Progression-free Survival Time Research Articles

The prognosis of patients with primary pulmonary mucosa-associated lymphoid tissue lymphoma: Treated with surgery or chemotherapy?

The goal of this project was to evaluate the effect of surgical treatment and the long-term survival of patients with staged IE/IIE pulmonary mucosa-associated lymphoid tissue (MALT) lymphoma. From January 2004 to December 2018, we retrospectively analysed 96 patients diagnosed with low-stage primary pulmonary MALT lymphoma according to the modified Ann Arbor staging system (IE/IIE). We compared the outcomes of different treatment modalities for staged IE/IIE MALT lymphoma. Progression-free survival (PFS) and overall survival were estimated using Kaplan-Meier curves, and the differences were compared using the log-rank test. The Cox proportional hazards model was used in this study. The median PFS time of low-staged MALT lymphomas was 118 months. The overall survival and PFS of the radical surgery group and the biopsy + chemotherapy group suggested no significant difference (P = 0.63, P = 0.65). Patients positive for Blc-2 and Ki-67 suffered from a compromised PFS (P = 0.023, P = 0.006). The Cox adjusted proportional hazards model analysis suggested that surgical procedures were not protective factors for patients with low-staged (IE/IIE) pulmonary MALT lymphoma, whereas being positive for Blc-2 and Ki-67 was a risk factor for patients with low-staged pulmonary MALT lymphoma (hazard ratio: 9.567; P = 0.044; hazard ratio: 6.042, P = 0.049). Our findings suggested that for staged IE/IIE pulmonary MALT lymphoma, radical surgical resection did not provide a survival benefit compared with chemotherapy after biopsy. Thus, radical surgery may be avoided unless biopsy is necessary for a diagnosis that requires sublobar resection. For those lesions that were Blc-2- or Ki-67-positive, compromised survival may be suggested.

The prognostic significance of programmed cell death protein 1 and its ligand on lymphoma cells and tumor-immune cells in diffuse large B-cell lymphoma, not otherwise specified.

Diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS) is the most common type non-Hodgkin's lymphoma, where the treatment of relapsed/refractory cases is the major challenge. Programmed cell death protein 1 (PD-1) and its ligand PD-L1 play a crucial role in the negative regulation of the immune response against the disease. The aim of the study was to analyze the expression of PD-1 and PD-L1 on lymphoma cells (LCs) and tumor-immune cells (TICs) and to investigate their correlation with outcome. Samples from 283 patients diagnosed with DLBCL, NOS (both germinal center B cell like [GCB] and non-GCB subtypes) were included in the study. Expression of PD-1 and PD-L1 was determined using double immunohistochemical staining (D-IHC) for PD-1/PAX5 and PD-L1/PAX5 on tissue microarrays. LCs were highlighted by D-IHC to obtain more accurate results. Clinical data and histologic diagnoses were obtained from electronic data records. We correlated clinical characteristics, and PD-1 and PD-L1 expression on LCs and TICs with progression-free survival (PFS) and overall survival (OS). Expression of PD-1 on TICs was observed in 38.4% and on LCs in 8.8% of cases, while PD-L1 was expressed on TICs in 46.8% and on LCs in 6.5% of cases. PD-L1 expression on LCs was more frequent in non-GCB subtype (p = 0.047). In addition, patients with PD-L1 expression on LCs had significantly shorter PFS (p = 0.015), and the expression retained significant in the multivariate model (p = 0.034). PD-L1 was more frequently expressed in LCs of the non-GCB subtype. Additionally, PD-L1 in LCs may predict shorter PFS time. D-IHC staining for PD-L1/PAX5 is a feasible method to assess PD-L1 expression on LCs of DLBCL, NOS patients and can be used to identify patients who may benefit from targeted immunotherapy with checkpoint inhibitors.

Prognostic significance of bone marrow fibrosis in diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphomas. The aim of this study is to determine the relationship between the increase in the degree of fibrosis in the bone marrow and prognosis and mortality in newly diagnosed DLBCL. Bone marrow biopsy of 153 newly diagnosed DLBCL patients was determined by staining with reticulin, Masson's trichrome histochemical stain, and the degree of fibrosis was determined. In the bone marrow biopsy performed at the time of diagnosis, bone marrow fibrosis (BMF) was observed in 70 patients. While BMF-1 was detected in 42 patients (60%), BMF-2 was detected in 25 patients (35%) and BMF-3 was detected in 3 patients (4%). As the degree of BMF increased, the median overall survival and median progression-free survival times were significantly shorter (p: 0.008), (p < 0.001). In patients with an increased degree of BMF, a significant decrease in leukocyte and neutrophil counts was observed after chemotherapy (p: 0.004). According to the results of the multivariate Cox regression model, it was determined that high NCCN-IPI risk (HR: 8.25; %95 CI: 1.09-62.52; p = 0.041) and being BMF ≥ 2 (HR: 3.75; %95 CI: 1.65-8.51; p = 0.002), increased the risk of death (p = 0.002, -2 loglikelihood = 392,553). When the literature was reviewed, it was seen that this study was the first to define that bone marrow fibrosis grade 2 and above in DLBCL is a prognostic marker associated with worse survival. In the bone marrow pathology, which is examined to detect advanced disease in DLBCL, besides lymphomatous involvement, the detection of fibrosis grade is very important.

Application of the Second Revision of the International Staging System (R2-ISS) in the prognostic assessment of newly diagnosed multiple myeloma

Objective: To investigate the prognostic value of the Second Revision of the International Staging System (R2-ISS) in patients with newly diagnosed multiple myeloma (NDMM) . Methods: The retrospective study was performed in 326 NDMM patients with immunomodulatory drugs and/or proteasome inhibitors as the first-line treatment attending the Department of Hematology, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, China, from December 2012 to March 2022. The Kaplan-Meier method was used for the survival analysis, with the Log-rank test comparing the between-group differences and Cox proportional risk regression modeling A multifactorial analysis was performed. Results: ①326 patients were included in the study, 190 of whom were males. The median age was 63 years, and the median followup time was 37 months. R2-ISS can effectively predict prognosis, particularly for R-ISS Ⅱ patients. The median progression-free survival (PFS) time of R2-ISS Ⅰ, R2-ISS Ⅱ, R2-ISS Ⅲ, and R2-ISS Ⅳ was 52, 29, 20, and 15 months (P<0.001), while the median overall survival (OS) time was 91, 60, 44, and 36 months (P<0.001). Multifactor analysis revealed that ISS Ⅱ, ISS Ⅲ, del (17p), t (4;14), 1q+, LDH increased, and age >65 years old were independent negative prognostic factors for OS. ISS Ⅱ, ISS Ⅲ, del (17p), t (4;14), 1q+, and LDH were independent negative prognostic factors for PFS. ②The C-index score of R2-ISS was 0.724, higher than that of R-ISS (0.678), indicating high prediction efficiency. ③The median PFS for 1q+-related double-hit in R2-ISS Ⅲ and Ⅳ were 20, 15 months (P=0.084) and the median OS were 35, 36 months (P=0.786), respectively. In R2-ISS Ⅲ, there were twenty-seven cases of 1q+-related double-hit, sixty-one cases of 1q+ single abnormality, and sixty-eight cases with no 1q+. The median PFS for the three groups were 20, 18, and 21 months (P=0.974), while the median OS was 35, 47, and 56 months (P=0.042), respectively. Adjusting the assignment of 1q+ to 1, the median PFS and OS of different R2-ISS stages differed significantly after regrouping (P<0.001) . Conclusions: The prognostic stratification value of R2-ISS is higher than R-ISS, particularly in the highly heterogeneous R-ISS Ⅱ population. Adjusting the assignment of the 1q+-related double-hit can improve R2-ISS, which should be validated in future studies with multi-center and expanded cases.

Impact of preoperative transcatheter arterial chemoembolization (TACE) on postoperative long-term survival in patients with nonsmall hepatocellular carcinoma: a propensity score matching analysis

BackgroundThe purpose of this propensity score matching (PSM) analysis was to compare the effects of preoperative transcatheter arterial chemoembolization (TACE) and non-TACE on the long-term survival of patients who undergo radical hepatectomy.MethodsPSM analysis was performed for 387 patients with hepatocellular carcinoma (HCC) (single > 3 cm or multiple) who underwent radical resection of HCC at our centre from January 2011 to June 2018. The patients were allocated to a preoperative TACE group (n = 77) and a non-TACE group (n = 310). The main outcome measures were progression-free survival (PFS) and overall survival (OS) since the treatment date.ResultsAfter PSM, 67 patients were included in each of the TACE and non-TACE groups. The median PFS times in the preoperative TACE and non-TACE groups were 24.0 and 11.3 months, respectively (p = 0.0117). The median OS times in the preoperative TACE and non-TACE groups were 41.5 and 29.0 months, respectively (p = 0.0114). Multivariate Cox proportional hazard regression analysis revealed that preoperative TACE (hazard ratio, 1.733; 95% CI, 1.168–2.570) and tumour thrombosis (hazard ratio, 0.323; 95% CI, 0.141–0.742) were independent risk factors significantly associated with OS.ConclusionsPreoperative TACE is related to improving PFS and OS after resection of HCC. Preoperative TACE and tumour thrombus volume were also found to be independent risk factors associated with OS.

Magnetic resonance and computed tomographic imaging characteristics and potential molecular mechanisms of feline meningioma associated calvarial hyperostosis.

Meningiomas are the most common feline primary brain tumours, and calvarial hyperostosis (CH) is frequently documented in association with this neoplastic entity. The clinical significance of and mechanisms driving the formation of CH in cats with meningiomas are poorly understood, although tumour invasion into the skull and tumour production of cytokines and enzymes have been implicated as causes of CH in humans. This retrospective study investigated relationships between signalment, MRI or CT imaging features, histopathologic tumour characteristics, alkaline phosphatase (ALP) isoenzyme concentrations, tumour expression of matrix metalloproteinases (MMP)-2, MMP-9, and interleukin-6 (IL-6), and progression free survival times (PFS) following surgical treatment in 27 cats with meningiomas with (n = 15) or without (n = 12) evidence of CH. No significant differences in breed, age, sex, body weight, tumour grade, tumour volume, peritumoral edema burden, ALP isoenzyme concentrations, tumour Ki-67 labelling indices or MMP-2 or MMP-9 expression and activity, or PFS were noted between cats with or without CH. There was a trend towards higher serum (p = .06) and intratumoral (p = .07) concentrations of IL-6 in cats with CH, but these comparisons were not statistically significant. Histologic evidence of tumour invasion into bone was observed in 5/12 (42%) with CH and in no (0/6) cats without CH, although this was not statistically significant (p = .07). Tumour invasion into bone and tumour production of IL-6 may contribute to the formation of meningioma associated CH in cats, although larger studies are required to further substantiate these findings and determine their clinical relevance.

Induction Chemotherapy Followed by Radiotherapy vs Chemoradiotherapy in Nasopharyngeal Carcinoma

Induction chemotherapy plus concurrent chemoradiotherapy is recommended for locoregionally advanced nasopharyngeal carcinoma but is associated with higher rates of acute toxic effects and low compliance. Evidence on de-escalating treatment intensity after induction chemotherapy is limited. To assess if radiotherapy was noninferior to chemoradiotherapy after induction chemotherapy for locoregionally advanced nasopharyngeal carcinoma. From April 2015 to March 2018, a multicenter, open-label, randomized, noninferiority, phase 3 trial was conducted at 5 Chinese hospitals. A total of 383 patients aged 18 to 70 years with an untreated histologically confirmed nonkeratinizing tumor, Karnofsky performance status score not worse than 70, proper organ function, and stage III to IVB nasopharyngeal cancer were enrolled. Data were analyzed from April 2023 to June 2023. Patients were assigned randomly. Both groups received 3 cycles of induction chemotherapy consisting of intravenous administration (on day 1) of cisplatin at 60 mg/m2 and docetaxel at 60 mg/m2 and continuous intravenous infusion (from day 1 to day 5) of daily fluorouracil (600 mg/m2), repeated every 21 days. Subsequently, the patients received radiotherapy alone (induction chemotherapy in combination with radiotherapy [IC-RT] group) or concomitant cisplatin (30 mg/m2/week) with radiotherapy for 6 to 7 weeks (induction chemotherapy combined with chemoradiotherapy [IC-CCRT] group). The primary end point was 3-year progression-free survival (time from the initiation of therapy until the first indication of disease progression or death), with a noninferiority margin of 10%. The secondary end points included overall survival, locoregional failure-free survival, distant metastasis-free survival, response rate, and toxic effects. A total of 383 patients (median [range] age, 48 [19-70] years; 100 women [26%]). Median follow-up time was 76 months (IQR, 70-89 months). The 3-year progression-free survival was 76.2% and 76.8% in the IC-RT (n = 193) and IC-CCRT groups (n = 190), respectively, in the intention-to-treat population, showing a difference of 0.6% (95% CI, -7.9% to 9.1%; P = .01 for noninferiority). Identical outcomes were reported in the per-protocol population. The incidence of grade 3 to 4 short-term toxic effects in the IC-RT group was less than the IC-CCRT group. No differences were observed in late toxic effects. The results of this randomized clinical trial suggest that after induction chemotherapy for locoregionally advanced nasopharyngeal carcinoma, radiotherapy alone was noninferior to chemoradiotherapy in terms of 3-year progression-free survival. ClinicalTrials.gov Identifier: NCT02434614.

Effects of combined sintilimab and chemotherapy on progression-free survival and overall survival in osteosarcoma patients with metastasis.

To explore the safety and efficacy of metastatic osteosarcoma treatment with combined sintilimab injection and chemotherapy. We performed a retrospective analysis of 32 patients with metastatic osteosarcoma admitted to the Affiliated Hospital of Beihua University between January 2019 and June 2020. The sample was divided into an observation group, treated with sintilimab injection combined with chemotherapy (n= 16) and a control group, treated with chemotherapy (n = 16). Clinical efficacy and adverse reactions were compared between the two groups. The overall response rates were 68.75% in the observation group and 31.25% in the control group (p < 0.05). The incidences of adverse reactions were 56.25% in the observation group and 81.25% in the control group. This was not a significant difference. In the observation group, the progression-free survival time was 8.13 ± 2.50 months, and the overall survival time was 22.75 ± 4.95 months. These were both significantly longer than the respective 6.44 ± 1.93 months and 19.69 ± 2.68 months in the control group (p < 0.05). The treatment of metastatic osteosarcoma with combined sintilimab injection and chemotherapy was found to prolong progression-free survival and overall survival time without increasing the incidence of adverse reactions.

Modified R-BAC plus BTK inhibitor regimen in newly diagnosed young patients with mantle cell lymphoma: a real-world retrospective study.

To explore the optimal treatment for young patients with untreated mantle cell lymphoma (MCL), we compared the efficacy and safety of R-CHOP/R-DHAP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone/rituximab, dexamethasone, cytarabine and cisplatin) and R-BAP (rituximab, bendamustine, cytarabine, and prednisone) plus BTK (Bruton's tyrosine kinase) inhibitors in newly diagnosed patients. Eighty-three young patients (≤ 65years old) with newly diagnosed MCL admitted to the First Affiliated Hospital of Zhengzhou University from January 1, 2014, to June 1, 2023, using R-CHOP/R-DHAP or R-BAP plus BTK inhibitor were assessed in this study. The median age at presentation was 60 (42-65) years in 83 patients, including 64 males and 19 females; 59 were treated with R-CHOP/R-DHAP regimen chemotherapy, and 24 were treated with R-BAP in combination with the BTK inhibitor regimen. The median follow-up was 17months (2-86months) in 83 patients, and the median PFS (progression-free survival) time was not reached. The CRR (complete response rate) of the R-BAP group was higher than that of the R-CHOP/R-DHAP group (87.5% vs. 54.2%, P = 0.005). The ORR (overall response rate) was not significantly different between the two groups (ORR: 91.7% vs. 84.7%, P = 0.497). The PFS (progression-free survival) of the R-BAP group was longer than that of the R-CHOP/R-DHAP group (P = 0.013), whereas OS was not significantly different between the two groups (P = 0.499). The most common adverse effect in both groups was hematotoxicity, with a higher incidence of grade 3-4 lymphopenia and grade 3-4 thrombocytopenia in the R-BAP group than in the R-CHOP/R-DHAP group (P = 0.015 and P = 0.039). Male sex (HR = 4.257, P = 0.013), LDH (lactate dehydrogenase) ≥ 245 U/L (HR = 3.221, P = 0.012), pleomorphic-blastoid (HR = 2.802, P = 0.043) and R-CHOP/R-DHAP regimen (HR = 7.704, P = 0.047) were independent risk factors for PFS. Ki67 ≥ 30% (HR = 8.539, P = 0.005) was an independent risk factor for OS. First-line treatment with R-BAP in combination with BTK inhibitor improved CRR and prolonged PFS in young patients with mantle cell lymphoma and adverse events were tolerable.

A nationwide analysis of the treatment patterns, survival, and medical costs in Korean patients with relapsed or refractory diffuse large B-cell lymphoma.

Approximately one-third of patients with diffuse large B-cell lymphoma (DLBCL) are refractory to treatment or experience relapse after initial therapy. Unfortunately, treatment options for older patients and those who experience relapse or become refractory to hematopoietic stem cell transplantation (HSCT) are limited. This nationwide population-based study aimed to identify treatment patterns, survival times, and treatment costs in patients with relapsed/refractory DLBCL (R/R DLBCL). Between 2011 and 2020, data on patients with R/R DLBCL were retrieved from the Korean Health Insurance Review & Assessment Service, encompassing the entire population. We identified the treatment patterns for each treatment line using a Sankey diagram and calculated the median time to the subsequent treatment in line. Median overall and progression-free survival times were estimated using the Kaplan-Meier survival curves. Finally, the medical costs incurred during DLBCL treatment were calculated for each treatment line and the costs related to HSCT were summarized at the episode level. A total of 864 patients with R/R DLBCL who received second-line treatment were identified, and a regimen of ifosfamide, carboplatin, and etoposide (ICE) was administered the most. Among them, 353 were refractory or relapsed cases that were treated with third-line treatments. The median times for second-line to third-line, third-line to fourth-line, fourth-line to fifth-line, and fifth-line to sixth-line treatment failures gradually decreased (3.93, 2.86, 1.81, and 1.38 months, respectively). The median overall survival time was 8.90 and 4.73 months following the second-line and third-line treatments, respectively. In the third-line treatment setting, the patients did not show a significant difference in survival time after HSCT. The median medical cost was $39,491 across all treatment lines including the cost of HSCT which was $22,054. The treatment patterns in patients with R/R DLBCL, especially at third-line treatments and thereafter, were complicated, and their prognosis was poor despite the high medical costs. Novel and effective treatment options are expected to improve the prognosis and alleviate the economic burden of patients with R/R DLBCL.

Hepatic arterial infusion chemotherapy combined with bevacizumab plus a PD-1 inhibitor for gallbladder cancer with hepatic oligometastasis: a real-world study.

Gallbladder cancer (GBC) is different from other biliary tract cancers in terms of molecular phenotype and microenvironment. Specific treatments for GBC need to be urgently explored. This study preliminarily investigated the clinical value of hepatic artery infusion chemotherapy (HAIC) combined with bevacizumab plus a programmed death receptor-1 (PD-1) inhibitor for treatment of GBC with hepatic oligometastasis. We retrospectively collected data on GBC patients with hepatic oligometastasis, who received this combination therapy. The clinical data, conversion rate, treatment response, adverse events (AEs), and short-term survival were summarized. The responses of primary gallbladder lesions and hepatic metastasis, and their effect on prognosis, were investigated. A total of 27 patients were included in the analysis. No grade 4 AEs were observed. The overall objective response rate (ORR) was 55.6% and the disease control rate (DCR) was 85.2%. Median overall survival (OS) time was 15.0 months and the 1-year survival rate was 64.0%. Median progression-free survival (PFS) time was 7.0 months and the 1-year PFS rate was 16.2%. Six patients (22.2%) were successfully converted to resection. Compared with primary gallbladder lesions, it appeared more difficult for patients with hepatic metastasis to achieve remission (ORR: 40.7% vs. 77.8%; P=0.012), but its response appeared to be closely related to the prognosis [median OS: 16.0 months in the complete response (CR) or partial response (PR) group vs. 11.0 months in the stable disease (SD) or progressive disease (PD) group, P=0.070; median PFS: 12.0 months in the CR or PR group vs. 6.5 months in the SD or PD group, P<0.001]. Preoperative CA19-9 of >1,900 U/mL and >5 cm metastatic lesions were associated with an unsatisfactory response, whereas a significant decrease of 18F-fluorodeoxyglucose (18F-FDG) uptake may be a marker of tumor remission. The combination of HAIC, a PD-1 inhibitor, and bevacizumab shows potential for advanced GBC with hepatic oligometastasis. The therapeutic response of hepatic metastasis had a greater influence on prognosis than that of primary gallbladder lesions.

Prognostic value of artificial intelligence (AI) –driven tumor estimation of PSMA PET total tumor burden (TTB) in newly diagnosed high-volume metastatic hormone-sensitive prostate cancer (mHSPC).

47 Background: Prostate cancer represents a significant economic burden for health systems; the identification of risk factors that allows the identification of subgroups of patients that require closer follow-up or more intense therapeutic regimens has a direct impact on the prognosis and expenses for the patient, there is currently great interest in patients with high-volume mHSPC, this group is defined according to the number of lesions and their location, this could represent a challenge in decision making due to the variety of presentations regarding tumor burden, currently with the development of AI algorithms it is possible to estimate the PSMA TTB by identifying patients who are candidates for specific therapies without exposing them to comorbidities associated to aggressive regimens. Methods: Baseline PSMA PET scans of patients with histopathological corroborated diagnosis of prostate cancer and considered as high volume according to 68Ga PSMA PET/CT imaging in the period from October 2017 to June 2020 were retrospectively analyzed using an automated algorithm to estimate PSMA TTB, the median follow-up was of 44 +/- 9.7 months. These patients were divided into two groups according to the optimal cutoff values of PSMA TTB and estimate progression-free survival after initial therapy with Kaplan-Meier curves and correlation index between tumor burden and prostatic specific antigen. Results: 53 patients with a mean age of 71 years (+/- 5.1) were included, 17 with Gleason 7 (4+3/3+4), 18; G8 (4+4), 15; G9 (5+4/4+5) and 3; G10 (5+5), ISUP group 3 (n=17), group 4 (n=18) group 5 (n=18), the mean PSA value at diagnosis was 62.1 ng/dL (range 25.2- 201.5). PSMA TTB mean was 100.1cm3 (range 21cm3- 518.8 cm3). Log-rank test revealed that PSMA TTB lower than 45 cm3 (n=21) presented higher time of progression-free survival in comparison with patients with PSMA TTB higher than 45 cm3 (n=32) (31.1 mo vs 47.8 mo, p &lt;0.003). TTB and PSA demonstrated a significant correlation (Pearson r= 0.526, p&lt; 0.0001). There was no difference between groups of low and high PSMA TTB and ISUP groups or Gleason score. Sites of visceral disease were lung (n=11), (pleura=9) liver (n=9), adrenal, (n=5) brain, (n=2), and sites of extra spinal and pelvic disease were ribs (n=24) femur (n=16), skull (n=8), scapula (n=7), humerus (n=7). All patients had one or more lesions at previously described sites. Conclusions: PSMA TTB has great value in predicting progression-free survival of patients with newly diagnosed high-volume metastatic hormone-sensitive prostate cancer and has a strong correlation with PSA, strengthening the role of next-generation molecular imaging with PSMA PET as an invaluable tool in initial diagnosis and potentially in follow-up by providing information on the biological behavior of the disease in a systemic way.

Circulating tumor cells reveal early predictors of disease progression in patients with stage III NSCLC undergoing chemoradiation and immunotherapy

Circulating tumor cells (CTCs) are early signs of metastasis and can be used to monitor disease progression well before radiological detection by imaging. Using an ultrasensitive graphene oxide microfluidic chip nanotechnology built with graphene oxide sheets, we were able to demonstrate that CTCs can be specifically isolated and molecularly characterized to predict future progression in patients with stage III non-small cell lungcancer (NSCLC). We analyzed CTCs from 26 patients at six time points throughout the treatment course of chemoradiation followed by immune checkpoint inhibitor immunotherapy. We observed that CTCs decreased significantly during treatment, where a larger decrease in CTCs predicted a significantly longer progression-free survival time. Durvalumab-treated patients who have future progression were observed to have sustained higher programmed death ligand 1+ CTCs compared to stable patients. Gene expression profiling revealed phenotypically aggressive CTCs during chemoradiation. By using emerging innovative bioengineering approaches, we successfully show that CTCs are potential biomarkers to monitor and predict patient outcomes in patients with stage III NSCLC.

A randomised phase II trial of temozolomide with or without cannabinoids in patients with recurrent glioblastoma (ARISTOCRAT): protocol for a multi-centre, double-blind, placebo-controlled trial

BackgroundGlioblastoma (GBM) is the most common adult malignant brain tumour, with an incidence of 5 per 100,000 per year in England. Patients with tumours showing O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation represent around 40% of newly diagnosed GBM. Relapse/tumour recurrence is inevitable. There is no agreed standard treatment for patients with GBM, therefore, it is aimed at delaying further tumour progression and maintaining health-related quality of life (HRQoL). Limited clinical trial data exist using cannabinoids in combination with temozolomide (TMZ) in this setting, but early phase data demonstrate prolonged overall survival compared to TMZ alone, with few additional side effects. Jazz Pharmaceuticals (previously GW Pharma Ltd.) have developed nabiximols (trade name Sativex®), an oromucosal spray containing a blend of cannabis plant extracts, that we aim to assess for preliminary efficacy in patients with recurrent GBM.MethodsARISTOCRAT is a phase II, multi-centre, double-blind, placebo-controlled, randomised trial to assess cannabinoids in patients with recurrent MGMT methylated GBM who are suitable for treatment with TMZ. Patients who have relapsed ≥ 3 months after completion of initial first-line treatment will be randomised 2:1 to receive either nabiximols or placebo in combination with TMZ. The primary outcome is overall survival time defined as the time in whole days from the date of randomisation to the date of death from any cause. Secondary outcomes include overall survival at 12 months, progression-free survival time, HRQoL (using patient reported outcomes from QLQ-C30, QLQ-BN20 and EQ-5D-5L questionnaires), and adverse events.DiscussionPatients with recurrent MGMT promoter methylated GBM represent a relatively good prognosis sub-group of patients with GBM. However, their median survival remains poor and, therefore, more effective treatments are needed. The phase II design of this trial was chosen, rather than phase III, due to the lack of data currently available on cannabinoid efficacy in this setting. A randomised, double-blind, placebo-controlled trial will ensure an unbiased robust evaluation of the treatment and will allow potential expansion of recruitment into a phase III trial should the emerging phase II results warrant this development.Trial registrationISRCTN: 11460478. ClinicalTrials.Gov: NCT05629702.

Bombarding Oligoprogression: Oncologic Outcomes After Radiation to Patients With Oligoprogressive Non-Small Cell Lung Cancer on Maintenance Systemic Therapy.

This study aims to evaluate the efficacy and toxicity of radiotherapy (RT) to oligoprogressive metastatic non-small cell lung cancer (NSCLC). This is a retrospective analysis of 23 patients with metastatic NSCLC on maintenance systemic therapy, developed oligoprogression (1 to 5 sites), and all oligoprogressive sites amenable to and treated with RT. The primary endpoints included progression-free survival (PFS) and median time to start next-line therapy (MTT). Kaplan-Meier survival analysis and log-rank testing were performed using R-Studio software. Twenty-three patients met the inclusion criteria. The median overall survival for the entire cohort was 31.3 months (interquartile range [IQR]: 17.86 to 45.4). The median event-free survival for the entire cohort was 8.3 months (IQR: 2.7 to 12). Patients with no prior radiation had longer median event-free survival of 11.9 months (IQR: 8.4 to 18.2) compared with patients with a history of prior radiation at 4.1 months (IQR: 2.7 to 12; P = 0.041). The local control rate for the treated lesions was 97.5%. At 12 months follow-up, 6 (43%) of 14 living patients maintained systemic therapy without initiating next-line therapy. The median PFS for the entire cohort was 8.4 months (IQR: 4.1 to 17.5). Patients who did not receive prior radiation had longer median PFS of 11.9 months (IQR: 8.4 to 18.2) compared with patients who received prior radiation 6.2 months (IQR: 2.7 to 8.5; P = 0.018). Two patients (9%) had grade 3 chronic toxicity related to RT and were medically managed. We identified that in patients with oligoprogressive metastatic NSCLC, targeted RT to all progressive sites yielded high LC and favorable rates of PFS and MTT.

Bevacizumab, Irinotecan, or Topotecan Added to Temozolomide for Children With Relapsed and Refractory Neuroblastoma: Results of the ITCC-SIOPEN BEACON-Neuroblastoma Trial.

Outcomes for children with relapsed and refractory high-risk neuroblastoma (RR-HRNB) remain dismal. The BEACON Neuroblastoma trial (EudraCT 2012-000072-42) evaluated three backbone chemotherapy regimens and the addition of the antiangiogenic agent bevacizumab (B). Patients age 1-21 years with RR-HRNB with adequate organ function and performance status were randomly assigned in a 3 × 2 factorial design to temozolomide (T), irinotecan-temozolomide (IT), or topotecan-temozolomide (TTo) with or without B. The primary end point was best overall response (complete or partial) rate (ORR) during the first six courses, by RECIST or International Neuroblastoma Response Criteria for patients with measurable or evaluable disease, respectively. Safety, progression-free survival (PFS), and overall survival (OS) time were secondary end points. One hundred sixty patients with RR-HRNB were included. For B random assignment (n = 160), the ORR was 26% (95% CI, 17 to 37) with B and 18% (95% CI, 10 to 28) without B (risk ratio [RR], 1.52 [95% CI, 0.83 to 2.77]; P = .17). Adjusted hazard ratio for PFS and OS were 0.89 (95% CI, 0.63 to 1.27) and 1.01 (95% CI, 0.70 to 1.45), respectively. For irinotecan ([I]; n = 121) and topotecan (n = 60) random assignments, RRs for ORR were 0.94 and 1.22, respectively. A potential interaction between I and B was identified. For patients in the bevacizumab-irinotecan-temozolomide (BIT) arm, the ORR was 23% (95% CI, 10 to 42), and the 1-year PFS estimate was 0.67 (95% CI, 0.47 to 0.80). The addition of B met protocol-defined success criteria for ORR and appeared to improve PFS. Within this phase II trial, BIT showed signals of antitumor activity with acceptable tolerability. Future trials will confirm these results in the chemoimmunotherapy era.

Prognosis of immunotherapy for non-small cell lung cancer with CDKN2A loss of function.

Immunotherapy has been widely used to treat non-small cell lung cancer (NSCLC) but is only effective in 20% of patients. Cyclin-dependent kinase inhibitor 2A (CDKN2A) is an important tumor suppressor gene, and its loss of function (LOF) is quite common in NSCLC. Pre-clinical studies suggest CDKN2A LOF promotes immune evasion; however, the results in relation to NSCLC are controversial, and debate continues as to the effect of CDKN2A LOF on immunotherapy. In this study, we collected the data of 49 CDKN2A LOF and 173 CDKN2A wild-type NSCLC consecutive patients treated by any line of immunotherapy. Through immunohistochemical (IHC) and immunofluorescent (IF) staining, we analyzed the CDKN2A predominant transcription protein p16INK4A in the CDKN2A LOF and CDKN2A wild-type NSCLC patients. Using Kaplan-Meier curves, we also examined the relationship between CDKN2A LOF and immunotherapy. The IHC and IF staining results showed that most CDKN2A LOF patients were p16INK4A negative, while most CDKN2A wild-type patients were p16INK4A positive. In the LOF group, five patients had partial responses, 35 had stable disease, and nine had progressive disease after the first evaluation of immunotherapy. The LOF group had a median progression-free survival (PFS) time of 4.67 months, while the wild-type group had a median PFS time of 8.63 months [hazard ratio (HR): 0.54; 95% confidence interval (CI): 0.38-0.77; P<0.001]. The LOF group had a median overall survival (OS) time of 9.07 months, while the wild-type group had a median OS time of 21.37 months (HR: 0.42; 95% CI: 0.29-0.61; P<0.001). Our study revealed that CDKN2A LOF NSCLC patients treated with immune checkpoint inhibitor (ICI) mono-therapy or combined therapy had a worse prognosis than those with CDKN2A wild-type NSCLC. However, our study also suggested that ICI could work quite effectively in selective CDKN2A LOF patients.

Effect of metabolic syndrome on testosterone levels in patients with metastatic prostate cancer: a real-world retrospective study.

Metabolic syndrome (MetS) has been shown to have a negative impact on prostate cancer (PCa). However, there is limited research on the effects of MetS on testosterone levels in metastatic prostate cancer (mPCa). This study aims to investigate the influence of MetS, its individual components, and composite metabolic score on the prognosis of mPCa patients, as well as the impact on testosterone levels. Additionally, it seeks to identify MetS-related risk factors that could impact the time of decline in testosterone levels among mPCa patients. A total of 212 patients with mPCa were included in the study. The study included 94 patients in the Non-MetS group and 118 patients in the combined MetS group. To analyze the relationship between MetS and testosterone levels in patients with mPCa. Additionally, the study aimed to identify independent risk factors that affect the time for testosterone levels decline through multifactor logistic regression analysis. Survival curves were plotted by the Kaplan-Meier method. Compared to the Non-MetS group, the combined MetS group had a higher proportion of patients with high tumor burden, T stage ≥ 4, and Gleason score ≥ 8 points (P < 0.05). Patients in the combined MetS group also had higher lowest testosterone values and it took longer for their testosterone to reach the lowest level (P < 0.05). The median progression-free survival (PFS) time for patients in the Non-MetS group was 21 months, while for those in the combined MetS group it was 18 months (P = 0.001). Additionally, the median overall survival (OS) time for the Non-MetS group was 62 months, whereas for the combined MetS group it was 38 months (P < 0.001). The median PFS for patients with a composite metabolic score of 0-2 points was 21 months, 3 points was 18 months, and 4-5 points was 15 months (P = 0.002). The median OS was 62 months, 42 months, and 29 months respectively (P < 0.001). MetS was found to be an independent risk factor for testosterone levels falling to the lowest value for more than 6 months. The risk of testosterone levels falling to the lowest value for more than 6 months in patients with MetS was 2.157 times higher than that of patients with Non-MetS group (P = 0.031). Patients with hyperglycemia had a significantly higher lowest values of testosterone (P = 0.015). Additionally, patients with a BMI ≥ 25 kg/m2 exhibited lower initial testosterone levels (P = 0.007). Furthermore, patients with TG ≥ 1.7 mmol/L experienced a longer time for testosterone levels to drop to the nadir (P = 0.023). The lowest value of testosterone in the group with a composite metabolic score of 3 or 4-5 was higher than that in the 0-2 group, and the time required for testosterone levels to decrease to the lowest value was also longer (P < 0.05). When monitoring testosterone levels in mPCa patients, it is important to consider the impact of MetS and its components, and make timely adjustments to individualized treatment strategies.

Effect of Serum Interleukin-6 Concentration on the Prognosis After Radiotherapy for Patients With Hepatocellular Carcinoma.

Objective: The aim of this study was to explore the association between interleukin-6 (IL-6) concentration before radiotherapy (RT) and the prognosis after RT for patients with hepatocellular carcinoma (HCC). Methods: The clinical data for 101 patients with HCC who received RT from October 2016 to June 2021 were retrospectively analyzed. In these patients, the tumors were confined to the liver, and IL-6 concentration was measured before RT. The survival rate was calculated using the Kaplan-Meier method, and the Cox proportional hazards regression model was used to explore the independent factors affecting the patients' prognosis. X-tile software was used to obtain the optimal cut-off value of pre-RT IL-6 concentration (7.8 pg/mL) for overall survival (OS). Results: The 1-, 2-, and 3-year OS rates were 84.4%, 55.8%, and 34.7%, respectively, for patients with a pre-RT IL-6 concentration > 7.8 pg/mL versus 96.0%, 80.1%, and 80.1%, respectively, for those with a pre-RT IL-6 concentration ≤ 7.8 pg/mL. The OS rates of the two groups were significantly different (p < 0.001). The median progression-free survival (PFS) time was 7.5 months versus 15.1 months for patients with pre-RT IL-6 concentrations > 7.8 pg/mL and ≤ 7.8 pg/mL, respectively (p=0.001). Pre-RT IL-6 concentration was an independent prognostic factor of OS (hazard ratio [HR] = 3.421, 95% confidence interval [CI]: 1.477-7.927, p=0.004). Pre-RT IL-6 concentration (HR = 2.235, 95% CI: 1.176-4.246, p=0.014) and age (HR = 0.615, 95% CI: 0.383-0.987, p=0.044) were independent prognostic factors for PFS. Conclusions: The prognosis of HCC patients receiving RT was worse for those with a pre-RT serum IL-6 concentration > 7.8 pg/mL than those with a pre-RT serum IL-6 concentration ≤ 7.8 pg/mL. Pre-RT IL-6 concentrations may affect the prognosis of HCC patients.

Efficacy and safety of lenvatinib plus pembrolizumab in patients with advanced and recurrent endometrial cancer: a systematic review and meta-analysis.

Various trials have demonstrated the clinical benefits of lenvatinib plus pembrolizumab in patients with advanced or recurrent endometrial cancer, regardless of mismatch repair (MMR) status or histologic subtype. The majority of the previously published trials had small sample sizes. Here, we aimed to assess the reported efficacy and safety profile of lenvatinib plus pembrolizumab in patients with advanced and recurrent endometrial cancer. We utilized the Cochrane Library, PubMed, Web of Science and Embase databases to identify clinical trials evaluating the efficacy and safety of lenvatinib plus pembrolizumab in patients with advanced and recurrent endometrial cancer. The outcomes analyzed were progression-free survival (PFS), overall survival (OS), the objective response rate (ORR), the disease control rate (DCR) and the incidence of adverse events (AEs). Subgroup analysis was conducted on the basis of MMR status (deficient, dMMR or proficient, pMMR). Four trials (582 patients) were included. The pooled ORR was 32.7% [95% confidence interval (CI): 28.9-36.5]. Subgroup analysis revealed an ORR of 48.1% (95% CI: 26.1-70.2) for dMMR group and 33.1% (95% CI: 25.7-40.6) for pMMR group. The pooled DCR was 74.9% (95% CI: 71.3-78.4%). Subgroup analysis revealed a DCR of 81.0% (95% CI: 64.5-97.6) for the dMMR group and 76.3% (95% CI: 66.3-86.3) for the pMMR group. Follow-up was reported in all included studies. The median range time of PFS and OS was 5.3 months-258 days and 17.2 months-not reached, respectively. Regarding safety, the overall pooled proportions of any-grade AE and AEs ≥ grade 3 were 95.8% (95% CI: 89.5-100.0) and 80.2% (95% CI: 59.9-100.0), respectively. Lenvatinib plus pembrolizumab showed a relevant clinical benefit and significant toxicity in patients with advanced and recurrent endometrial cancer. Further studies encompassing long-term outcomes are warranted. https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=522160/, identifier CRD42024522160.