Poor Progression-free Survival Research Articles

Serum EZH2 is a novel biomarker for bladder cancer diagnosis and prognosis.

The primary objective of this study was to examine the levels of serum EZH2 in patients diagnosed with bladder cancer, and subsequently evaluate its potential as a biomarker for both the diagnosis and prognosis of bladder cancer. Blood samples were obtained from 115 bladder cancer patients and 115 healthy persons. We measured the EZH2 concentrations in the serum of these subjects via enzyme-linked immunosorbent assay (ELISA). To assess the diagnostic performance of serum EZH2 in detecting bladder cancer, we plotted receiver operating characteristic (ROC) curves and calculated their corresponding area under the curve (AUC). We also used the Cox regression model and log-rank test to investigate the correlation between EZH2 levels and clinicopathological characteristics, and survival rates of bladder cancer patients. Serum EZH2 levels were significantly higher in bladder cancer patients when compared to those in healthy persons. Serum EZH2 levels exhibited a significant correlation with TNM stage, lymph node metastasis, muscle invasion, and tumor size. At a cutoff value of 8.23 ng/mL, EZH2 was able to differentiate bladder cancer patients from healthy persons, with an AUC of 0.87, a sensitivity of 81.31%, and a specificity of 78.42%. High EZH2 levels correlated with poor overall survival rates and progression-free survival rates of bladder cancer patients. Serum EZH2 levels were elevated in bladder cancer patients, and patients with higher serum EZH2 levels exhibited a poorer prognosis. This indicates that serum EZH2 could be a novel biomarker for bladder cancer diagnosis and prognosis. Such findings could improve the prognosis of bladder cancer patients by facilitating early detection and continuous monitoring.

Clinical characteristics and prognostic analysis of postoperative recurrence or metastasis of low-risk gastrointestinal stromal tumors

BackgroundGastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the digestive tract. This study aimed to investigate the clinical characteristics and prognosis of postoperative recurrence or metastasis in patients with low-risk stromal tumors, in order to take individualized postoperative management and treatment for patients with low-risk GISTs with relatively high recurrence.MethodsWe retrospectively analyzed the clinicopathological and follow-up data of patients with GISTs who underwent surgical resection in Nanjing Drum Tower Hospital from March 2010 to December 2021. A total of 282 patients with low-risk GISTs were included, none of whom were treated with imatinib. Univariate and multivariate Cox analysis and survival curves were used to explore the relationship between clinical features and recurrence or metastasis in patients with low-risk GISTs.ResultsOf the 282 patients with low-risk GISTs who met inclusion criteria, 14 (4.96%) had recurrence or metastasis. There was a correlation between tumor size, primary site, resection type, Ki67 index, neutrophil lymphocyte ratio (NLR) and CD34 expression and postoperative recurrence or metastasis of GISTs (P < 0.05). Subsequently, multifactorial analysis showed that tumor primary site, tumor size, and Ki67 index were independent risk factors affecting postoperative recurrent or metastasis in patients with low-risk GISTs (P < 0.05). Ultimately, According to Kaplan-Meier analysis, non-gastric primary tumors, larger tumors, and high Ki67 index were significantly associated with poor progression-free survival ( PFS ).ConclusionsTumor location, tumor size and Ki-67 were independent risk factors for postoperative recurrence and metastasis in patients with low-risk GISTs. Based on the 2008 modified NIH recurrence risk grading system, combined with the above three factors, it can be used to evaluate the prognosis of patients with low-risk GISTs and provide personalized postoperative review and follow-up management recommendations.

Clinical characteristics, outcomes and prognostic factors in KRAS mutant lung cancers: experience from a tertiary care cancer center in India.

Kirsten rat sarcoma viral oncogene homologue (KRAS) mutations in lung cancers, long considered untargetable, have had a recent rise in interest due to promising data of agents targeting KRAS p.G12C. As Indian data are scarce, we sought to identify baseline clinical characteristics, prognostic factors and outcomes of lung cancer patients with KRAS mutations at our hospital. Patients with KRAS mutant lung cancers treated at our institute from 2016 to 2022 were analysed. 133 patients with KRAS mutant lung cancers were identified. Median age was 57 (interquartile range 28-78) years, and 58 (43.6%) were smokers. 17 (12.7%) had brain metastases. The commonest variant was p.G12C, seen in 53 (39.8%) patients. Six (4.5%) had programmed death ligand 1 (PDL-1) expression >50% by Ventana SP263 PDL-1 assay, and 13 (9.7%) had epidermal growth factor mutation. Of 92 patients with available treatment details, the majority received intravenous chemotherapy, nine (9.8%) received tyrosine kinase inhibitors and four (4.4%) received immunotherapy (pembrolizumab). Median progression-free survival (PFS) with first-line therapy was 6 (95% confidence interval (CI) 2.8-9.2) months and median overall survival (OS) was 12 (CI 9.2-14.8) months. The incidence of brain metastases was higher in patients with G12C mutations (p = 0.025). Brain metastases (HR: 3.57, p < 0.001), Eastern Cooperative Oncology Group performance status (PS) ≥ 2 (HR: 2.13, p = 0.002) and G12C mutation (HR: 1.84, p = 0.011) were associated with inferior PFS, while brain metastases (HR: 4.6, p < 0.001), PS ≥ 2 (HR: 2.33, p = 0.001) and G12C mutation (HR: 1.93, p = 0.01) were associated with inferior OS. This is the largest dataset of KRAS mutant lung cancers from India. Brain metastases were higher in patients with G12C mutations and associated with poorer PFS and OS. G12C mutation and PS ≥ 2 were also associated with inferior PFS and OS. Experience with targeted therapy for KRAS mutations remains an area of future exploration due to the unavailability of these agents in India.

Influence of lamina propria invasion extension on T1 high-grade non-muscle-invasive bladder cancer in patients undergoing BCG or radical cystectomy.

To evaluate the prognostic value of T1 substaging in patients treated with bacillus Calmette-Guérin (BCG) or immediate radical cystectomy (iRC). We performed an institutional review board-approved retrospective study analysing non-muscle-invasive bladder cancer (NMIBC) patients with pT1 disease treated with either BCG or iRC between 2000 and 2020. Lamina propria (LP) invasion characteristics were extracted from the pathology report. The Kaplan-Meier method was used to calculate overall survival (OS), cancer-specific survival (CSS) and metastasis-free survival (MFS). Multivariable Cox models were used to determine the association between progression-free survival (PFS) and characteristics in the BCG cohort. A logistic regression model explored the relationship between T1 substaging and upstaging to >pT2 at iRC. A total of 411 T1 high-grade patients were identified. LP invasion characteristics were as follows: not specified: 115 (28%); focal/superficial (F/S): 147 (35.8%); and extensive/multifocal (E/M): 149 (36.2%). Overall, 303 patients (73.7%) received BCG, and 108 patients (26.3%) underwent iRC. The median (interquartile range) follow-up was 53 (32-96) months. Patients with E/M LP invasion were significantly more likely to undergo iRC (34% vs. 19%; P = 0.003). Patients with E/M LP invasion showed poorer MFS and CSS compared to those with F/S LP invasion when treated with BCG but not when treated with iRC. Among BCG-treated patients, progression occurred in 41 patients and E/M LP invasion was independently associated with progression after BCG (hazard ratio 5.3, 95% confidence interval [CI] 2.2-13.1; P < 0.001). T1 substaging was not associated with upstaging at RC (odds ratio 3.15, 95% CI 0.82-12.12; P = 0.095). Extensive/multifocal LP invasion was associated with poor PFS, MFS and CSS in patients treated with BCG. T1 substaging provides valuable prognostic information and should be reported in pathology reports.

The frequency and clinical outcome of mono-hit and multi-hit TP53 aberrations in newly diagnosed multiple myeloma

We investigated the frequency and outcome of mono-hit and multi-hit TP53 aberrations [biallelic or ≥1 TP53 mutations (TP53mut) or TP53mut with variant allele frequency (VAF) ≥55%] in an Indian cohort of newly diagnosed multiple myeloma (NDMM) patients. We employed fluorescence insitu hybridisation (FISH; n=457) and targeted next-generation sequencing (NGS; n=244) on plasma cell-enriched samples. We also studied the impact of TP53mut in cases with and without TP53 deletions (TP53del). In our cohort with a median age of 60 years, TP53del and TP53mut were seen in 12.9% (n=59/457; 14-95% cells) and 10.2% (n=25/244; 30 variants; VAF 3.4-98.2%; median 38.2%) respectively. Mono-hit and multi-hit-TP53 aberrations were observed in 10.2% and 7.8%, respectively. Compared to TP53-wild-type (TP53wt), mono-hit and multi-hit TP53 aberrations were associated with significantly poorer progression-free survival (PFS) (22.6 vs 12.1 vs 9.5 months; p=0.004) and overall survival (OS) [not reached (NR) vs 13.1 vs 15.6 months respectively; p=0.024]. However, multi-hit TP53 did not significantly differ in OS/PFS compared to mono-hit cases. Compared to TP53wt, PFS and OS were significantly poorer in patients with TP53mut only (9.5 vs 22.6 months and 12.1 months vs NR, respectively; p=0.020/0.004). TP53mut retained its significance even in the presence of any Revised International Staging System (HR 2.1; 95% CI 1.1-3.8; p=0.015) for OS. The detection of additional cases with TP53 aberrations, as well as poor survival associated with the presence of mutation alone, supports TP53mut testing in NDMM at least in patients without TP53del and other high-risk cytogenetic abnormalities.

Is there a preferred platinum and fluoropyrimidine regimen for advanced HER2-negative esophagogastric adenocarcinoma? Insights from 1293 patients in AGAMENON–SEOM registry

BackgroundThe optimal chemotherapy backbone for HER2-negative advanced esophagogastric cancer, either in combination with targeted therapies or as a comparator in clinical trials, is uncertain. The subtle yet crucial differences in platinum-based regimens' safety and synergy with combination treatments need consideration.MethodsWe analyzed cases from the AGAMENON–SEOM Spanish registry of HER2-negative advanced esophagogastric adenocarcinoma treated with platinum and fluoropyrimidine from 2008 to 2021. This study focused exclusively on patients receiving one of the four regimens: FOLFOX (5-FU and oxaliplatin), CAPOX (capecitabine and oxaliplatin), CP (capecitabine and cisplatin) and FP (5-FU and cisplatin). The aim was to determine the most effective and tolerable platinum and fluoropyrimidine-based chemotherapy regimen and to identify any prognostic factors.ResultsAmong 1293 patients, 36% received either FOLFOX (n = 468) or CAPOX (n = 466), 20% CP (n = 252), and 8% FP (n = 107). FOLFOX significantly increased PFS (progression free survival) compared to CP, with a hazard ratio of 0.73 (95% CI 0.58–0.92, p = 0.009). The duration of treatment was similar across all groups. Survival outcomes among regimens were similar, but analysis revealed worse ECOG–PS (Eastern Cooperative Oncology Group–Performance Status), > 2 metastatic sites, bone metastases, hypoalbuminemia, higher NLR (neutrophil-to-lymphocyte ratio), and CP regimen as predictors of poor PFS. Fatigue was common in all treatments, with the highest incidence in FOLFOX (77%), followed by FP (72%), CAPOX (68%), and CP (60%). Other notable toxicities included neuropathy (FOLFOX 69%, CAPOX 62%), neutropenia (FOLFOX 52%, FP 55%), hand–foot syndrome in CP (46%), and thromboembolic events (FP 12%, CP 11%).ConclusionsFOLFOX shown better PFS than CP. Adverse effects varied: neuropathy was more common with oxaliplatin, while thromboembolism was more frequent with cisplatin.

Neoplasia-related and treatment-induced lymphopenia: impact on the outcome of chemoradiotherapy in laryngeal cancer

Introduction The role of the immune system in the efficacy of radiotherapy (RT) has been well established. We examined the role of neoplasia-related and treatment-induced lymphopenia in the outcome of RT or chemoradiotherapy (CRT) in squamous cell laryngeal cancer. Materials and Methods We retrospectively analyzed a series of 135 laryngeal carcinomas treated with radical or postoperative RT/CRT. Six lymphocyte-related variables were defined and examined: i. lymphocyte counts (LCs) before a brief course of induction chemotherapy, ii. pre-RT LCs, iii. post-RT LCs, iv. pre-RT neutrophil/lymphocyte ratio (N/L), v. pre-RT monocyte/lymphocyte ratio (M/L), and vi. pre-RT platelet/lymphocyte ratio (Pt/L). Results RT and CRT resulted in a significant decrease of LCs at the end of therapy, and this was significantly more prominent in patients treated with radical intent and neck irradiation (median LC nadir 810/μl vs. 1250/μl; p = .0003). Induction chemotherapy did not intensify the lymphotoxic effect of RT. LCs lower than the 33rd percentile before RT (<1718/μl) and after RT (<720/μl) were significantly linked to poor locoregional progression-free survival (LRFS; p = .02 and p = .08, respectively) and disease-specific overall survival (OS; p = .02 and p = .03, respectively). This was also confirmed multivariate analysis (LRFS: p = .006/HR = 2.41 and p = .08/HR = 1.76, respectively; OS: p = .001/HR = 3.06 and p = .02/HR = 2.07, respectively). High pre-RT N/L, M/L, and Pt/L ratios were also of ominous prognostic relevance. Conclusions Both neoplasia-related and RT-induced lymphopenia define the outcome of RT in terms of locoregional failure, incidence of metastasis, and, finally, disease-specific survival of patients with laryngeal cancer. Restoration of pre-RT lymphopenia and protection of peripheral lymphocytes during RT emerge as critical issues that demand therapeutic interventions to maximize the efficacy of RT/CRT in patients with laryngeal cancer.

Disease Behaviour Classification: A pragmatic model for predicting outcomes in Interstitial Lung Disease

Background and objectiveThe interstitial lung diseases (ILD) are a heterogenous group of disorders with similar clinical presentation, but widely varying prognoses. The use of a pragmatic disease behaviour classification (DBC), first proposed in international guidelines in 2013, categorises diseases into five behavioural classes based on their predicted clinical course. This study aimed to determine the prognostic utility of the DBC in an ILD cohort. MethodsConsecutive patients presented at the weekly multidisciplinary meeting (MDM) of a specialist ILD centre were included. MDM consensus was obtained for diagnosis and DBC category (1–5). Baseline and serial clinical and physiological data were collected over the study period (median 3.9 years, range 0–5.4 years). The relationship between DBC and prognostic outcomes was explored. Results137 ILD patients, [64 (47%) female] were included with mean age 67.0 ± 1.1 years, baseline FVC% 72.7 ± 1.7, and baseline DLco% 57.8 ± 1.6%. Patients were stratified into DBC by consensus at MDM: DBC1 n = 0 (0%), DBC2 n = 16 (12%), DBC3 n = 10 (7.3%), DBC4 n = 55 (40%), and DBC5 n = 56 (41%). On univariable Cox regression, increasing DBC class was associated with poorer progression-free survival (HR 1.6, 95% CI 1.2–2.0, p < 0.001). On multivariable Cox regression, DBC remained predictive of PFS when combined with age and gender (HR 1.4, 95% CI 1.1–1.9, p = 0.011), baseline FVC% (HR 1.5, 95% CI 1.1–1.8, p = 0.003) and ILD diagnosis (HR 1.6, 95% CI 1.2–2.2, p < 0.0001). ConclusionDBC as determined at ILD multidisciplinary meeting may be a useful prognostic tool for the management of ILD patients.

High serum proteinase-3 levels predict poor progression-free survival and lower efficacy of bevacizumab in metastatic colorectal cancer.

To improve the prognosis of patients with metastatic colorectal cancer (mCRC), investigating predictive biomarkers of their prognosis and chemotherapeutic responsiveness is necessary. This study aimed to analyze the clinical significance of serum proteinase-3 (PRTN3) as a predictor for prognosis and chemosensitivity, especially to bevacizumab therapy, in mCRC. This single-center retrospective observational study enrolled 79 patients with mCRC in our hospital and 353 patients with colorectal cancer in the TCGA database. Preoperative serum PRTN3 levels were measured using an enzyme-linked immunosorbent assay. The clinicopathological characteristics and prognosis according to serum PRTN3 levels were then evaluated. PRTN3 expression in tumor and stromal cells was evaluated immunohistochemically. The impact of PRTN3 levels on angiogenesis and bevacizumab sensitivity was evaluated using the tube formation assay. Serum PRTN3 levels were an independent poor prognostic factor for progression-free survival (PFS) (hazard ratio, 2.082; 95% confidence interval, 1.118-3.647; P=0.010) in patients with mCRC. Similarly, prognostic analysis with TCGA data sets showed poorer overall survival in patients with PRTN3 expression than that in patients without PRTN3 expression, especially in patients with stage IV. Immunohistochemical analysis of resected specimens revealed that stromal neutrophils expressed PRTN3, and their expression level was significantly correlated with serum PRTN3 levels. Interestingly, the effectiveness of first-line chemotherapy was significantly poorer in the high serum PRTN3 level group. High serum PRTN3 was significantly associated with poor PFS (hazard ratio, 3.027; 95% confidence interval, 1.175-7.793; P=0.0161) in patients treated with bevacizumab, an anti-angiogenic inhibitor. The tube formation assay revealed that PRTN3 administration notably augmented angiogenesis while simultaneously attenuating the anti-angiogenic influence exerted by bevacizumab therapy. Serum PRTN3 levels could be a novel predictive biomarker of PFS of first-line chemotherapy, especially for bevacizumab therapy, in patients with mCRC.

Neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio as biomarkers to prognosticate survival in advanced gastric cancer patients in the era of immunotherapy: a systematic review and meta-analysis.

Gastric cancer (GC) remains an important global health concern with limited treatment options for advanced cases. Immunotherapy has shown promising results, but identifying predictive biomarkers for treatment efficacy is challenging. Novel inflammatory markers, such as the platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR), derived from complete blood count measurements, have gained attention as potential prognostic indicators. This systematic review and meta-analysis investigates the roles of the PLR and NLR as predictors of overall survival (OS) and progression-free survival (PFS) in advanced GC and gastroesophageal junction cancer (GEJC) patients treated with immunotherapy. A comprehensive search of the literature was conducted through PubMed, Embase, and Cochrane Library to identify relevant studies. A total of 16 studies involving NLR and 8 studies involving PLR were included. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated to assess the association between high biomarker values and poor OS and PFS. Subgroup analyses were performed to explore potential sources of heterogeneity. Poor OS, PFS were defined by each study as statistically significant shorter survival. A high NLR was significantly associated with worse OS (HR: 2.11; 95% CI: 1.70-2.62) and PFS (HR: 1.76; 95% CI: 1.43-2.17). High PLR was also significantly associated with poorer OS (HR: 1.77; 95% CI: 1.44-2.17) and PFS (HR: 1.61; 95% CI: 1.33-1.96). Subgroup analyses and sensitivity analyses supported the robustness of these findings. Publication bias was noted in NLR analysis for OS but not for PFS. PLR analysis showed low publication bias. Elevated NLR and PLR are associated with unfavorable OS and PFS outcomes in advanced GC/GEJC patients on immunotherapy. These findings imply the utility of these easily accessible biomarkers in prognostic assessment. However, standardized cutoff values and further research on interactions with the tumor microenvironment and comorbidities are needed. Additional prospective studies are warranted to validate these findings for both biomarkers.

Single-cell analysis of immune and stroma cell remodeling in clear cell renal cell carcinoma primary tumors and bone metastatic lesions

BackgroundDespite therapeutic advances, once a cancer has metastasized to the bone, it represents a highly morbid and lethal disease. One third of patients with advanced clear cell renal cell carcinoma (ccRCC) present with bone metastasis at the time of diagnosis. However, the bone metastatic niche in humans, including the immune and stromal microenvironments, has not been well-defined, hindering progress towards identification of therapeutic targets.MethodsWe collected fresh patient samples and performed single-cell transcriptomic profiling of solid metastatic tissue (Bone Met), liquid bone marrow at the vertebral level of spinal cord compression (Involved), and liquid bone marrow from a different vertebral body distant from the tumor site but within the surgical field (Distal), as well as bone marrow from patients undergoing hip replacement surgery (Benign). In addition, we incorporated single-cell data from primary ccRCC tumors (ccRCC Primary) for comparative analysis.ResultsThe bone marrow of metastatic patients is immune-suppressive, featuring increased, exhausted CD8 + cytotoxic T cells, T regulatory cells, and tumor-associated macrophages (TAM) with distinct transcriptional states in metastatic lesions. Bone marrow stroma from tumor samples demonstrated a tumor-associated mesenchymal stromal cell population (TA-MSC) that appears to be supportive of epithelial-to mesenchymal transition (EMT), bone remodeling, and a cancer-associated fibroblast (CAFs) phenotype. This stromal subset is associated with poor progression-free and overall survival and also markedly upregulates bone remodeling through the dysregulation of RANK/RANKL/OPG signaling activity in bone cells, ultimately leading to bone resorption.ConclusionsThese results provide a comprehensive analysis of the bone marrow niche in the setting of human metastatic cancer and highlight potential therapeutic targets for both cell populations and communication channels.

Clinically relevant molecular hallmarks of PFA ependymomas display intratumoral heterogeneity and correlate with tumor morphology

Posterior fossa type A (PF-EPN-A, PFA) ependymoma are aggressive tumors that mainly affect children and have a poor prognosis. Histopathology shows significant intratumoral heterogeneity, ranging from loose tissue to often sharply demarcated, extremely cell-dense tumor areas. To determine molecular differences in morphologically different areas and to understand their clinical significance, we analyzed 113 PF-EPN-A samples, including 40 corresponding relapse samples. Cell-dense areas ranged from 0 to 100% of the tumor area and displayed a higher proportion of proliferating tumor cells (p < 0.01). Clinically, cell density was associated with poor progression-free and overall survival (pPFS = 0.0026, pOS < 0.01). Molecularly, tumor areas with low and high cell density showed diverging DNA methylation profiles regarding their similarity to distinct previously discovered PF-EPN-A subtypes in 9/21 cases. Prognostically relevant chromosomal changes at 1q and 6q showed spatial heterogeneity within single tumors and were significantly enriched in cell-dense tumor areas as shown by single-cell RNA (scRNA)-sequencing as well as copy number profiling and fluorescence in situ hybridization (FISH) analyses of different tumor areas. Finally, spatial transcriptomics revealed cell-dense areas of different tumors to be more similar than various different areas of the same tumor. High-density areas distinctly overexpressed genes encoding histone proteins, WNT5A, TGFB1, or IGF2. Relapsing tumors displayed a higher proportion of cell-dense areas (p = 0.036), a change in PF-EPN-A methylation subtypes (13/32 patients), and novel chromosome 1q gains and 6q losses (12/32 cases) compared to corresponding primary tumors. Our data suggest that PF-EPN-A ependymomas habor a previously unrecognized intratumoral heterogeneity with clinical implications, which has to be accounted for when selecting diagnostic material, inter alia, by histological evaluation of the proportion of cell-dense areas.

Baseline Serum neutrophil-to-lymphocyte ratio in acral melanoma compared with nonacral melanoma and its prognostic significance

BackgroundAcral lentiginous melanoma (ALM), a cutaneous melanoma subtype, exhibits a poorer prognosis than non-acral cutaneous melanoma (NACM). The neutrophil-to-lymphocyte ratio (NLR) is emerging as a prognostic indicator across diverse cancers. ObjectiveWe explored the baseline NLR disparities between ALM and NACM, and the NLR’s prognostic significance in patients with ALM. MethodsWe reviewed records of patients with ALM and NACM diagnosed between 1997 and 2022, analyzing medical data. ResultsAmong 327 and 159 patients with ALM and NACM, respectively, baseline NLR varied based on distinct clinicopathological factors between ALM and NACM. In stage 3–4 melanomas, the median NLR for ALM (2.18; interquartile range, 1.70–3.08) significantly surpassed NACM (1.74; interquartile range, 1.33–2.53) (P=0.029). In patients with ALM, high NLR (hazard ratio, 1.64; 95% confidence interval, 1.02–2.66; P=0.043) was independently correlated with poor progression-free survival when adjusting for ulceration, Breslow thickness ≥2 mm, and nodal invasion. LimitationsSingle-center, retrospective design. ConclusionAdvanced-stage ALM exhibited a significantly higher baseline NLR compared to that of NACM. Evaluating baseline NLR could provide valuable prognostic insights for patients with ALM.

Clinicopathological implications of immunohistochemical expression of TBX21, CXCR3, GATA3, CCR4, and TCF1 in nodal follicular helper T-cell lymphoma and peripheral T-cell lymphoma, not otherwise specified.

The classification of nodal peripheral T-cell lymphoma (PTCL) has evolved according to histology, cell-of-origin, and genetic alterations. However, the comprehensive expression pattern of follicular helper T-cell (Tfh) markers, T-cell factor-1 (TCF1), and Th1- and Th2-like molecules in nodal PTCL is unclear. Eighty-two cases of nodal PTCL were classified into 53 angioimmunoblastic T-cell lymphomas (AITLs)/nodal T-follicular helper cell lymphoma (nTFHL)-AI, 18 PTCLs-Tfh/nTFHL-not otherwise specified (NOS), and 11 PTCLs-NOS according to the revised 4th/5th World Health Organization classifications. Immunohistochemistry for TCF1, TBX21, CXCR3, GATA3, and CCR4 was performed. TCF1 was highly expressed in up to 68% of patients with nTFHL but also in 44% of patients with PTCL-NOS (p > .05). CXCR3 expression was higher in AITLs than in non-AITLs (p = .035), whereas GATA3 expression was higher in non-AITL than in AITL (p = .007) and in PTCL-Tfh compared to AITL (p = .010). Of the cases, 70% of AITL, 44% of PTCLTfh/ nTFHL-NOS, and 36% of PTCL-NOS were subclassified as the TBX21 subtype; and 15% of AITL, 38% of PTCL-Tfh/nTFHL-NOS, and 36% of PTCL-NOS were subclassified as the GATA3 subtype. The others were an unclassified subtype. CCR4 expression was associated with poor progression-free survival (PFS) in patients with PTCL-Tfh (p < .001) and nTFHL (p = .023). The GATA3 subtype showed poor overall survival in PTCL-NOS compared to TBX21 (p = .046) and tended to be associated with poor PFS in patients with non-AITL (p = .054). The TBX21 subtype was more prevalent than the GATA3 subtype in AITL. The GATA3 subtype was associated with poor prognosis in patients with non-AITL and PTCL-NOS.

Potential biomarkers for treatment response in advanced non-pancreatic neuroendocrine tumors.

599 Background: Well-differentiated NETs are highly vascular and hence, inhibition of angiogenesis is of interest. VEGF, a key molecule in promoting angiogenesis, has also been shown to promote an immunosuppressive tumor microenvironment. Nintedanib, an oral inhibitor of FGFR1–3, VEGFR1–3 and PDGFRA, has previously been evaluated in a phase II clinical trial in well-differentiated, non-pancreatic NETs, where 83% of the evaluable patients were progression-free at 16 weeks and median PFS was 11 months. In preclinical studies, nintedanib has been shown to increase PD-L1 expression in tumor cells, which then results in improved outcomes with immune checkpoint inhibition. There are multiple indicators of T-cell exhaustion, including PD-L1 and LAG-3. LAG-3+ T-cells have been found to correlate with poor response to treatment in neuroendocrine neoplasms. Given these findings, this study evaluates serum VEGF and LAG-3 expression to determine potential biomarkers of response in patients treated with nintedanib. Methods: 27 sets of paired samples collected at baseline and 8-weeks post treatment with nintedanib, from clinical trial NCT02399215 were used for this study. With IRB approval, we tested for serum VEGFa and serum LAG-3 using Luminex test kits: HCKP1-11K-01 (LAG-3) and HCYTA-60K-01 (VEGFa). We compared the baseline, 8-week, and percentage change in serum VEGF and serum LAG-3 levels with Rd Cd8+ pAkt+ T-cells (activated cytotoxic T-cells) as a marker of immune activation, Rd CD25+ pAkt+ T-cells (regulatory T-cells) as a marker of immune suppression, and PFS. Results: The median VEGF levels at baseline and 8-weeks were 10.50 pg/mL and 11.90 pg/mL respectively. The median LAG-3 level at baseline and 8-weeks were 59000 pg/mL and 62900 pg/mL respectively. Higher VEGFa levels in the post-treatment samples were associated with poorer progression free survival (HR= 1.009, 95% HR CI: [0.999, 1.019], with P= 0.0760). Higher levels of VEGF at baseline were also associated with lower numbers of Rd CD8+ pAkt + cells (Pearson coefficient = -0.42, p-value 0.04) at baseline. Increased baseline CD25+ pAkt+ levels were positively correlated with percent change in serum LAG-3 levels between baseline and post-treatment samples. (Pearson Co-efficient: 0.45; p=value: 0.02). Conclusions: Elevated serum VEGFa levels at 8-weeks post treatment correlated with lower PFS. Serum VEGFa level is a potential indicator of effector T-cell suppression, as evidenced by low number of activated cytotoxic T-cells in patients with higher VEGFa levels at baseline. Higher baseline regulatory T-cells were associated with a greater increase in serum LAG-3 levels, suggesting that serum LAG-3 may be an indicator of an immunosuppressive tumor microenvironment.

Bulky nodal disease as distinctive prognosticator in anal cancer management.

1 Background: This study aimed to investigate the prognostic value of bulky nodal involvement in patients with squamous cell carcinoma of anus treated with definitive chemoradiotherapy. Methods: Medical records of patients with anal squamous cell carcinoma receiving definitive chemoradiotherapy at three medical centers from 2004 to 2021 were retrospectively analyzed. Exclusion criteria were (1) distant metastasis including non-regional nodal involvement at diagnosis, (2) 2D radiotherapy, and (3) salvage treatment for local relapse. Bulky nodal disease was defined as node with long-diameter 2cm or greater. Results: A total of 104 patients were accrued, consisting of 51 patients without, 46 patients with non-bulky, and 7 patients with bulky nodal involvement. Median follow-up duration was 54.0 months (range, 6.4-162.2 months). Estimated progression-free survival (PFS), loco-regional recurrence free survival (LRRFS) and overall survival (OS) at 5 years for patients with bulky nodal disease were 42.9%, 42.9%, and 89.4%, respectively. Compared to without or with non-bulky nodal involvement, bulky nodal involvement was significantly related with poor PFS and LR RFS. New staging incorporating bulky nodal disease as N2 stage was devised: T1-2N0-1 as stage I, T3-4N0-1 as stage II, and N2 as stage III. Estimated PFS, LRRFS, and OS at 5 years were as follows: 83.5%, 85.9%, and 91.3%, 60.9%, 67.7% and 93.3%, and 42.9%, 42.9%, and 55.6% for patients with stage I, II, and III disease, respectively (p = 0.0024 for PFS, 0.0015 for LRRFS, and 0.28 for OS, respectively). Conclusions: Patients with bulky nodal disease receiving standard chemoradiotherapy had poor survival outcomes compared to the other patient groups, suggesting the need for further treatment intensification. Moreover, incorporating bulky nodal disease into the staging system improved the prognosis predictability.

Efficacy and safety of hepatic arterial infusion chemotherapy combined with lenvatinib and tislelizumab for unresectable hepatocellular carcinoma: A single-arm, phase II study.

500 Background: Unresectable hepatocellular carcinoma (uHCC) patients (pts) had high unmet medical needs in practice. Retrospective studies suggested a potent antitumor effect and long-term survival benefit of hepatic arterial infusion chemotherapy (HAIC) plus programmed death-1 inhibitor and lenvatinib. This prospective phase II study aimed to evaluate the efficacy and safety of HAIC combined with lenvatinib and tislelizumab in uHCC pts. Methods: Eligible pts were aged ≥18 years and had histologically confirmed uHCC, ECOG PS ≤1, Child-Pugh (C-P) A/B, and ≥1 measurable lesion per RECIST 1.1. Pts received HAIC of modified FOLFOX (oxaliplatin, 85 mg/m2; leucovorin, 400 mg/m2; 5-fluorouracil bolus, 400 mg/m2 on day 1; 5-fluorouracil infusion, 2400 mg/m2 for 46 h), lenvatinib (8 or 12 mg once daily for body weight &lt;60 or ≥60 kg), and tislelizumab (200 mg every 3 weeks). HAIC was allowed to repeat on demands. Primary endpoint was objective response rate (ORR) per RECIST 1.1. Secondary endpoints included ORR per mRECIST, disease control rate (DCR), surgical conversion rate, progression-free survival (PFS), overall survival (OS), and adverse events (AEs). Results: Between June 2021 and January 2023, 46 pts were enrolled. The median age of pts was 51-year-old, most were male 42 (91.3%), ECOG PS 0 33 (71.7%), C-P A 44 (95.7%), tumor diameter ≥10 cm 31 (67.4%), multiple tumors 33 (71.7%), vascular invasion 38 (82.6%), extrahepatic metastasis 7 (15.2%). As of August 15, 2023, . All pts entered efficacy and safety analysis, ORR was 52.2% (0 complete response [CR], 24 partial response [PR]) per RECIST 1.1; ORR was 84.8% per mRECIST, with 5 CR and 34 PR. DCR was 95.6% per either RECIST 1.1 or mRECIST. Surgical conversion rate was 21.7% (10/46). Median PFS was 10.9 (95% CI, 8.0-13.8) months; 12-month OS rate was 41.3%. COX analysis revealed that ECOG PS 1 (HR, 3.17; 95% CI, 1.43-7.03; p=0.005), multiple tumors (HR, 3.68; 95% CI, 1.22-11.14; p=0.021), and extrahepatic metastasis (HR, 4.04; 95% CI, 1.57-10.40; p=0.004) were independently associated with poor PFS. Any-grade AEs occurred in 43 (93.5%) pts, the most common were proteinuria (43.4%), aspartate aminotransferase (AST) increased (35.8%), and alanine aminotransferase (ALT) increased (32.1%). Grades ≥3 AEs occurred in 10 (21.7%) pts and mainly included AST increased (7.5%), hypertension (3.8%), and hyperbilirubinemia (3.8%). Conclusions: HAIC combined with lenvatinib and tislelizumab showed meaningful clinical benefits and acceptable safety in uHCC pts. The study is ongoing, OS will be reported later. Clinical trial information: ChiCTR2200064384 .

Prognostic role of platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR) in advanced gastric cancer treated with immunotherapy: A systematic review and meta-analysis.

397 Background: Recent advances in the treatment of Gastric Cancer (GC) have introduced immunotherapy as a promising approach for advanced disease. In this context, potential biomarkers such as the platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR) have gained attention for their roles in predicting treatment outcomes. In this meta-analysis, we explore the clinical significance of PLR and NLR as predictors of Overall Survival (OS) and Progression-Free Survival (PFS) in advanced GC patients undergoing immunotherapy. Methods: Two independent reviewers systematically searched electronic databases, including PubMed, Embase and Scopus. The search incorporated controlled vocabulary (MeSH terms) and keywords related to Gastric Cancer, immunotherapy, platelet-to-lymphocyte ratio (PLR), and neutrophil-to-lymphocyte ratio (NLR). Eligible studies were selected based on predefined criteria, including HR availability, and were assessed for quality and bias using the Newcastle-Ottawa Scale. Data extraction was independently performed by two reviewers, and discrepancies in study selection and data extraction were resolved by a third reviewer. Subgroup analyses were performed to explore potential variations in the study outcomes. All analyses were conducted with RevMan 5.4 and employed random-effects model. Results: In total, 16 studies encompassing 1176 patients for NLR and 8 studies covering 766 patients for PLR were included in this systematic review and meta-analysis. The studies spanned the years between 2018 and 2023. Our analysis revealed significant associations between high NLR and poor OS (HR: 2.11, 95% CI: 1.70-2.62, p &lt; 0.00001) and PFS (HR: 1.76, 95% CI: 1.43-2.17, p &lt; 0.00001). Similarly, elevated PLR was significantly associated with worse OS (HR: 1.77, 95% CI: 1.44-2.17, p &lt; 0.00001) and PFS (HR: 1.61, 95% CI: 1.33-1.96, p &lt; 0.00001). In all conducted subgroup analyses, high NLR and PLR were consistently associated with poor survival outcomes. Conclusions: Our analysis supports the significance of NLR and PLR as accessible and cost-effective biomarkers for predicting survival outcomes in the context of immunotherapy for advanced GC. These findings underscore their potential significance in guiding clinical decisions. Further investigation should be carried out to validate our findings.

Construction of a Prognostic Prediction Model of Patients with Pathologic N0 in Resected Invasive Mucinous Adenocarcinoma of the Lung

Invasive mucinous adenocarcinoma (IMA) was a rare and specific type of lung adenocarcinoma, which was often characterized by fewer lymphatic metastases. Therefore, it was difficult to evaluate the prognosis of these tumors based on the existing tumor-node-metastasis (TNM) staging. So, this study aimed to develop Nomograms to predict outcomes of patients with pathologic N0 in resected IMA. According to the inclusion criteria and exclusion criteria, IMA patients with pathologic N0 in The Affiliated Lihuili Hospital of Ningbo University (training cohort, n=78) and Ningbo No.2 Hospital (validation cohort, n=66) were reviewed between July 2012 and May 2017. The prognostic value of the clinicopathological features in the training cohort was analyzed and prognostic prediction models were established, and the performances of models were evaluated. Finally, the validation cohort data was put in for external validation. Univariate analysis showed that pneumonic type, larger tumor size, mixed mucinous/non-mucinous component, and higher overall stage were significant influence factors of 5-year progression-free survival (PFS) and overall survival (OS). Multivariate analysis further indicated that type of imaging, tumor size, mucinous component were the independent prognostic factors for poor 5-year PFS and OS. Moreover, the 5-year PFS and OS rates were 62.82% and 75.64%, respectively. In subgroups, the survival analysis also showed that the pneumonic type and mixed mucinous/non-mucinous patients had significantly poorer 5-year PFS and OS compared with solitary type and pure mucinous patients, respectively. The C-index of Nomograms with 5-year PFS and OS were 0.815 (95%CI: 0.741-0.889) and 0.767 (95%CI: 0.669-0.865). The calibration curve and decision curve analysis (DCA) of both models showed good predictive performances in both cohorts. The Nomograms based on clinicopathological characteristics in a certain extent, can be used as an effective prognostic tool for patients with pathologic N0 after IMA resection.

Efficacy, safety, and predictive model of Palbociclib in the treatment of HR-positive and HER2-negative metastatic breast cancer

PurposeThis research designeded to: 1. Analyze the efficacy and safety of Palbociclib treatment in HR-positive and HER2-negative (HR + /HER2-) metastatic breast cancer(MBC) patients. 2. Establish and validate a nomogram model for predicting the progression-free survival (PFS) rates of 6 months, 12 months, and 18 months in HR + /HER2- MBC patients after receiving Palbociclib plus endocrine therapy (ET).Patients and methods1. This research retrospectively analyzed the efficacy and safety of Palbociclib combined with ET in 214 patients with HR + /HER2- MBC. 2. A nomogram was designed and constructed with the retrospective clinical data of 214 patients with HR + /HER2- MBC who received Palbociclib plus ET at Zhejiang Cancer Hospital in China from August 2018 to August 2022. Among these patients, 161 were randomly assigned to the training cohort, while 53 to the validation cohort. The predictive accuracy of the nomogram was assessed through the analysis the area under the receiver operating characteristic(ROC) curve, calibration curve, and decision curve analysis(DCA).Results1. Median PFS was 7.17 months (95% CI: 7.61—10.05 months), with an objective response rate (ORR) of 2.80% and a disease control rate (DCR) of 34.58%. The most prevalent grade 3–4 adverse event was neutropenia (38.79%). 2. Multiple variable analysis of the training set revealed that age < 60 years old, PR < 20%, Ki-67 ≥ 20%, luminal B molecular subtype, primary resistance to ET, receipt of late-stage chemotherapy, and presence of liver metastasis or ≥ 2 visceral metastases were independent prognostic factors associated with poor PFS (P < 0.05). Then, the predictive model underwent development and validation utilizing the aforementioned parameters. On the one hand, the area under the ROC curve (AUC) values of the training set at 6 months, 12 months, and 18 months were 0.771, 0.783, and 0.790, respectively, indicating a strong predictive ability of the developed model. On the other hand, the AUC of the validation set at 6 months, 12 months, and 18 months were 0.720, 0.766, and 0.754, respectively, suggesting the favorable discriminatory ability of the model. The calibration curves also exhibited a good fit with the ideal curves, and the DCA demonstrated the clinical applicability of the model. The nomogram's different scores could distinguish PFS.ConclusionThis retrospective study demonstrates the efficacy of Palbociclib in Chinese breast cancer patients. Moreover, the clinical parameters showed a significant association with the prognosis of HR + /HER2- MBC, and the prognostic models constructed based on these variables also displayed robust predictive power, which could offer more intuitive and convenient references for clinical doctors to formulate follow-up treatment plans.