloan Kettering Cancer Center were retrospectively identified by screening of our targeted exome sequencing (MSK-IMPACT) database. Groups are defined by 1st line systemic therapy regimens: IO/IO, IO/VEGFR, and other (VEGFR-targeted monotherapy, IO monotherapy, everolimus/bevacizumab, and chemotherapy). PFS-2 is defined as time from start of 1st line to progression on next therapy, or death. ORR, PFS, and PFS-2 were measured by an independent RECIST radiologist (CD). PFS, PFS-2, and OS are estimated using the Kaplan-Meier method. Results: Histologic subtypes in the overall cohort were unclassified (N=25), clear cell (N=7), and papillary (N=3). ORR of IO containing regimens in any line of treatment (N=29) was 57% (95% CI 37, 75). In the 1st line setting, 8 patients received IO/IO, 12 received IO/VEGFR, and 15 received other regimens with an ORR of 38% (95% CI 9, 76), 75% (95% CI 43, 95), and 23% (95% CI 5, 54), respectively. Thirty-three patients were included for PFS and PFS-2 analysis and 34 for OS with a median duration of follow-up of 40 months. Median PFS is 11 months (95% CI 4, 19; 26 events), median PFS-2 is 14 months (95% CI 9, 25; 25 events) and median OS is 27 months (95% CI 13, 65; 21 events). PFS, PFS2, and OS did not differ by 1st line treatment group. Among patients who received any IO exposure in the 1st line versus patients who received non-IO-based therapy, there was no significant difference in median PFS (12 (95% CI 5, 22) vs 5 (95% CI 2,21) months, p=0.39), PFS2 (17 (95% CI 9, 28) vs 13 (95% CI 3, 25) months, p=0.49), or OS (27 (95% CI 13, 73) vs 26 (95% CI 4, NE), p=0.90). OS did not differ by tumor histologic subtype; however, sample size limits power to detect differences. Conclusion: In comparison to clear cell RCC, prognosis for patients with NF2-mutated RCC remains poor. IO-based therapy has activity in treating NF2-mutated RCC; patients may derive benefit even if first exposure to IO occurs ≥2nd treatment line. There was no significant difference in PFS, PFS2, or OS based on 1st line regimen for patients with NF2-mutated RCC. Further investigation of inhibitors specifically targeting downstream effectors of the Hippo pathway are warranted. Citation Format: Kelly N. Fitzgerald, Cihan Duzgol, Andrea Knezevic, Rachel Jacobi, Ritesh R. Kotecha, David H. Aggen, Maria I. Carlo, Neil J. Shah, Martin H. Voss, Darren R. Feldman, Robert J. Motzer, Chung-Han Lee. Clinical outcomes in NF2-mutated RCC treated with contemporary immunotherapy regimens [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr B022.

Predictive value of 18F-FDG PET/CT multi-metabolic parameters and tumor metabolic heterogeneity in the prognosis of gastric cancer.

We aimed to investigate the predictive value of pre-treatment 18F-FDG PET/CT multi-metabolic parameters and tumor metabolic heterogeneity for gastric cancer prognosis. Seventy-one patients with gastric cancer were included. All patients underwent 18F-FDG PET/CT whole-body scans prior to treatment and had pathologically confirmed gastric adenocarcinomas. Each metabolic parameter, including SUVmax, SUVmean, MTV, and TLG, was collected from the primary lesions of gastric cancer in all patients, and the slope of the linear regression between the MTV corresponding to different SUVmax thresholds (40% × SUVmax, 80% × SUVmax) of the primary lesions was calculated. The absolute value of the slope was regarded as the metabolic heterogeneity of the primary lesions, expressed as the heterogeneity index HI-1, and the coefficient of variance of the SUVmean of the primary lesions was regarded as HI-2. Patient prognosis was assessed by PFS and OS, and a nomogram of the prognostic prediction model was constructed, after which the clinical utility of the model was assessed using DCA. A total of 71 patients with gastric cancer, including 57 (80.3%) males and 14 (19.7%) females, had a mean age of 61 ± 10 years; disease progression occurred in 27 (38.0%) patients and death occurred in 24 (33.8%) patients. Multivariate Cox regression analysis showed that HI-1 alone was a common independent risk factor for PFS (HR: 1.183; 95% CI: 1.010-1.387, P < 0.05) and OS (HR: 1.214; 95% CI: 1.016-1.450, P < 0.05) in patients with gastric cancer. A nomogram created based on the results of Cox regression analysis increased the net clinical benefit for patients. Considering disease progression as a positive event, patients were divided into low-, intermediate-, and high-risk groups, and Kaplan-Meier survival analysis showed that there were significant differences in PFS among the three groups. When death was considered a positive event and patients were included in the low- and high-risk groups, there were significant differences in OS between the two groups. The heterogeneity index HI-1 of primary gastric cancer lesions is an independent risk factor for patient prognosis. A nomogram of prognostic prediction models constructed for each independent factor can increase the net clinical benefit and stratify the risk level of patients, providing a reference for guiding individualized patient treatment.

MOLECULAR PROFILING TO UNDERSTAND TREATMENT RESISTANCE AND RESPONSE IN GLIOBLASTOMA

Abstract Patients with glioblastoma experience a wide variation in response to standard treatment, with nearly 30% experiencing tumour progression during treatment, and nearly 7% surviving more than 5 years. CEST-MRI is sensitive to treatment-induced changes in tumour metabolism and can be used to evaluate treatment response, allowing for the differentiation between early and late progressors before treatment initiation. OBJECTIVE: The purpose of this study is to establish genomic and transcriptomic profiles of early and late progressors in patients with glioblastoma who have undergone CEST-MRI. METHODS: Patients (n=25) were imaged with CEST-MRI at multiple time points throughout standard chemoradiation treatment. DNA and RNA were co-extracted from 25 fresh-frozen matched normal and tumour pairs and processed for whole genome sequencing and gene expression analysis using Nanostring. RESULTS: Early progressors (n = 12) and late progressors (n =13) had significant differences in OS and PFS (log rank &amp;lt;0.0001) as well as in gene expression and pathway deregulation. Genes significantly expressed in early progressors compared to late progressors include CCNA1 (p =0.000557), IGFBP3 (p = 0.000602), ASS1 (p = 0.000698), and ID1 (p= 0.000993), which were also prognostic of PFS and OS in a Cox regression model. CONCLUSION: Upon validation in a larger cohort, this data may serve as a radiogenomic biomarker to assess treatment response within early phases of treatment and adapt the treatment plan to individual biology.

Factors predicting recurrence after left‑sided pancreatectomy for pancreatic ductal adenocarcinoma

BackgroundRecurrence after resection is the main factor for poor survival. The relationship between clinicopathological factors and recurrence after curative distal pancreatectomy for PDAC has rarely been reported separately.MethodsPatients with PDAC after left‑sided pancreatectomy between May 2015 and August 2021 were retrospectively identified.ResultsOne hundred forty-one patients were included. Recurrence was observed in 97 patients (68.8%), while 44 (31.2%) patients had no recurrence. The median RFS was 8.8 months. The median OS was 24.9 months. Local recurrence was the predominant first detected recurrence site (n = 36, 37.1%), closely followed by liver recurrence (n = 35, 36.1%). Multiple recurrences occurred in 16 (16.5%) patients, peritoneal recurrence in 6 (6.2%) patients, and lung recurrence in 4 (4.1%) patients. High CA19-9 value after surgery, poor differentiation grade, and positive lymph nodes were found to be independently associated with recurrence. The patients receiving adjuvant chemotherapy had a decreased likelihood of recurrence. In the high CA19-9 value cohort, the median PFS and OS of the patients with or without chemotherapy were 8.0 VS. 5.7 months and 15.6 VS. 13.8 months, respectively. In the normal CA19-9 value cohort, there was no significant difference in PFS with or without chemotherapy (11.7 VS. 10.0 months, P = 0.147). However, OS was significantly longer in the patients with chemotherapy (26.4 VS. 13.8 months, P = 0.019).ConclusionsTumor biologic characteristics, such as T stage, tumor differentiation and positive lymph nodes, affecting CA19-9 value after surgery are associated with patterns and timing of recurrence. Adjuvant chemotherapy significantly reduced recurrence and improved survival. Chemotherapy is strongly recommended in patients with high CA199 after surgery.