Terms Of Progression-free Survival Research Articles

Pharmacoeconomic study of the effectiveness of cytogenetic studies in patients with MM before prescribing first-line therapy

Purpose of the study. Conducting an assessment of the economic consequences (clinical and economic analysis) when conducting cytogenetic studies before prescribing various first-line treatment regimens for multiple myeloma (MM). Materialsand methods. The pharmacoeconomic study was carried out using the method of cost analysis, “cost-effectiveness” within the framework of the State Guarantee Program (SGP). Results. A review of the literature demonstrated that a limited number of data are currently available on the clinical effectiveness of the analyzed regimens in the first line, both in patients with normal and high cytogenetic risk. The cost-effectiveness analysis showed that among the three studied 1st-line treatment regimens (VMP, Rd, VRd), in terms of PFS (progression-free survival), the coefficient was minimal for the VMP regimen in patients with high cytogenetic risk. Conclusion. The study showed that the choice and prescription of first-line therapy, depending on the results of a cytogenetic study, is a clinically effective and cost-effective approach to organizing medical care for adult patients with multiple myeloma in the Russian Federation. This could be used in the future to formulate.

Occult metastasis is no burden factor in oral squamous cell carcinoma patients when adhering to a standardized approach in neck dissection

ObjectivesManagement of the neck in patients with oral squamous cell carcinoma (OSCC) is pivotal to oncologic control and survival. However, there is controversy regarding necessity of neck dissection (ND) in patients with clinically node-negative neck. We aimed to assess risk factors for occult metastasis and to explore whether the presence of occult lymph node metastases (LNMs) has an impact on recurrence and survival.Material and methodsA retrospective cohort study was performed including patients with primary OSCC who underwent radical tumor resection and ND in a high-volume center adhering to the prevailing German guideline. The ND was performed according to a standardized approach.ResultsFour hundred twenty-one patients with primary surgically treated OSCC were included. The incidence of occult metastasis was 14.49%. A pathological T stage > 1 (multivariate analysis, odds ratio (OR) 3.958, p = 0.042) and the presence of extranodal extension in LNMs (multivariate analysis, OR 0.287, p = 0.020) were identified as independent risk factors for occult metastasis. When comparing patients with and without occult metastasis, there were no significant differences in terms of progression-free survival (log-rank, p = 0.297) and overall survival (log-rank, p = 0.320). There were no cases of ipsilateral neck recurrence. One patient developed contralateral neck metastasis; however, he initially presented with a unilateral pT1 pN0 tumor.ConclusionsOverall, our findings suggest that conducting a standardized approach in ND should be applied in terms of management of the neck in order to maintain survival rates and to prevent neck recurrence in OSCC patients.Clinical relevance.None of the risk factors for occult metastasis can be reliably assessed preoperatively. Although elective ND does not guarantee the complete prevention of neck recurrence, it increases the likelihood of either timely removal of micrometastases or strengthens the justification for adjuvant therapy. Consequently, this approach leads to improvements in clinical outcomes.

A retrospective analysis of the prognostic impact of KRAS G12D mutation in patients with RAS-mutated metastatic colorectal cancer.

105 Background: KRAS is an oncogene that is mutated in about half of all metastatic colorectal cancers (mCRC). Recently, a novel therapy targeting KRAS G12C mutation has demonstrated promising efficacy for advanced solid tumors, including mCRC. A therapy targeting KRAS G12D mutation is also under development and promising efficacy is expected. However, the prognostic impact of the KRAS G12D mutation in patients with mCRC is still unclear. Methods: We retrospectively reviewed the medical records of patients with mCRC harboring RAS mutation who received first-line chemotherapy between January 2013 and December 2022 at our hospital in Japan. We compared the survival outcomes between patients with KRAS G12D mutation (G12D group) and those with non- KRAS G12D mutations (non-G12D group) in terms of progression-free survival (PFS) and overall survival (OS), using the Kaplan–Meier method and the log-rank test. Hazard ratios (HRs) and 95% confidence intervals (95%CIs) were estimated by univariate and multivariate Cox regression analysis. Results: A total of 340 patients were included in this study. The main RAS mutations were KRAS G12D in 80 patients (23.4%), KRAS G12V in 72 (21.2%), KRAS G13D in 43 (12.6%) and KRAS G12C in 16 (4.7%). There were 80 patients in the G12D group and 260 in the non-G12D group. Patient backgrounds did not differ significantly in terms of age (median 61/63), sex (male 49%/48%), performance status (PS0 32%/32%), site of primary tumor (right 33%/32%), number of metastatic sites (3≤ 28%/23%), treatment regimen (doublet 90%/92%, triplet 3%/4%), or first line bevacizumab (yes 81%/79%). Median PFS was 9.2 months (95%CI: 7.8-12.2) in the G12D group vs. 11.5 months (95%CI: 9.2-13.1) in the non-G12D group (HR 0.97 [95%CI: 0.73-1.28]; p=0.81). Median OS was 25.8 months (95%CI: 18.8-39.8) vs 32.9 months (95%CI: 28.5-36.1) (HR 0.84 [95%CI: 0.60-1.19]; p=0.33). Second-line treatment was administered in 55 (69%) vs 192 (74%) patients in the G12D and non-G12D group, respectively. Conversion surgery was performed in 4 (5%) vs 18 (7%) patients in the G12D and non-G12D group, respectively. Multivariate analysis adjusted for PS, sex, age, site of primary tumor, number of metastatic sites and treatment regimen showed no significant differences in PFS and OS between the G12D and non-G12D groups. Conclusions: The KRAS G12D mutation did not show a detrimental prognostic impact on PFS and OS compared to KRAS non-G12D mutations in patients with RAS-mutated mCRC.

Real-world data of anlotinib for gastrointestinal tumors with liver metastases in China.

738 Background: Patients with advanced gastrointestinal tumors, such as gastric cancer (GC), colorectal cancer (CRC), esophageal squamous cell carcinoma (ESCC), biliary tract cancer (BTC) and pancreatic cancer (PC), often develop liver metastases with poor prognosis. Recent clinical studies have implicated that anlotinib (a novel anti-angiogenesis agent) could improve survival outcomes in gastrointestinal tumors with liver metastases, albeit with limited real-world evidence. This study aimed to report the efficacy and safety of anlotinib for gastrointestinal tumors with liver metastases in real-world practice. Methods: Demographic and clinical data of patients treated with anlotinib in any line of treatment for solid tumors with liver metastases (excluding primary liver cancer) was collected retrospectively through 5 large hospitals in China, between Jan, 2016 and Feb, 2023. The primary endpoints were progression-free survival (PFS) and objective overall response (ORR). Secondary endpoints included overall survival (OS), hepatic PFS (hPFS), hepatic ORR (hORR) and safety. In this abstract, we present data from patients with gastrointestinal tumors. PFS, hPFS and OS were estimated using the Kaplan-Meier method and compared using the log-rank test. Results: A total of 475 patients were enrolled in the study and 238 patients with gastrointestinal tumors were analyzed, including 73 (30.7%) GC, 71 (29.8%) CRC, 46 (19.3%) ESCC, 24 (10.1%) PC, and 24 (10.1%) BTC. 75.2% were <75 years old, 82.4% were male, 63.9% had a normal body mass index (BMI) (18.5-24 kg/m2), 87.8% received third-line anlotinib, and 90.3% received anlotinib monotherapy. At data cut-off (Feb 28, 2023), the median PFS was 5.90 months (95% CI: 5.23-6.77), the median hPFS was 6.20 months (95% CI: 5.27-6.77), and the median OS was 9.37 months (95% CI: 8.40-NR). There was no statistically significant difference according to the tumor types in terms of PFS (p=0.66), hPFS (p=0.8) and OS (p=0.72). We also found patients with a BMI < 18.5 kg/m2 had significantly shorter PFS (p=0.005) and hPFS (p=0.01). Adverse events (AEs) were manageable and tolerable, 30 (12.6%) patients had treatment-emergent adverse events (TEAEs) and 3 patients (1.3%) had ≥3 TEAEs. The most common treatment-related adverse events (TRAEs) were leukopenia (5.9%). Conclusions: To our knowledge, this is the first real-world report about anlotinib for gastrointestinal tumors with liver metastases in China, showed the clinical benefit of anlotinib in any line of treatment for gastrointestinal tumors with liver metastases and indicated that anlotinib could be a feasible treatment option in this specific population.

Phase I/II clinical trial of regorafenib plus durvalumab (MEDI4736) in patients with chemotherapy-refractory advanced biliary tract cancers.

TPS581 Background: Biliary tract cancers (BTC) are a heterogeneous group of cancers affecting the epithelial lining of the intra- and extrahepatic portions of the biliary tree, ranking as the second most prevalent primary liver cancer after hepatocellular carcinoma. A subgroup of BTC was found to have an abundant tumor specific neoantigen expression, enriched expression of immune related genes and genes regulating inhibitory immune checkpoint proteins. Recent advancements in BTC treatment include the TOPZ-1 trial, which established the survival advantage of adding durvalumab to the gemzar + cisplatin regimen with an estimated 24-month overall survival rate of 24.9% versus 10.4% for placebo. The hazard ratio for progression-free survival favored durvalumab at 0.75 (95% CI, 0.63 to 0.89; P=0.001). Objective response rates also showed improvement, with 26.7% for durvalumab and 18.7% for placebo. Furthermore, single agent regorafenib has exhibited efficacy in patients with refractory advanced metastatic cholangiocarcinoma, particularly in terms of progression-free survival, favoring regorafenib over placebo, the overall toxicity profile was as expected. Regorafenib targets multiple tyrosine kinases and has been reported to show immunomodulatory properties that may counteract tumor-induced immunosuppression, providing a rationale for combining it with checkpoint inhibitors. We believe that modulating the tumor microenvironment with small molecule inhibitors like regorafenib will have synergistic effect when combined with checkpoint-based immunotherapy like durvalumab in patients with chemo refractory BTC. Methods: This study comprises a single-arm, unblinded Phase I/II trial designed to assess the safety and efficacy of the combination therapy involving regorafenib and durvalumab in patients with chemo-refractory advanced BTC. The Phase I portion employed a 3 + 3 design with two dose levels of regorafenib (80 mg and 120 mg) administered in conjunction with 1500 mg IV durvalumab every 28 days. Phase I successfully completed, and the Data Monitoring Committee (DMC) endorsed the continuation of the trial as planned. Eligibility: Histologically confirmed unresectable or metastatic disease. Progressed on at least one line of therapy. May have received checkpoint inhibitor in the past. Inclusion criteria also include ECOG PS 0-1. Objectives:Primary Phase I: Safety of regorafenib in combination with durvalumab.Phase II: Progression-free survival (PFS).Secondary:Disease Control Rate (DCR), Overall response rate (ORR), Overall survival (OS). Statistical Plan: Interim futility testing after one year, halting if conditional power < 20%. Final analysis: PFS and OS via Weibull Regression. Enrollment is currently ongoing with 8 out of 40 patients enrolled.

A network meta-analysis of efficacy and safety for first-line and second/further-line therapies in postmenopausal women with hormone receptor-positive, HER2-negative, advanced breast cancer

BackgroundHormone receptor-positive/human epidermal growth factor receptor 2-negative (HR + /HER2 −) advanced breast cancer is a prevalent subtype among postmenopausal women. Despite the growing number of randomized clinical trials (RCTs) exploring this topic, the efficacy and safety of first-line and second/further-line treatments remain uncertain. Accordingly, our aim was to conduct a comprehensive evaluation of the efficacy and safety of these therapies through network meta-analysis.MethodsRCTs were identified by searching Pubmed, Embase, and major cancer conferences. The efficacy of interventions was assessed using the hazard ratios (HRs) of progression-free survival (PFS) and overall survival (OS), while safety was indicated by the incidence of any grade adverse events (AEs), grade 3–5 AEs, AEs leading to treatment discontinuation, and AEs leading to death. Both time-variant HRs fractional polynomial models and time-invariant HRs Cox-proportional hazards models were considered for handling time-to-event data. Safety indicators were analyzed using Bayesian network meta-analysis. Additionally, subgroup analyses were conducted based on patient characteristics.ResultsA total of 41 RCTs (first-line 17, second/further-lines 27) were included in the analysis. For first-line treatment, the addition of Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors to endocrine therapy significantly improved therapeutic efficacy in terms of both PFS and OS, demonstrating the best performance across all mechanisms. Specifically, the combination of Abemaciclib and Letrozole demonstrated the most favorable performance in terms of PFS, while Ribociclib plus Fulvestrant yielded the best outcomes in OS. Incorporating the immune checkpoint inhibitor Avelumab into the regimen with CDK4/6 inhibitors and selective estrogen receptor degraders significantly enhanced both PFS and OS in second-line or later treatments. Regarding safety, endocrine monotherapy performed well. Regarding safety, endocrine monotherapy performed well. There is mounting evidence suggesting that most CDK4/6 inhibitors may demonstrate poorer performance with respect to hematologic AEs. However, additional evidence is required to further substantiate these findings.ConclusionsCDK4/6 inhibitors, combined with endocrine therapy, are pivotal in first-line treatment due to their superior efficacy and manageable AEs. For second/further-line treatment, adding immune checkpoint inhibitors to CDK4/6 inhibitors plus endocrine therapy may produce promising results. However, to reduce the results’ uncertainty, further trials comparing these novel treatments are warranted.Trial registrationRegistration number: PROSPERO (CRD42022377431).

Beneficial Use of the Combination of Gemcitabine and Dacarbazine in Advanced Soft Tissue Sarcomas: Real-World Data.

The combination of gemcitabine and dacarbazine has exhibited efficacy in terms of progression-free survival (PFS) and overall survival (OS) for aSTSs, albeit without robust confirmation from larger clinical trials. We conducted a retrospective study in a single institution involving aSTS patients treated with gemcitabine and dacarbazine. 95 patients were assessed, pointing to a benefit in PFS of 3.5 months and an OS of 14.2 months. Patients with translocated histotypes had better PFS, while those with platelet-lymphocyte ratios (PLRs) surpassing a specific threshold or lower albumin levels had poorer overall survival. This study validates previous findings from three phase I-II trials, affirming the utility of this treatment approach in routine clinical practice.

Immunohistochemical analysis of epidermal growth factor receptor as a predictive biomarker in lung adenocarcinoma – A cross-sectional study of 33 cases on computed tomography-guided core needle biopsy specimens

Background: Lung cancer is the second most common cause of cancer in all ages and both genders and is the leading cause of cancer death. Two major groups of lung cancers are – small cell lung carcinoma (SCLC) and non-SCLC (NSCLC). Due to discovery of driver mutation such as epidermal growth factor receptor (EGFR) mutation in NSCLC, the paradigm of lung cancer therapy has shifted from cytotoxic platinum based therapy to tyrosine kinase inhibitor (TKI) therapy. In this study, we have analyzed EGFR expression in NSCLC by immunohistochemistry (IHC) and studied the response to TKI therapy in terms of progression free survival (PFS) and overall survival (OS). Aims and Objectives: In this study, we have retrospectively analyzed the EGFR overexpression in adenocarcinoma of lung in core needle biopsy (CNB) specimen by IHC analysis and correlated with the therapeutic response and survival rate (OS and PFS) in lung carcinoma patients. Materials and Methods: We have analyzed retrospectively EGFR expression in lung adenocarcinoma cases (computed tomography-guided CNB specimen) by IHC. In our study, we have used monoclonal primary antibodies against two most common EGFR mutations, that is, L858R point mutation and E 746–A 750 deletion. Results: Out of 33 cases, EGFR expression was seen in 28 cases. For EGFR expression assessment by IHC, both cytoplasmic and/or membranous staining taken into consideration. EGFR positivity was interpreted only when >10% tumor cells having 2+ or more intensely staining pattern. The response to TKI therapy in terms of PFS and OS was also studied. Conclusion: IHC analysis of EGFR mutation using specific antibodies has extremely high specificity with good sensitivity. Use of targeted therapy in the form of TKI in EGFR positive lung adenocarcinoma has high response rate and long duration of survival (PFS and OS) with acceptable toxicity profile in contrast to the conventional therapy.

Real-world effectiveness of palbociclib in HR+/HER2- metastatic breast cancer: a literature review

Approximately 70% of newly diagnosed breast cancers are of the HR+/HER2- subtype. For the treatment of patients with HR+/HER2- metastatic breast cancer, current guidelines recommend the use of a CDK4/6 inhibitor (palbociclib, ribociclib or abemaciclib) in combination with endocrine therapy. In this review we assess existing literature concerning real-world effectiveness of palbociclib. Survival outcomes in terms of progression-free survival and overall survival are discussed and compared among the included real-world studies and in relation to the phase III PALOMA trials.

Analysis of Immune-Related Adverse Events of Atezolizumab and Bevacizumab in Patients with Hepatocellular Carcinoma: A Multicentre Cohort Study

<b><i>Introduction:</i></b> Despite the emergence of atezolizumab and bevacizumab (A + B) as standard first-line systemic therapy for unresectable hepatocellular carcinoma (HCC), a comprehensive understanding of the clinical significance of immune-related adverse events (irAEs) remains limited. We aimed to assess the impact of irAEs on patients with HCC undergoing A + B treatment. <b><i>Methods:</i></b> This multicentre retrospective study included consecutive patients with HCC who were treated with the A + B regimen from September 2020 to December 2022. Patients were categorized into three groups based on the severity of irAEs, ranging from those without any experience of irAEs to those with severe irAEs. <b><i>Results:</i></b> This study included 150 patients with HCC, with a mean age of 63.3 years. Among them, 93.3% of patients were classified as Barcelona Clinic Liver Cancer stage C, 52.0% had portal vein tumour thrombosis (PVTT), and 60.7% extrahepatic spread. Patients were classified as follows: group 1 (<i>n</i> = 84) had no irAEs, group 2 (<i>n</i> = 37) had mild irAEs (grade 1-2), and group 3 (<i>n</i> = 29) had severe irAEs (grade ≥3). The median overall survival (OS), progression-free survival (PFS), and time-to-treatment discontinuation (TTD) were 13.6, 5.7, and 3.6 months, respectively. Group 2 demonstrated significantly superior OS compared to group 1 (9.5 months) and group 3 (5.6 months), with a median OS of 23.0 months (<i>p</i> < 0.001). Furthermore, group 2 demonstrated significantly better outcomes in terms of PFS and TTD compared to both group 1 and group 3 (<i>p</i> < 0.001 for both). Multivariate analysis identified mild irAEs (hazard ratio [HR], 0.353; <i>p</i> = 0.010), ALBI grade 1 (HR, 0.389; <i>p</i> = 0.006), Child-Pugh class A (HR, 0.338; <i>p</i> = 0.002), and the absence of PVTT (HR, 0.556; <i>p</i> = 0.043) as independent predictors of better OS. <b><i>Conclusion:</i></b> Our study highlights the significant impact of irAE severity on the outcomes of patients with HCC receiving A + B. Notably, the occurrence of mild irAEs was independently associated with favourable survival, suggesting their potential role as surrogate indicators of HCC prognosis.

Technical evaluation of a novel digital PCR platform for detecting EGFR/KRAS mutations in NSCLC archived plasma specimens

IntroductionKRAS p.G12C hot spot mutations has rapidly modified diagnostic algorithm for lung cancer patients electing Non-Small Cell Lung Cancer (NSCLC) patients to target treatment. As regards, patients that harbor this hallmark showed a clinical benefit in terms of progression-free survival (PFS) and overall survival (OS) in comparison with control group under target treatment. In this scenario, KRAS p.G12C mutation requires optimized testing strategy in diagnostic routine practice. Although the widespread diffusion of NGS platforms, a not negligible percentage of Italian diagnostic institutions adopt singleplex technology (RT-PCR, dPCR) for molecular testing. Here, we aim to technically validate a novel dPCR system (QIAcuity™ Digital PCR System, Qiagen; Hilden, Germany) on a retrospective series of cfDNA samples from previously tested with a custom NGS system. (1,2)Methods: n = 50 liquid biopsy specimens (n = 25 KRAS/EGFR mutated and n = 25 wild type for actionable KRAS/EGFR mutations) from diagnostic routine NSCLC patients previously tested with a custom NGS panel were retrieved from our internal archival. Each sample was tested by adopting n = 5 KRAS and n = 3 EGFR commercially available dPCR assays on QIAcuity™ Digital PCR System (Qiagen; Hilden, Germany); an ultra-deep dPCR walk-away platform that automatizes molecular analysis. Technical sensitivity, technical specificity, and concordance rate between “gold standard” NGS system and QIAcuity™ Digital PCR System (Qiagen; Hilden, Germany) were assessed. ResultsOverall, all specimens were successfully analyzed with dPCR system. In details, 24 out of 25 mutated and 21 out of 24 wild type cases were detected. A technical sensitivity, specificity, and a concordance rate of 96.0 % (24/25), 88.0 % (22/25) and 92.0 % (46/50) were evaluated taking into account a MAF cut-off ≥ 0.2 % and a partition number of 100 positive partitions in wild-type channel. ConclusionQiacuity (Qiagen; Hilden, Germany) platform enables accurate molecular analysis of diagnostic routine specimens. Optimized technical workflow is required to technically implement this platform in diagnostic routine setting.

Comparison of different maintenance regimens following first-line immunochemotherapy for advanced non-small cell lung cancer.

Immunochemotherapy is the standard first-line treatment for non-small cell lung cancer (NSCLC). However, the ideal combination strategy and maintenance regimen remain uncertain. This study aims to compare the clinical efficacy of different first-line maintenance regimens for advanced EGFR/ALK (epidermal growth factor receptor/anaplastic lymphoma Kinase) negative NSCLC and explore the eligibility of chemo-free maintenance. We conducted a retrospective evaluation of 1,510 EGFR/ALK negative NSCLC patients who received immune checkpoint inhibitors (ICIs) treatment in our center from 2019 to 2021. Patients who had controlled disease after 2-6 cycles of first-line ICIs in combination with platinum-based doublet chemotherapy with or without anti-angiogenesis were included. Four maintenance regimens were analyzed: ICIs plus platinum-free chemotherapy with (group 1, I+C+A) or without anti-angiogenesis maintenance (group 2, I+C), single-agent ICIs maintenance (group 3, I) or ICIs plus anti-angiogenesis maintenance (group 4, I+A). For group 3-4, rechallenge with initial chemo-agents was given upon the first progression, those who achieved controlled disease were repeatedly followed by another chemo-free period. The primary outcome was progression-free survival (PFS). Notably, for group 3-4, PFS was characterized as the duration between treatment initiation and failure of rechallenge (last disease progression). In total, 140 eligible patients in the maintenance phase were analyzed, with 20, 40, 42, and 38 patients in groups 1 to 4, respectively, displaying comparable baselines. Median PFS was similar in the I+C+A maintenance group (22.6 months), I+C maintenance group (21.0 months), and I+A maintenance group (21.5 months), whereas PFS was inferior in group 4 with I maintenance alone (13.4 months). Median chemo-free duration were 6.3 months in I maintenance group, while 13.5 months in I+A maintenance group. During the maintenance period of group 1 to 4, 25%, 25%, 19%, and 42% of patients experienced partial response (PR) again, respectively. Fifty-five percent, 65%, 48% and 61% of patients sustained durable disease control at the end of follow-up. In group 4, 39% of patients received progressive disease (PD) and rechallenge initial chemo-agents. Fifty percent of patients achieved PR and resumed to chemo-free maintenance. We showed that following first-line immunochemotherapy, chemo-free maintenance by ICIs plus anti-angiogenesis and on-demand chemo-rechallenge provided comparable efficacy to chemo-on maintenance in terms of PFS, thus allowing the minimization of cytotoxic drugs without compromising therapeutic effectiveness. In addition, anti-angiogenesis is essential during chemo-free maintenance.

Surgical outcomes and follow-up results of 53 pediatric craniopharyngioma cases: a single-center study.

Craniopharyngiomas are locally invasive neoplasms, and they cause potential lifelong morbidity because of their tendency for local recurrence. Despite advancements in endoscopic techniques, gross-total resection (GTR) of tumors with invasion or adhesion to important surrounding anatomical structures is extremely difficult. The authors present a single-center study that evaluated the impact of the endoscopic endonasal approach (EEA) on the surgical outcomes of pediatric craniopharyngiomas, the factors affecting the resection rate, and recurrence. A total of 44 pediatric patients (age ≤ 18 years) who were treated via the EEA for craniopharyngioma from August 1997 to June 2022, as well as their 53 operations, were included in this study. The preoperative radiological configuration and surgical data of these cases were assessed. Also, preoperative and postoperative clinical (endocrinologic, neurological, and ophthalmological), hypothalamic, physical and social development, and neurocognitive assessment data were described. In total, 37 cases (69.8%) had no history of operation beforehand. The most common symptoms at presentation were endocrine disturbances (98.1%), headache without vomiting (84.3%), and visual disturbance (51%). Cases were classified as infrasellar (1.9%), sellar (32.1%), sellar-suprasellar (52.8%), and suprasellar (13.2%) localization. GTR was achieved in 34/53 cases (64.1%). The rate of GTR was higher in infrasellar and sellar tumors compared with sellar-suprasellar and suprasellar tumors (p = 0.003), and preoperative hypothalamic involvement was associated with lower likelihood of GTR (p = 0.024). Moreover, with experience, the rate of GTR increased (p = 0.037). Postoperative complications, other than endocrine impairment, occurred in 10/53 cases (18.9%). The mean duration of follow-up was 53.57 months. At follow-up, 21/53 (39.6%) cases presented with tumor recurrence. The 5-year progression-free survival (PFS) rate was 48.5%. There was a statistically significant difference between the GTR and other-than-GTR groups in terms of PFS (p < 0.001). According to univariate analysis, smaller tumor (p = 0.017), infrasellar and sellar localization (p = 0.031), and GTR (p < 0.001) were significantly associated with decreased rate of recurrence. Also, there was a statistically significant association between the recurrence rate and adhesion strength of the tumor (p < 0.001). This retrospective cohort study revealed surgical indications for EEA, as well as factors affecting the resection rate, recurrence, and quality of life during the follow-up period of the included cases. The authors believe that GTR should be the goal for craniopharyngioma treatment, but the authors' treatment approach was to provide a balance between radical surgery with maximum safety and adjuvant treatment for long-term disease control.

Results of an Italian Retrospective Clinical Experience on Mediastinal Gray Zone Lymphoma

Introduction and methods: Mediastinal gray zone lymphoma (GZL) emerged as a rare and challenging entity due to its high rate of pathological reclassification and heterogeneous clinical management. The bio-GZL2020 study was designed to centralize histological samples and clinical data of patients (pts) diagnosed with GZL between 2006 and 2020 in 16 Italian hematological centers. We here report the preliminary clinical results of this retrospective analysis. Results: Overall, we collected samples and clinical data of 68 pts with GZL. According to the 2022 WHO and ICC classifications we excluded nine pts for lacking mediastinal involvement, hence 59 pts were analyzed. Pts were mostly stage I-II (62.7%); 57.6% had a mediastinal bulky disease. The site of diagnostic biopsy was the mediastinum in 29 pts. Additional clinical characteristics at baseline are reported in Table 1. One patient died before the start of treatment and was excluded from survival analysis. First line chemotherapy (CHT) consisted in DA-EPOCH in 31 pts, CHOP-like regimens in 17 pts, ABVD in six pts, MACOP-B in three pts and DHAP in only one case. Eight pts did not receive rituximab with CHT (six ABVD pts, two CHOP-like pts). Dose escalation in R-DA-EPOCH was performed in 75% of pts, with 18 pts (64.3%) attaining level 3 or higher. Four advanced stage, high-risk pts received central nervous system prophylaxis. Twenty-two pts performed an interim PET-scan during first line therapy; data on Deauville score was available in 19 cases, with 9 pts obtaining a score 1-3. Restaging after first line CHT showed 37 pts in complete remission (CR; 63.8%), nine pts in partial remission (PR; 15.5%), five pts in stable disease (SD; 8.6%) and seven pts in progressive disease (PD; 12.1%). Thirty-one pts (53.4%) received a consolidative treatment (26 pts radiotherapy (RT) only, seven pts autologous transplant (ASCT) only, two pts both RT and ASCT). Restaging after first line consolidation showed 43 CR (74.1%), four PR (6.9%), two SD (5.2%) and eight PD (13.8%). Nineteen pts underwent a second line CHT, 16 of them with a platinum-based regimen; brentuximab vedotin, BeGEV and HyperCVAD were used in one patient each. Second line consolidation ASCT was performed in seven pts, while one received an allogeneic transplant. Of the 17 restaged pts after second line CHT seven were in CR, 10 were not responsive (four SD, six PD). Considering all salvage lines five pts received a checkpoint inhibitor, nine underwent brentuximab vedotin treatment. Overall survival (OS) was 86.9% at 5 years and 71.3% at 10 years; beta2-microglobulin (available only in 32 pts) and the response after first line therapy were associated to a statistically significant difference in OS in univariate analysis. Progression-free survival (PFS) was 61.9% at 5 and 10 years. The use of rituximab, the Deauville score 1-3 at interim PET during induction, and the response after first line therapy were associated to a statistically significant difference in PFS in univariate analysis. ABVD was associated to poorer results in terms of OS and PFS although no significant difference was observed. No statistically significant difference in term of PFS was observed between pts treated with intensified regimens (DA-EPOCH, MACOP-B, DHAP) and other treatments in first line. Excluding pts directly shifted to salvage therapy, consolidative RT after first line CHT showed no statistically significance in term of both OS and PFS. Conclusions: To our knowledge our study represents the largest retrospective data collection on GZL among hematological Italian centers. This preliminary analysis did not show a clear advantage of intensive therapies such as DA-EPOCH or MACOPB, while the positive prognostic role of rituximab was confirmed in PFS. The prognostic role of interim PET-CT scan seems interesting and should be evaluated in subsequent trials. Further refinement of the reported results is expected in relation of an ongoing central pathological review by a panel of expert hematopathologists.

Unveiling Novel Therapeutic Targets for CAR Therapy in Multiple Myeloma through Single-Cell RNA Sequencing

Multiple Myeloma (MM) is a hematological malignancy characterized by the clonal proliferation of plasma cells. Among the different therapeutic options in this setting, chimeric antigen receptor (CAR) T cells recently showed unprecedent achievements in term of progression free survival. However, despite advancements in current therapies, the disease's heterogeneity remains a major challenge and all patients unavoidably relapse, rendering innovative approaches to identify precise therapeutic targets eagerly awaited. Along this line, the revolution of single-cell (sc) technologies brings new opportunities to identify precise therapeutic targets, including abundant and unique surface proteins for CAR therapy. In this study, by analyzing individual cancer cells at sc level, we aim to identify novel surface targets, facilitating the development of novel personalized cellular therapies as well as treatment sequences. To this end, we used samples collected from 9 publicly available single-cell RNA sequencing (scRNA-seq) datasets (GEO accession numbers: GSE176131, GSE189460, GSE223060, GSE210079, GSE145977, GSE124310, GSE161801, GSE163278, GSE161722) obtained from 156 patients affected by monoclonal gammopathies (19 monoclonal gammopathy of undetermined significance (MGUS), 10 smoldering multiple myeloma (SMM), 78 MM and 25 relapsed/refractory multiple myeloma (RRMM)) and 24 normal bone marrows (NBM), to conduct an unbiased search for genes showing specific expression in plasma cells (PCs), regardless of disease status. We found 15 genes showing differential expression in PCs (adj.pval&amp;lt;0.01 and logFC&amp;gt;1) and coding for surface proteins: TNFRSF17(BCMA), SDC1 (CD138), FCRL5 (GPRC5D), TNFRSF13B (TACI), CD38, SLAMF7 (CS1), CD59, FCGR2B, FGFR3, SLC44A1 (CTL1), CD320, FCRL2, IL15RA, INSR and SLAMF1. As expected, most of these molecules already represent critical therapeutic targets. After completing our initial analysis, we compared PCs transcriptomes from MM/RRMM patients with NBM, MGUS, and SMM samples. Among previously identified genes, CD320 only was significantly overexpressed in MM PCs. Next, we investigated associations between cytogenetic-related cell subclusters and previously identified surface markers. Interestingly, we found a significant association between the expression levels of TACI/CD59 and the overexpression of CCND2 and MAF, both associated with the presence of t(14:16). Next, we decided to focus on the first five genes (according to expression ranking) that do not currently have an active clinical development program in advanced phases, namely: TNFRSF13B, CD59, FCGR2B, SLC44A1, and CD320 (Fig. 1 A, values dichotomized based on their median) to uncover their (potential) impact/association with patient's outcome. In our analysis of different available expression profiling datasets (GSE4204, GSE2658, GSE57317, GSE4581, GSE4452, GSE9782, the CoMMpass study NCT01454297) involving around 2000 MM patients, we observed TNFRSF13B, CD59, and FCGR2B expression correlated with improved outcome while CD320 and SLC44A1 expression associated with worse outcome (Fig. 1 B). In conclusion, we integrated results from both scRNAseq and bulk-RNAseq/microarray data to identify new targets genes to be used in the context of personalized medicine. Interestingly, CD320 emerges as a potential candidate biomarker useful for monitoring disease evolution and predicting worse outcomes. Additionally, this approach led us to identify a series of potential new targets for MM patients, depicting a new scenario where each patient could be “screened” to identify the best molecule to be targeted. While further investigation is necessary to assess off-target toxicity and confirm clinical relevance, our analyses significantly streamline the search for tumor markers with a method potentially applicable to different malignancies, bringing us closer to identifying the best candidates for effective CAR therapy.

Safety Profile in Patients with Chronic Lymphocytic Leukemia Undergoing Treatment with 1st and 2nd Generation Bruton Tyrosine Kinase Inhibitors: Multicentric Real-World Experience

INTRODUCTION Chronic lymphocytic leukemia (CLL) is the most frequent leukemia, being more frequent in older adults. Bruton's tyrosinkinase inhibitors (BTKi) have revolutionized the treatment, displacing immunochemotherapy treatment in all patient profiles. The selectivity profile in the action of these drugs means that the toxicity of first and second generation BTKi is different, resulting in higher rates of atrial fibrillation and arterial hypertension, mainly in patients treated in the second line or later, while maintaining their efficacy. Real-life studies are needed to be able to demonstrate the effects in first-line treatment in a more heterogeneous patient profile, without the strict exclusion and inclusion criteria used in clinical trials. METHODS An observational, retrospective, multicenter, retrospective study was performed. Patients with in treatment with Ibrutinib or Acalabrutinib in first line or later were included. Demographic data, comorbidity, cytogenetic and mutational disease data, adverse effect profile, comprehensive geriatric assessment (if applicable) and treatment response evaluation data are collected. RESULTS A total of 91 patients were included with a median age of 73.22 years SD 11.06. Fifty-three (58.2%) were male. Fifty-three (58.2%) were treated in frontline, 31.9% (29) in second line and 9.9% (9) in subsequent lines. Acalabrutinib was used in 25 (27.5%) patients and Ibrutinib in 66 (72.5%). Patient characteristics are shown in Table 1. Differences were revealed between these two BTKis in terms of line of treatment, with the majority being treated first (P=0.006) and Rai stage, with Rai II predominating (P=0.014). No differences were found between the two BTKis according to the rest of the characteristics. In terms of toxicity, 14 (15.4%) of patients treated with Ibrutinib developed arterial hypertension, compared to no patients in the Acalabrutinib arm (p=0.009). With respect to the development of cardiac toxicity, 19 (20.9%) patients suffered some cardiotoxic event, 3 (3.3%) in patients on acalabrutinb and 16 (17.6%) on ibrutinib, with no significant differences found between the two drugs (p=0.2). No significant differences were found with respect to other toxicities (hematologic, digestive, bleeding and infections). Table 2 No differences were found in terms of progression-free survival or overall survival. CONCLUSIONS The iBTKs have changed the treatment of CLL, although the second-generation iBTKs have a safer cardiovascular profile and are just as effective in our cohort, even in the frontline.

Retrospective Analysis of Four Frailty Assessment Tools in Elderly Patients with Multiple Myeloma

INRTODUCTION : The International Myeloma Working Group (IMWG) developed the frailty index (IMWG-FI) to predict the toxicity and mortality risk faced by elderly patients with multiple myeloma. However, due to the time-consuming nature and subjectivity of IMWG-FI, alternative frailty assessment tools have been developed to reduce subjectivity and enhance the ability to identify frailty. O BJECTIVE (S) To assess the consistency of various frailty assessment tools in elderly patients with multiple myeloma and their predictive efficacy for patients survival. M ETHOD (S) We systematically assessed 84 newly diagnosed multiple myeloma patients aged≥60 years old using various frailty assessment tools, including the IMWG frailty index (IMWG-FI), Mayo frailty score, simplified IMWG frailty index（IFM）, and British Myeloma Research Alliance Risk (MRP) score. We compared progression-free survival (PFS) and overall survival (OS) outcomes based on these different assessment tools. For the purpose of analysis, we combined patients categorized as Fit or Intermediate Fit into a single group called Non-Frail. RESULTS (S) The median age of the included patients was 68 years, ranging from 60 to 84 years. Among them, 59.5% were male. Additionally, 53.8% had an ECOG score of ≥2 and 26.9% had a CCI score of ≥2. Patients who chose the regimens based on ixazomib, bortezomib, and thalidomide were 11.2%, 70.7%, and 3.3%, respectively, while 7.8% of patients refused chemotherapy. The incidence of frailty in this cohort was as follows: 53.6% according to the IMWG-FI, 23.8% based on the Mayo frailty score, 46.4% using the MRP frailty score, and 67.85% according to the simplified IMWG frailty index. The consistency among the four frailty assessment tools was low, with a total of 64 patients (76.2%) identified as frail by at least one tool. Among them, 48 patients (75.0%) were identified as frail by at least two tools, while only 14 patients (21.9%) were classified as frail by all four tools. Among the cohort of 73 patients eligible for OS and PFS analysis, utilization of the IMWG-FI to evaluate frailty status revealed that the non-frail and frail groups exhibited median OS durations of undisclosed levels and 15.5 months, respectively ( P=0.01). In terms of PFS, the corresponding median durations were 42.5 months and 10.0 months, respectively ( P=0.011). When employing the Mayo frailty score, the non-frail and frail groups demonstrated median OS durations of 26.0 months and 7.0 months, respectively ( P=0.004), alongside median PFS durations of 42.5 months and 7.0 months, respectively ( P=0.024). Application of the MRP score to assess frailty resulted in non-frail and frail groups achieving undisclosed levels and a median OS of 15.0 months, respectively ( P&amp;lt;0.001). Their corresponding median PFS durations were 42.5 months and 9.0 months, respectively ( P&amp;lt;0.001). Additionally, the utilization of the simplified IMWG frailty index for frailty assessment rendered non-frail and frail groups achieving undisclosed levels and a median OS of 19.0 months, respectively ( P=0.225). Regarding the median PFS durations, they reached undisclosed levels and 15.0 months for the non-frail and frail groups, respectively ( P=0.495). CONCLUSION (S) The results of the four frailty assessment tools in this cohort vary significantly. The MRP score and IMWG frailty index demonstrate higher consistency and better prognostic stratification efficiency compared to the Mayo score and simplified IMWG frailty index. Therefore, combining the MRP score with the IMWG frailty index can effectively enhance the recognition ability for newly diagnosed elderly patients with frail multiple myeloma.

Treatment with Daratumumab Plus Bortezomib, Cyclophosphamide, and Dexamethasone May Result in Both Hematologic and Metabolic Complete Response to Achieve Long-Term Progression Free Survival Among Patients Presenting with Extra-Medullary Disease: A European Myeloma Network Study (EMN19)

Introduction: Multiple myeloma (MM) with extramedullary disease (EMD) is an aggressive disease that requires innovative treatment strategies. Methods: The ongoing multinational, open-label phase 2 EMN19 trial (NCT04166565) enrolled patients (pts) with MM and EMD either as newly diagnosed MM (NDMM) or at first relapse (RMM). Pts received Daratumab (Dara) in combination with bortezomib (V), Cyclophosphamide (C), and Dexamethasone (D) (DaraVCD), either until disease progression or for a maximum of 36 months, along with autologous stem cell transplantation. Response to treatment was assessed using both the International Myeloma Working Group (IMWG) and the Impetus criteria for evaluating the EMD responses. Complete metabolic response (CMR) was defined as: Deauville scores 1, 2 or 3, with absence of FDG-avid bone marrow lesion(s), irrespective of a persistent mass on CT, or complete disappearance of EMD. Partial metabolic response as: Deauville score of 4 or 5 with decreased uptake compared to baseline and absence of structural progression development on CT or 50% reduction in EMD size. MRD assessment was performed locally at the time of CR or at an earlier time point, as per clinical practice. Pts without MRD assessment were included in the denominator when estimating the MRD(-) rate. Pts who had discontinued treatment by Cycle 4 were considered as non-responders (both in terms of hematologic and EMD response). Progression-Free Survival (PFS) was analyzed by the Kaplan-Meier method. Cox regression analysis with Firth's correction was used for the estimation of the hazard ratios (HRs) and 95% confidence intervals (CIs). Results: A cohort of 40 pts (73% NDMM; 28% RMM) was enrolled. The mean age was 58 years, with 22 (55%) of the pts being male. At baseline, 33 (83%) of the pts were in stage ≤II of the International Staging System and 6 (15%) were classified as high-risk according to FISH (t(4;14), t(14;16) and/or del17p). Among the pts, 22 (55%) had extramedullary plasmacytomas (PCTs), 14 (35%) had paraosseous involvement, and 4 (10%) had both. The median number of PCTs per pt was 2. At the cut-off date with a median follow-up (FU) of 23 months, 17 (43%) pts were still on treatment, while 23 (58%) had discontinued treatment mainly due to disease progression (13, 33%), inadequate response at the end of cycle 3 (5, 13%) or death (3, 8%). In the overall population, deepest responses were as follows: MRD(-) was achieved by 15 (38%) pts, ≥Complete response (CR) by 18 (45%) pts, ≥VGPR by 30 (75%) pts with an overall response rate (ORR) of 80% (32 pts). The median (range) time to MRD(-) was 19 months (4-33); 13 of the 15 MRD(-) pts were NDMM. Median PFS (24-months PFS rate) was 26 months (56%) in NDMM and 15 months (36%) in RMM. Overall, 28/40 (70%) pts had a concurrent hematologic and EMD response of partial response (PR) or better; the best hematologic responses achieved among those pts were: MRD(-) (15 pts), ≥CR (16 pts), VGPR (10 pts) and PR (2 pts). Additionally, 4/40 pts had a response of ≥PR (1 stringent CR, 1 CR and 2VGPR) without achieving an EMD response, while 8/40 pts had discontinued treatment by cycle 4 and did not have a hematologic or EMD response. The combinations of hematologic and EMD responses for 28 pts with concurrent hematologic and EMD response are shown in Figure 1. As seen in Figure 2, pts with concurrent hematologic CR (hemCR) and CMR had the best outcomes in terms of PFS, while having only one type of response (hematologic or EMD) was associated with inferior outcomes compared to having a response in and outside of marrow (p&amp;lt;0.001 overall and in NDMM). Overall, the respective HRs (95% CI) were: no response vs both types: 20.5 (3.5-119.8), p&amp;lt;0.001; one type vs both types: 8.3 (1.2-58.2), p=0.034. The median (range) time to first concurrent hemCR and CMR was 6 months (3-15); for pts achieving only one type of response (hemCR or CMR) the median (range) time to first response was 5 months (1-11). Conclusions: After a median FU of 23 months of DaraVCD treatment, 33% of the pts have achieved both deep hematological responses with MRD(-) and CMR resulting in a median PFS of 20 months. However, having only one type of response (hemCR or CMR) is associated with an inferior outcome. These results, in terms of response, are comparable to those found in the LYRA study in which NDMM EMD pts are treated using a similar DaraVCD protocol. Even in this high-risk population of unmet need, long-term deep responses can be achieved with DaraVCD in and outside of marrow.

A Multicenter Phase 2 Trial Evaluating the Efficacy and Safety of Preoperative Lenvatinib Therapy for Patients with Advanced Hepatocellular Carcinoma (LENS-HCC Trial)

&lt;b&gt;&lt;i&gt;Introduction:&lt;/i&gt;&lt;/b&gt; The phase III REFLECT trial demonstrated that lenvatinib was superior to sorafenib in terms of progression-free survival (PFS), time to progression, and objective response rate (ORR) for patients with unresectable hepatocellular carcinoma (HCC). This study assessed the efficacy and safety of preoperative lenvatinib therapy for patients with oncologically or technically unresectable HCC. &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; In this multicenter single-arm phase II trial, patients with advanced HCC and factors suggestive of a poor prognosis (macroscopic vascular invasion, extrahepatic metastasis, or multinodular tumors) were enrolled. Patients with these factors, even with technically resectable HCC, were defined as oncologically unresectable because of the expected poor prognosis after surgery. After 8 weeks of lenvatinib therapy, the patients were assessed for resectability, and tumor resection was performed if the tumor was considered technically resectable. The primary endpoint was the surgical resection rate. The secondary endpoints were the macroscopic curative resection rate, overall survival (OS), ORR, PFS, and the change in the indocyanine green retention rate at 15 min as measured before and after lenvatinib therapy. The trial was registered with the Japan Registry of Clinical Trials (s031190057). &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; Between July 2019 and January 2021, 49 patients (42 oncologically unresectable patients and 7 technically unresectable patients) from 11 centers were enrolled. The ORR was 37.5% based on mRECIST and 12.5% based on RECIST version 1.1. Thirty-three patients underwent surgery (surgical resection rate: 67.3%) without perioperative mortality. The surgical resection rate was 76.2% for oncologically unresectable patients and 14.3% for technically unresectable patients. The 1-year OS rate and median PFS were 75.9% and 7.2 months, respectively, with a median follow-up period of 9.3 months. &lt;b&gt;&lt;i&gt;Conclusions:&lt;/i&gt;&lt;/b&gt; The relatively high surgical resection rate seen in this study suggests the safety and feasibility of lenvatinib therapy followed by surgical resection for patients with oncologically or technically unresectable HCC.

Low-Intensity and Chemo-Free Treatments in Ph+ ALL: Progression-Free Survival Based on Indirect Comparisons.

In Philadelphia chromosome-positive B-cell (Ph+) acute lymphoblastic leukemia (LLA), growing evidence has accumulated regarding the efficacy of low-intensity and chemo-free regimens. Our objective was to analyze all recent trials evaluating these treatments and to compare them in terms of efficacy. We applied the Shiny method, an artificial intelligence technique, to analyze Kaplan-Meier curves and reconstruct patient-level data. Reconstructed patient data were then evaluated through standard survival statistics and subjected to indirect head-to-head treatment comparisons. The endpoint was progression-free survival (PFS). Based on 432 reconstructed patients, eight trials were analyzed. The survival data from these trials were pooled into three types of treatments: (i) treatments based on tyrosine kinase inhibitors (TKIs) combined with reduced-intensity chemotherapy (denoted as TKICHE); (ii) TKIs associated with steroids with no chemotherapy (TKISTE); (iii) chemotherapy-free combinations of blinatumomab plus TKIs (TKIBLI). According to the Shiny method, the three PFS curves were reported in a single Kaplan-Meier graph and subjected to survival statistics. In terms of PFS, TKIBLI ranked first, TKICHE second, and TKISTE third; the differences between these three regimens were statistically significant. This multi-treatment Kaplan-Meier graph, generated through the Shiny method, summarized the current evidence on these treatments in both qualitative and quantitative terms.