Worse Progression-free Survival Research Articles

The value of multiparametric MRI combined with clinical prognostic parameters in predicting the 5-year survival of stage IIIC1 cervical squamous cell carcinoma

ObjectivesTo explore the value of multiparametric magnetic resonance imaging（MRI）in predicting the 5-year progression-free survival (PFS) and overall survival (OS) of cervical squamous cell carcinoma (CSCC) in 2018 FIGO stage IIIC1. MethodsThis retrospective study collected156 patients with CSCC from Dec. 2014 to Jul. 2018. Sixty-one patients underwent radical hysterectomy (RH), and 95 patients underwent concurrent chemoradiotherapy (CCRT). Clinical and MR parameters of primary tumours were analysed. A 1:1 ratio propensity score matching (PSM) was performed for the RH group and CCRT group according to T stage. The Cox proportional hazard model was used to evaluate the associations between imaging or clinical variables and PFS and OS. ResultsThe 5-year PFS and OS rates were 72.6% and 78.3%, respectively. The analysis results show that the treatment method, ADCmin < 0.604 × 10−3 mm2/s, and Ktrans < 0.699 min−1 correlated with worse PFS, while SCC-Ag > 6.7 ng/L, ADCmin < 0.604 × 10−3 mm2/s, and Ktrans < 0.699 min−1 correlated with worse OS. After PSM, we confirmed that the treatment methods did not affect the long-term survival of patients with stage IIIC1 disease, and a low Ktrans value was an independent poor prognostic factor. ConclusionFunctional MRI parameters and SCC-Ag have potential predictive value for the 5-year survival of 2018 FIGOIIIC1 CSCC. There were no significant differences in survival between CCRT and RH + adjuvant therapy for IIIC1 stage CSCC if the T stage was earlier.

Uzak metastazlı kanser hastalarında iskelet kası kütlesinin prediktif ve prognostik değeri

Aim:Skeletal muscle loss is an indicator of cachexia and a strong prognostic factor for some types of cancer. After strict standardization, we aim to evaluate both the predictive and prognostic value of low muscle mass (LMM) in common cancer types for first-line chemotherapy. Methods: This retrospective single-center study was conducted in a regional hospital between 2015 and 2020. Patients diagnosed with distant metastatic cancer were screened and included in the study if they had abdominal computed tomography 45 days prior to first-line chemotherapy. The relationship between LMM and progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) was evaluated. Results: Initially, 289 patients with metastatic cancer were included. The median duration of follow-up was 17 months, with a mean age of 61.09±13.03 years (range 25 to 95), and 45.9% of patients were female. In total, 50.5% of patients had LMM, which was adjusted for gender. LMM was associated with worse OS and PFS in univariate analysis (HR:1.598;1.216-2.100; p=0.001 for OS and HR:1.583;1.216-2.059; p=0.001 for PFS), and this positive association was maintained after adjusted for diagnosis and age. Better ORRs were obtained in respiratory and gastrointestinal tract cancers, breast, prostate and gynecological cancer in non-LMM groups. Conclusion:LMM has not only prognostic value but also predictive value for many types of cancer. Therefore, the assessment of muscle loss should be incorporated as part of the initial routine clinical evaluation.

High serum levels of inflammatory markers are associated with early recurrence in patients with high-grade serous ovarian cancer after platinum therapy

ObjectiveTo determine if inflammatory biomarkers can predict the long-term outcome of platinum therapy in patients with high-grade serous ovarian cancer. MethodsWomen diagnosed with high-grade serous epithelial ovarian cancer (n = 70) at a single institution were enrolled in a prospective serum collection study between 2005 and 2020. Seventeen markers of inflammation and oxidative stress were measured in serum samples on a chemistry analyzer. Association was tested for serum levels with progression-free survival (PFS), time to recurrence (TTR), overall survival (OS), and time to death (TTD) using Cox proportional hazards and Kaplan-Meier curves. Patient survival was censored at 10 years. ResultsHigher serum levels of LDH were associated with worse PFS (HR 2.57, p = 0.028). High serum levels of BAP (HR 0.38, p = 0.025), GSP (HR 0.40, p = 0.040), HDL-c (HR 0.27, p = 0.002), and MG (HR 0.36, p = 0.017) were associated with improved PFS. Higher expression of LDH was associated with worse OS (HR 2.16, p = 0.023). Higher levels of CK.nac (HR 0.39, p = 0.033) and HDL-c (HR 0.35, p = 0.029) were associated with improved OS. Similar outcomes were found with TTR and TTD analyses. ConclusionGeneral inflammatory biomarkers may serve as a guide for prognosis and treatment benefit. Future studies needed to further define their role in predicting prognosis or how these markers may affect response to therapy.

Factors associated with refractoriness or early progression after idecabtagene vicleucel in patients with relapsed/ refractory multiple myeloma: US Myeloma Immunotherapy Consortium real world experience.

While response rates and survival outcomes have been very promising for idecabtagene vicleucel (ide-cel), a proportion of patients do not respond or relapse early after this B-cell maturation antigen (BCMA) targeted chimeric antigen receptor (CAR) T-cell therapy. Understanding the characteristics of these patients is important for patient selection and development of novel strategies to improve outcomes. We evaluated factors associated with early progression (progression or death due to myeloma ≤3 months after CAR T-cell infusion) in patients treated with standard of care ide-cel at 11 US academic centers. Among 211 patients that received ide-cel, 43 patients had a progressive event ≤3 months of infusion. Patients with a history of extramedullary disease, prior BCMA targeted therapy, elevated ferritin at lymphodepletion, use of bridging therapy, Hispanic ethnicity, plasma cell leukemia and t(4;14) were more likely to progress ≤3 months of infusion (P<0.05). Of these risk factors for early progression identified in univariate analyses, history of extramedullary disease, prior BCMA targeted therapy, elevated ferritin at lymphodepletion, plasma cell leukemia, and t(4;14) were associated with worse progression-free survival (PFS) in multivariable analysis. Presence of three or more of these factors had a significant negative impact on PFS (P<0.001; median PFS for ≥3 factors, 3.2 months vs. 0 factors, 14.1 months). This study helps identify patients at high risk of early progression after CAR T-cell therapy who may benefit from specific interventions pre and post CAR T-cell therpy to improve outcomes.

Dose-Escalated Radiation Therapy Is Associated With Improved Outcomes for High-Grade Meningioma

The optimal modern radiation therapy (RT) approach after surgery for atypical and malignant meningioma is unclear. We present results of dose escalation in a single-institution cohort spanning 2000 to 2021. Consecutive patients with histopathologic grade 2 or 3 meningioma treated with RT were reviewed. A dose-escalation cohort (≥66 Gy equivalent dose in 2-Gy fractions using an α/β=10) was compared with a standard-dose cohort (<66 Gy). Outcomes were progression-free survival (PFS), cause-specific survival, overall survival (OS), local failure (LF), and radiation necrosis. One hundred eighteen patients (111 grade 2, 94.1%) were identified; 54 (45.8%) received dose escalation and 64 (54.2%) standard dose. Median follow-up was 45.4 months (IQR, 24.0-80.0 months) and median OS was 9.7 years (Q1: 4.6 years, Q3: not reached). All dose-escalated patients had residual disease versus 65.6% in the standard-dose cohort (P < .001). PFS at 3, 4, and 5 years in the dose-escalated versus standard-dose cohort was 78.9%, 72.2%, and 64.6% versus 57.2%, 49.1%, and 40.8%, respectively, (P=.030). On multivariable analysis, dose escalation (hazard ratio [HR], 0.544; P=.042) was associated with improved PFS, whereas ≥2 surgeries (HR, 1.989; P=.035) and older age (HR, 1.035; P < .001) were associated with worse PFS. The cumulative risk of LF was reduced with dose escalation (P=.016). Multivariable analysis confirmed that dose escalation was protective for LF (HR, 0.483; P=.019), whereas ≥2 surgeries before RT predicted for LF (HR, 2.145; P=.008). A trend was observed for improved cause-specific survival and OS in the dose-escalation cohort (P < .1). Seven patients (5.9%) developed symptomatic radiation necrosis with no significant difference between the 2 cohorts. Dose-escalated RT with ≥66 Gy for high-grade meningioma is associated with improved local control and PFS with an acceptable risk of radiation necrosis.

Outcomes with Bridging Radiation Therapy Prior to CAR-T Cell Therapy in Pts with Aggressive B Cell Lymphomas.

Select patient (pts) with relapsed/refractory aggressive B cell lymphoma may benefit from bridging radiation (bRT) prior to anti-CD19-directed chimeric antigen receptor T cell therapy (CART). Here, we examined pt and treatment factors associated with outcome after bRT and CART. We retrospectively reviewed adults with DLBCL who received bRT prior to axicabtagene ciloleucel 11/2017-12/2022. Clinical/treatment characteristics, response, and toxicity were extracted. Progression free survival (PFS), disease specific survival (DSS) and overall survival (OS) were modeled using Kaplan-Meier for events distributed over time, or binary logistic regression for disease response. Fisher's Exact Test or Mann-Whitney U methods were used. Among 40 pts, 11 (28%) had limited stage disease at apheresis, and 14 (35%) received bRT in addition to bridging systemic therapy. Thirty-two (80%) pts received bRT post-leukapheresis. bRT was delivered with a median dose of 30 Gy (range: 4-46) in 10 fractions (range: 2-23). Eighteen (45%) pts received <30 Gy. Twenty-two pts (55%) received bRT comprehensively to all sites of disease, including 9 pts who had limited stage. Eleven pts had bulky disease (≥ 10 cm) at the time of bRT. After CART, 4 pts (10%) experienced Grade ≥3 cytokine release syndrome (CRS), 16 (40%) had Grade ≥2 CRS, and 16 (38%) had Grade ≥3 neurotoxicity. Twenty-three pts (57.5%) had CR at 30 days post-CART infusion. Nine had PR (22.5%), of whom 2 pts eventually developed CR at three months and 1 at nine months. Eight pts (20%) had either PD or SD. Of 23 pts who experienced CR, 11 relapsed-6 at three months and 5 at six months. At a median follow up of 9.6 months (95% CI: 6.6-16.2), 22 pts relapsed: 6 (27.3%) in-field, 10 (5.5%) out-of-field, 4 (18.2%) both, and 2 (9.1%) unknown. The median PFS was 8.87 months and median OS was 22 months. PFS at 1 year was 70% (53-82) and at 2 years was 42% (27-57). OS at 1 and 2 years was 72.5% (56-84) and 51% (34-65), respectively. Seventeen pts (42.5%) remain alive at last follow-up, 13 (76.5%) of whom have no evidence of disease (NED). On univariate analysis, OS and PFS at 1 year were 67% (43-83) and 49% (27-68) for those who received RT comprehensively (n = 22), and 41.9% (19-64) and 33.3% (14-54) for those who did not (n = 18; both p≤0.03). Disease bulk (≥10 cm) was associated with significant decrement in DSS (p = 0.03), but not PFS (p = 0.16) or OS (p = 0.24). Among pts treated comprehensively with bRT (n = 22), there was no association of tumor bulk with OS, PFS, or DSS (p>0.2). IPI ≥3 was associated with worse DSS (p = 0.045) and trended towards worse PFS (p = 0.054), but not OS (p = 0.23). There was no difference in PFS, OS, or DSS between pts who received bRT or chemoRT (p>0.3). bRT and CART is a good treatment strategy for select pts with aggressive B cell lymphoma. When feasible, and with a caveat that other variables influence patient disposition, bRT for CART is associated with improved outcomes after comprehensive RT to all sites of disease.

Dynamic Responses of Circulating T Cells After Stereotactic Body Radiation Therapy for Bone Metastasis in Patients With Breast Cancer

Preclinical studies have shown that radiation therapy modulates antitumor immune responses. However, circulating T-cell responses after radiation therapy in patients with cancer have been poorly characterized. This study aims to explore the changes in circulating T cells after stereotactic body radiation therapy (SBRT). Peripheral blood samples of 30 patients with breast cancer who underwent SBRT for bone metastasis were analyzed using multicolor flow cytometry. Phenotypes of PD-1+ CD8+ T cells and regulatory T (TREG) cells were examined. Additionally, plasma protein levels were analyzed using a bead-based immunoassay. Circulating PD-1+ CD8+ T cells, which are enriched for tumor-specific clonotypes, were activated at 1 week after SBRT. However, circulating TREG cells were also activated after SBRT; this pattern was also evident among effector Foxp3hiCD45RA- TREG cells. We observed no difference in T-cell responses according to the fraction size and number. Notably, activation of TREG cells was more prominent in patients who experienced greater activation of PD-1+ CD8+ T cells. Plasma level changes in TGF-β1, soluble CTLA-4, and soluble 4-1BB at 1 week after SBRT were associated with PD-1+ CD8+ T-cell responses. Activation of TREG cells at 1 week after SBRT was associated with worse progression-free survival. Clinical factors including molecular subtype were not associated with the T-cell responses. SBRT induced activation of both potentially tumor-specific CD8+ T cells and TREG cells, which were tightly associated with each other. These results may support the use of TREG cell-modulating strategies with SBRT to improve the antitumor immune response.

Impact of Immune, Inflammatory, and Nutritional Indices on Outcome in Patients with Cervical Cancer Treated with Definitive (Chemo)radiotherapy

Systemic immune, inflammatory, and nutritional indices have been shown to be prognostic for outcome across a range of tumor sites. However, a comprehensive analysis of these markers in patients with cervical cancer treated with definitive (chemo)radiotherapy [(C)RT] has not been performed. We hypothesized that systemic immune, inflammatory, and nutritional indices may be associated with progression free survival (PFS) and overall survival (OS) in patients undergoing definitive (C)RT for cervical cancer. Patients with cervical cancer treated with definitive (C)RT from 1999 - 2015 were identified from a single cancer institution's retrospective clinicopathological database. Pre-treatment immune, inflammatory, and nutritional parameters were collected, and indices derived. Systemic immune-inflammation index (SII) = neutrophil count x platelet count / lymphocyte count(10^9/L); PLR = platelet count / lymphocyte count(10^9/L), NLR = neutrophil count / lymphocyte count (10^9/L); MLR = monocyte count / lymphocyte count (10^9/L); albumin to alkaline phosphatase ratio (AAPR) = serum albumin level (g/L)/alkaline phosphatase level (U/L) and prognostic nutritional index (PNI) = serum albumin (g/L) + 5 x lymphocyte count (10^9/L). Univariate analysis was first performed on each parameter as continuous variables for PFS and OS. For variables with statistically significant associations, ROC curves were analyzed to determine if an optimal cut point could be established for each outcome. Common cut points were then defined for each variable. PFS and OS were analyzed by the Kaplan-Meier method and the Log-Rank test. Multivariate analysis was performed using Cox regression with covariates of tumor stage, histology, and age. P-values of <0.05 were considered statistically significant. A total of 196 patients were identified; median follow-up 7 years. 131 (67%) had stage I-II and 65 (33%) stage III-IV disease. 187 (95%) received CRT and 9 (5%) RT alone. Higher SII (≤700 vs >700; p = 0.01), higher PLR (≤ 250 vs >250; p<0.001) and higher NLR (≤ 5 vs >5; p = 0.003) were associated with worse PFS. Higher SII [≤700 vs >700: 5y OS 74.9 vs 55.8; p = 0.02], higher PLR [≤ 250 vs >250: 5y OS 69.9% vs 42.0%; p<0.001] and higher NLR [≤ 5 vs >5: 5y OS 65.3% vs 51.0%; p = 0.01] were associated with worse OS. MLR, AAPR and PNI were not associated with outcome on univariate analysis. On multivariate analysis, SII and PLR were independently associated with both PFS [SII: HR 1.647 (CI 1.029-2.639), p = 0.038; PLR: HR 2.301 (95% CI 1.507 - 3.512), p = <0.001], and OS [SII: HR 1.649 (95% CI 1.009-2.696), p = 0.046; PLR: HR 2.212 (95% CI 1.416-3.455), p<0.001]; NLR did not remain statistically significant. SII and PLR, but not nutritional indices, were independently associated with PFS and OS in patients with cervical cancer treated with definitive (C)RT. Further evaluation of these systemic immune and inflammatory indices in a validation set will be required to better define their clinical utility.

Anlotinib in patients with recurrent platinum resistant/refractory ovarian cancer: a prospective, single arm, phase II study

ObjectiveThis study aimed to prospectively evaluate the efficacy and safety of anlotinib in patients with platinum resistant/refractory ovarian cancer.MethodsIn this prospective, single arm, phase II study, patients with platinum resistant/refractory...

Experience with 177Lu-Dotatate in Patients with Metastatic Gastroenteropancreatic Neuroendocrine Tumors at a Single Urban Cancer Center

177Lu-Dotatate is an FDA approved peptide receptor radiotherapeutic (PRRT) agent for metastatic well differentiated midgut neuroendocrine tumors (NETs). Questions remain regarding tolerability in diverse subpopulations with higher grade disease, more than one prior line of treatment, and in non-ileal primaries. In this retrospective analysis, we review the outcomes of patients with histologically proven metastatic GEP-NETs who received 177Lu-Dotatate at a single racially diverse urban cancer center. Treated patients had disease that progressed on systemic therapy. Uptake at disease sites was demonstrated in all patients using 68-Gallium-Dotate PET/CT. ECOG performance score (PS) was 0 to 2. 177Lu-Dotatate was administered in 200 mCi doses every 8 weeks for a total of 4 cycles and a maximum of 800 mCi. Patients were followed with serial CT scan and/or abdominal MRI with best objective response assessed per RECIST criteria. Fifty-one patients were treated between December 2017 and September 2021. 42 patients completed a minimum 3-month follow-up imaging. Median age was 66 years, 59% were female, 66% identified as white, 26% as Black, 8% as other or chose not to specify. Most frequent primary site was small intestine (69%). All had metastatic disease involving the liver except for one. Median time from diagnosis to 177Lu-Dotatate was 51 months. Time from first line therapy to first 177Lu-Dotatate was 3.65 years CTCAE grade 3/4 hematologic toxicity was seen in 6 of 51 patients (12%) of patients. Grade 3/4 thrombocytopenia occurred in 3 pts, grade 3/4 leukopenia occurred in 2 pts and grade 3 anemia occurred in 1 patient. One patient developed myelodysplastic syndrome 1 year after first 177Lu-Dotatate. Patients who identified as non-white did not experience significantly higher rate of toxicity. Of the 42 patients who reached 3-month follow-up 29% had a partial response, 45% had a mixed or stable response, and 36% had progressive disease. Only gender demonstrated significant difference; with male gender associated with worse response categories (p = 0.001). Median overall survival (OS) was 2.13 years. Metastatic disease in the liver only (p = 0.013), tumor grade > 1 (p = 0.027), and no history of surgery (p = 0.011) were associated with significantly worse OS. The median progression free survival (PFS) was 1.56 years. Patients of male gender (p = 0.037), with liver only metastases (p = 0.013), and with higher grade tumors (p = 0.024) had worse PFS. There was no difference in PFS by race, primary tumor site (pancreatic vs small bowel), performance status, or prior treatment history. In this retrospective study, investigating a racially and socioeconomically diverse patients, we report similar toxicity to prior studies investigating 177Lu-Dotatate. Despite similar toxicity, median PFS and OS were inferior to reported outcomes in NETTER-1 which we suspect may be partly due to timing of treatment and differences in patient populations.

Clinical Outcomes and Dosimetric Predictive Factors in Patients Undergoing Reirradiation for Recurrent Meningiomas

Re-irradiation (reRT) of intracranial meningiomas is often limited by radiation tolerance of the surrounding normal tissue and the risk of side effects. Aim of this retrospective study is to report outcomes, toxicity and prognostic factors of reRT in a large cohort of patients with recurrent meningiomas (RM) treated with different RT techniques. A multi-institutional database of intracranial meningioma patients who recurred after prior radiation treatment was collected. Patients underwent reRT with one of the following techniques: radiosurgery (SRS), multi-fraction stereotactic radiotherapy (f-SRT), proton therapy (PT), Intensity-Modulated radiotherapy (IMRT) and External Beam radiotherapy (EBRT). Biologically Equivalent Doses in 2 Gy-fractions (EQD2) and Biological Effective Dose (BED) for surrounding normal tissue and tumor were estimated for each RT course, assuming an a/b = 2 for brain tissue and a/b = 4 for meningioma. Progression-free survival (PFS) was the primary outcome measure. Secondary outcomes were overall survival (OS) and treatment-related toxicity, according to Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0). Kaplan-Meier curves were used to estimate the effect of several parameters on PFS and on OS; Cox regression models assessed predictors of PFS and OS. Between 2003 and 2021, 181 patients (pts) were included. They were re-treated with SRS (n = 75; 41.4%), f-SRT (n = 63; 34.8%), PT (n = 31; 17.1%) and conventional radiotherapy (n = 12; 6.7%). 78 pts were identified with WHO Grade I disease, 65 pts with Grade II and 10 pts had Grade III disease. 28 pts without histologic sampling were included among Grade I patients for further analysis. Median age at re-irradiation was 62 (range 20-89) and median KPS 90 (range 60-100). After a median follow-up of 4.6 years (IQR 1.7-6.8), 3-year PFS was 51.6% and 3-year OS 72.5%. At univariate analysis Ki67 >5% (HR 2.81, 95% CI 1.48-5.34, p = 0.002) and WHO grade > I (HR 3.08, 95% CI 1.80-5.28, p< 0.001) were correlated with worse PFS, whereas f-SRT (HR 0.32, 95% CI 0.19-0.55, p<0.001), longer time to reRT (HR 0.37, 95% CI 0.21-0.67, p = 0.001) and higher tumor BED (HR 0.45 95% CI 0.27-0.76, p = 0.003) favorably correlated with PFS. At multivariate Cox analysis only f-SRT, time to reRT and tumor BED kept their statistically significant prognostic impact on PFS (HR 0.36, 95% CI 0.21-0.64, p<0.001; HR 0.38, 95% CI 0.20-0.72, p = 0.003 and HR 0.47 95% CI 0.26-0.83, p = 0.01, respectively). In addition, larger tumor GTV had a statistically significant higher risk of acute and late toxicity (p = .0.004 and p = 0.005, respectively). Reirradiation of RM progressing after previous RT seems to be feasible, with encouraging outcomes and an acceptable toxicity profile. Prognostic factors in the treatment-algorithm have been identified and should be adopted in clinical daily practice.

Outcomes Following Dose Escalated Radiotherapy for High Grade Meningioma

Conventionally fractionated radiotherapy (RT) is a defined treatment following surgery for atypical and malignant meningioma. However, the optimal radiotherapeutic approach is not well defined. We present the results of our dose-escalation strategy. Consecutive patients with a histopathologic grade 2 or 3 meningioma treated with RT were retrospectively reviewed. The primary outcome was progression-free survival (PFS), and secondary outcomes included cause-specific survival (CSS), overall survival (OS), local failure and incidence of radiation necrosis. We specifically compared the dose-escalation cohort, defined as those treated with ≥66 Gy EQD2 (equivalent dose in 2 Gy fractions, a/b = 10), to the standard dose cohort receiving <66 Gy EQD2. We defined adjuvant as RT delivered within 6 months of surgery otherwise the treatment was salvage. A total of 118 patients with Grade 2 (111/118) or 3 (7/118) meningioma were identified. 54/118 (45.8%) received dose-escalation and 64/118 (54.2%) standard dosing. 34/54 (63.0%) dose-escalated and 45/64 (70.3%) standardly dosed were treated adjuvantly. The median follow-up was 45.4 months (IQR: 24.0-80.0 months) and median OS was 9.7 years. Post-operative residual disease was present in all dose-escalated patients, as compared to 65.6% in the standard dose cohort. PFS at 3-, 4- and 5-years in the dose-escalated vs. standard dose cohort were 78.9%, 72.2% and 64.6% vs. 57.2%, 49.1% and 40.8%, respectively, (p = 0.030). On multivariable (MVA) analysis, dose-escalation (HR: 0.544, 95% CI: 0.303-0.977, p = 0.042) was associated with improved PFS, whereas ≥2 surgeries (HR: 1.989, 95% CI: 1.049-3.773, p = 0.035) and older age (HR: 1.035, 95% CI:1.015-1.056, p<0.001) associated with worse PFS. The cumulative risk of local failure at 3-, 4- and 5-years in the dose-escalated vs. standard dose cohort were 16.9%, 23.8% and 31.8% vs. 39.6%, 45.6% and 53.9%, respectively, favoring dose-escalation (p = 0.016). MVA confirmed dose-escalation as predictive of a lower risk of LF (HR: 0.483, 95% CI: 0.263-0.887, p = 0.019), while ≥2 surgeries prior to RT predicted for greater LF rates (HR:2.145, 95% CI:1.220-3.771, p = 0.008). A trend was observed for prolonged CSS and OS in the dose escalation cohort (p = <0.1). Seven patients (5.9%) developed symptomatic radiation necrosis (RN) with no significant difference between the two cohorts. Dose-escalated radiotherapy for high grade meningioma to at least 66 Gy is associated with significantly improved rates of local control and PFS with an acceptable risk of RN.

Multi-Institutional Study of Stereotactic Radiosurgery for Recurrent WHO Grade 2/3 Meningiomas: An Interim Analysis

Meningiomas are the most common tumors of the central nervous system (CNS). Approximately 80% are classified as World Health Organization (WHO) grade 1, while 20% correspond to grade 2 or grade 3. In those with grade 2/3 disease, local recurrence is not uncommon. Salvage treatment options vary widely and include resection, external beam radiation therapy (EBRT), stereotactic radiosurgery (SRS), and/or clinical trials. Although retrospective studies have reported on the use of upfront SRS in grade 2/3 meningiomas, large-scale outcomes with SRS in the recurrent setting are lacking. The objective of this study was to report on oncologic outcomes for patients with recurrent grade 2/3 meningioma treated with SRS. This is an ongoing multi-institutional retrospective cohort study. Eligibility criteria include patients >18 years old with pathologically confirmed WHO grade 2 or 3 meningioma treated with SRS monotherapy at the time of first recurrence. Patients require pathologic confirmation only at time of diagnosis; those with upfront grade 1 disease must have pathologic confirmation of grade 2/3 disease at time of first recurrence. Patients with multifocal disease upfront were excluded from this study. A total of 60 patients met eligibility criteria. Baseline demographics at time of initial diagnosis are shown in table 1. At the time of first recurrence, 57 (95%) were WHO grade 2, and 3 (5%) were grade 3. Median follow up time from first recurrence was 5.02 years. Median marginal SRS dose was 16 Gy (IQR 14-17) to a 2.67cc planning treatment volume (IQR 1.4-5.1). 92% of patients received single fraction SRS. Median time to second recurrence was 5.92 years. 1, 3, and 5-year progression-free survival (PFS) was 95%, 68%, and 51%, respectively. 1, 3, and 5-year overall survival (OS) was 100%, 98%, and 96%, respectively. On multivariate analysis, grade 3 disease was independently associated with worse PFS (HR 15.7, p = 0.03). Median SRS dose and treatment volume did not correlate with PFS. 1 patient (1.7%) experienced symptomatic radiation necrosis requiring steroids, 3 (5.0%) experienced new seizure activity, and 2 (3.3%) additional patients showed clinical evidence of post-treatment neurocognitive decline. Based on this interim analysis, primary SRS for recurrent grade 2/3 meningioma appears safe and feasible, with outcomes comparable to prospective data on high-risk grade 2/3 patients treated with post-operative fractionated EBRT. We look forward to further analysis with a larger cohort which may help guide further prospective studies.

Change in Quality of Life after Stereotactic Body Radiation Therapy (SBRT) on a Prospective Trial of Peripheral Stage I or II Non-Small Cell Lung Cancer Predicts Survival

We previously reported the results of a randomized, multi-institutional phase II clinical trial evaluating one versus three fractions of SBRT for peripheral Stage I to II non-small cell lung cancer (NSCLC). A secondary objective to compare quality of life (QOL) data and its association with survival outcomes is reported. Medically inoperable patients with biopsy-proven peripheral T1-2N0M0 NSCLC were enrolled. Patients were randomized to 30 Gy in 1 fraction (arm 1) or 60 Gy in 3 fractions (arm 2) and stratified by performance status. QOL scores from the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) and EORTC QLQ Lung Cancer-Specific Module (EORTC QLQ-LC13) questionnaires were required at baseline and each follow-up visit. Univariate models were generated to evaluate associations between QOL scores and survival with 95% confidence intervals (CI) calculated at each time point. Among 98 patients enrolled (49 in each arm), 88 patients had data available for QOL analysis. At 6 month follow up, patients with stable or decreased (n = 49) versus those with increased global QOL scores (n = 27) had worse progression-free survival (HR [Hazards' Ratio] 2.32 [CI, 1.14-4.73], p = 0.021) and overall survival (HR 2.13 [CI, 1.01-4.51], p = 0.048). Similar results persisted at the 12 month follow up for progression-free survival (HR 3.90 [CI, 1.52-10.04], p = 0.016) and overall survival (HR 3.25 [CI, 1.25-8.43], p = 0.016). Median overall survival for patients with stable or decreased global QOL versus increased global QOL at 6 month follow up was 39.0 vs 60.3 months (p = 0.032). Change in QOL is an early predictor of survival following SBRT for patients with peripheral early-stage NSCLC.

Peripheral T-Cell Priming and Micrometastatic Disease Control with Metastasis-Directed Therapy: Multidimensional Immunogenomic Profiling of Oligometastatic Prostate Cancer in the EXTEND Trial

Comprehensive metastasis-directed therapy (MDT) for oligometastatic prostate cancer extended progression-free survival (PFS) and time to new lesion formation in the intermittent hormone therapy (HT) basket of EXTEND. To better understand the mechanism of MDT benefit, we pooled the intermittent and continuous HT baskets of EXTEND and tested the hypothesis that adding MDT to HT would program systemic T-cells to control micrometastatic disease. A total of 174 men were randomized to HT with or without MDT to up to 5 sites of metastases. HT was given for 6 months (intermittent basket, n = 87) or indefinitely (continuous basket, n = 87). Peripheral blood samples were drawn at enrollment, at the end of MDT, at 3 months follow-up (3 mo F/U), and at progression and then analyzed by flow cytometry, T-cell receptor (TCR)-β CDR3 variable region sequencing, multiplex cytokine profiling, and next-generation circulating tumor DNA (ctDNA) sequencing. TCR clonal expansion was determined using a published betabinomial model. Repertoire changes were assessed by Morisita's index, and dominant TCR repertoire motifs were characterized with ImmunoMap. Associations between blood markers and PFS were evaluated with Cox regression adjusted hazard ratios (aHR) accounting for randomization arm and stratifying for intermittent vs continuous HT. Randomization to MDT+HT was associated with T-cell activation, proliferation, and clonal expansion. This response was first observed at end-MDT as upregulated expression of T-cell activation and inhibition markers (i.e., ICOS, Tim-3, and LAG-3) and increases in highly proliferative CD4+ and CD8+ Ki67hi T-cells (all P<0.05). TCR sequencing of 7,678,911 T-cells revealed that MDT+HT was associated with TCR clonal expansion, remodeling of the TCR repertoire, and changes in dominant TCR motifs at end-MDT and 3 mo F/U (all P<0.05). Observed T-cell priming could be driven by signaling networks of canonical T-cell stimulatory cytokines (IL-2, IL-12, and IL-15), which were upregulated at end-MDT and persisted at 3 mo F/U (all P<0.05). This modulation of T-cell phenotype, clonotype, and cytokine concentrations was not observed in the HT-monotherapy arm. At end-MDT, systemic T-cell responses were associated with improved PFS, most notably CD8+ T-cell expression of LAG-3 (aHR 0.22, 95% CI 0.03-0.91) and high TCR clonal expansion (aHR 0.13, 95% CI 0.02-0.52). High ctDNA burden at end-MDT correlated with worse PFS (aHR 1.41, 95% CI 1.04-2.54), as did CD8+ T-cell expression of inhibitory receptor TIGIT at 3 mo F/U (aHR 1.03, 95% CI 1.01-1.06). The addition of MDT to HT induced systemic T-cell activation and expansion, which was not observed in the HT-only arm. This systemic immune response was independently associated with improved PFS. In addition to cytoreduction of macroscopic disease, MDT-induced immune education may be an important complementary mechanism of micrometastatic control in oligometastatic prostate cancer.

Differential roles of highly expressed PFKFB4 in colon adenocarcinoma patients

Colon adenocarcinoma (COAD) is a common malignant tumor, and the role of the protein PFKFB4 in glycolysis and pentose phosphate pathways is crucial. Researchers investigated the clinical significance of PFKFB4 in COAD by studying its expression in 79 tissue samples using immunohistochemistry. We found that PFKFB4 expression was significantly higher in COAD patients, particularly in the sigmoid colon. Interestingly, high PFKFB4 expression was associated with both improved overall survival (OS) and post-progression survival (PPS) in COAD patients. Further analysis revealed that genes associated with PFKFB4 were linked to various metabolic pathways, including amino acid biosynthesis, glycolysis, gluconeogenesis, glucose metabolism, and inflammatory response. PFKFB4 expression also showed correlations with the infiltration of different immune cell types in COAD patients, such as CD8+ T cells, CD4+ T cells, regulatory T cells (Tregs), macrophages, neutrophils, dendritic cells, active mast cells, and resting NK cells. Overall, the relationship between PFKFB4 expression and the prognosis of COAD is complex and diverse, possibly playing different roles at different stages of the disease. Moreover, its mechanism might involve interactions with various metabolic pathways and immune infiltration in the tumor microenvironment. These findings provide valuable insights into the potential role of PFKFB4 as a biomarker or therapeutic target in COAD.

TP53 mutation and abnormal p53 expression in endometrial cancer: Associations with race and outcomes

ObjectiveThis multi-center cohort study assessed associations between race, TP53 mutations, p53 expression, and histology to investigate racial survival disparities in endometrial cancer (EC). MethodsBlack and White patients with advanced or recurrent EC with Next Generation Sequencing data in the Endometrial Cancer Molecularly Targeted Therapy Consortium database were identified. Clinicopathologic and treatment variables were summarized by race and compared. Overall survival (OS) and progression-free survival (PFS) among all patients were estimated by the Kaplan-Meier method. Cox proportional hazards models estimated the association between race, TP53 status, p53 expression, histology, and survival outcomes. ResultsBlack patients were more likely than White patients to have TP53-mutated (N = 727, 71.7% vs 49.7%, p < 0.001) and p53-abnormal (N = 362, 71.1% vs 53.2%, p = 0.003) EC. Patients with TP53-mutated EC had worse PFS (HR 2.73 (95% CI 1.88–3.97)) and OS (HR 2.20 (95% CI 1.77–2.74)) compared to those with TP53-wildtype EC. Patients with p53-abnormal EC had worse PFS (HR 2.01 (95% CI 1.22–3.32)) and OS (HR 1.61 (95% CI 1.18–2.19)) compared to those with p53-wildtype EC. After adjusting for TP53 mutation and p53 expression, race was not associated with survival outcomes. The most frequent TP53 variants were at nucleotide positions R273 (n = 54), R248 (n = 38), and R175 (n = 23), rates of which did not differ by race. ConclusionsBlack patients are more likely to have TP53-mutated and p53-abnormal EC, which are associated with worse survival outcomes than TP53- and p53-wildtype EC. The higher frequency of these subtypes among Black patients may contribute to survival disparities.

Endothelial activation and stress index as a prognostic factor of diffuse large B-cell lymphoma: the report from the nationwide multi-center Thai Lymphoma Study Group.

Several prognostic models have been introduced to predict outcomes of patients with diffuse large B-cell lymphoma (DLBCL). Endothelial activation and stress index (EASIX) is a surrogate of endothelial dysfunction which has been shown to predict outcomes of patients with various hematologic malignancies. However, the prognostic implication of EASIX for DLBCL is limited and warrants exploration. We conducted a retrospective study enrolling adult DLBCL patients including a discovery cohort from the single-centered university hospital database and a validation cohort from the independent nationwide multi-center registry. EASIX scores were calculated using creatinine, lactate dehydrogenase, and platelet levels. The receiver operating characteristic curve analysis was used to determine optimal cutoff. Statistical analysis explored the impact of EASIX on survival outcomes. A total of 323 patients were included in the discovery cohort. The optimal EASIX cutoff was 1.07 stratifying patients into low (53.9%) and high EASIX (46.1%) groups. Patients with high EASIX had worse 2-year progression-free survival (PFS) (53.4% vs. 81.5%, p<0.001) and overall survival (OS) (64.4% vs. 88.7%, p<0.001) than patients with low EASIX. Multivariate analysis revealed that older age, bulky disease, impaired performance status, and high EASIX were associated with an unfavorable OS. In the validation cohort of 499 patients, the optimal EASIX cutoff was 1.04. Similar to the discovery cohort, high EASIX score was associated with high-risk diseases, worse PFS, and inferior OS. In conclusion, EASIX score was significantly associated with survival outcomes and may be used as a simple prognostic tool to better risk-classify DLBCL.

Survival and biomarkers for cachexia in non-small cell lung cancer receiving immune checkpoint inhibitors.

The presence of cachexia negatively impacts the prognosis of patients with cancer. However, the mechanisms behind the development of cachexia and its prognostic impact on immunotherapy efficacy are not fully understood. We retrospectively screened patients with advanced or recurrent non-small cell lung cancer (NSCLC) who received PD-1/PD-L1 inhibitor monotherapy. Among 183 patients, pre-treatment plasma samples were available from 100 patients. We defined cancer cachexia as weight loss of at least 5% during the past 6 months or weight loss of at least 2% and BMI <20. We analyzed 75 soluble immune mediators in pre-treatment plasma samples to explore the possible mechanisms behind the development of cancer cachexia. We also investigated whether cancer cachexia affects prognosis. Among 100 patients, 35 had cancer cachexia. Logistic regression analysis identified ghrelin, c-reactive protein (CRP), pentraxin-3 (PTX-3), and osteopontin (OPN) as factors associated with cachexia. Patients with cachexia had worse progression-free survival (PFS) and overall survival (OS), although we did not detect statistically significant differences. Analyzing the soluble immune mediators associated with cachexia, the combination of cachexia and PTX-3 or OPN expression levels was predictive for PFS and the combination of cachexia and CRP or OPN expression levels was predictive for OS. Pre-treatment ghrelin, CRP, PTX-3, and OPN may be associated with cachexia. Among patients with NSCLC who received PD-1/L1 inhibitor monotherapy, those with cachexia had worse survival than those without cachexia. Larger studies will be required to confirm our data and better understand the mechanisms behind the development of cachexia.

Long-term outcomes among adults with Langerhans cell histiocytosis

AbstractAdvances in the treatment of Langerhans cell histiocytosis (LCH) have resulted in a growing survivor population. There is a lack of data on long-term outcomes among adults with LCH. We conducted a retrospective record review of 219 adults (aged ≥18 years) with LCH. Most common presentation was multisystem (34.2%), followed by single-system pulmonary (32%), unifocal (28.3%), and single-system multifocal (5.5%) LCH. Risk organ involvement (the liver, spleen, or bone marrow) was seen in 8.7% of cases, and 40 of 88 (45.5%) tested cases were BRAFV600E. At a median follow-up of 74 months, 5-year progression-free survival (PFS) was 58.3% and estimated median PFS was 83 months. Median overall survival (OS) was not reached; 5- and 10-year OS rates were 88.7% and 74.5%, respectively. Risk organ involvement was associated with worse PFS (hazard ratio [HR], 4.5) and OS (HR, 10.8). BRAFV600E was not associated with risk organ involvement or survival. When compared with matched unaffected US population, individuals with LCH had a significantly higher risk of overall mortality (standardized mortality ratio [SMR], 2.66), specifically among those aged <55 years at diagnosis (SMR, 5.94) and those with multisystem disease (SMR, 4.12). Second cancers occurred in 16.4% cases, including diverse hematologic and solid organ malignancies. LCH-associated deaths constituted 36.1% of deaths and occurred within 5 years of diagnosis. After 5 years, non-LCH causes of death, including second cancers, chronic obstructive pulmonary disease, and cardiovascular diseases, predominated. Our study highlights, to our knowledge, for the first time, that adults with LCH experience early and late mortality from non-LCH causes and the need for development of targeted survivorship programs to improve outcomes.