Median Overall Survival For Patients Research Articles

The choice of radiotherapy dose fractionation regimen for grade 4 gliomas depending on the status of MGMT

Objective. To investigate the effect of two fractionation regimes on subsequent survival in patients with grade 4 gliomas, depending on the status of MGMT. Material and methods. MGMT status was evaluated in 134 patients: IDH1 mutation was found in 18 patients (13.4%; G4 astrocytoma), while the rest were diagnosed as G4 glioblastoma (GBM) without IDH1 mutation (86.6%). A total of 66 patients were treated with the prescribed dose of 2 Gy, and 68 patients were treated with 3 Gy. Results. Fatal outcome was recorded in 105 (78.4%) patients. Median overall survival in patients with MGMT promoter methylation was 32.5 months (95% Cl: 23.9—41.1), in the absence of methylation — 18.8 months (95% Cl: 16.9—20.7; p=0.007). In gliomas of grade 4 malignancy with MGMT (+), the median overall survival was 59.24 months (95% Cl: 34.6—83.9) with 3 Gy fractionation regimen and 23.75 months (95% Cl: 13.2—34.3; p=0.006) with 2 Gy regimen. For GBM, the reliability between fractionation regimens was maintained (p=0.037). In the absence of MGMT(-) promoter methylation, no differences were noted between the two radiotherapy programs; median overall survival was 20.01 (95% Cl: 17.4—22.6) and 17.22 (95% Cl: 13.2—21.2) months, respectively, for the 3/2 Gy regimens (p=0.731). Conclusion. When the MGMT promoter is methylated, fractionation with a prescribed dose of 3 Gy has a significant advantage over the standard radiation therapy program for both grade 4 gliomas and GBM. In patients without MGMT promoter methylation, more stringent approaches with increasing single dose do not improve treatment outcomes.

Evolution of Survival in Patients with Multiple Myeloma over Two Decades: A Real-World Experience from a Medium-Level Hospital.

The gradual introduction of numerous therapeutic advancements over recent years in the treatment of patients with multiple myeloma (MM) appears to have contributed to significant improvements in overall survival (OS). We conducted a single-center retrospective observational study, including all MM patients treated at the University Hospital of Jerez de la Frontera, diagnosed between 1 January 2000, and 31 December 2022. Patients were divided into three calendar periods (2000-2007, 2008-2015, and 2016-2022) and two patient groups (candidates and non-candidates for autologous hematopoietic progenitor transplantation). A total of 420 myeloma patients were included in this study, with a median age of 64 years. The median survival steadily improved from 50.7 months (33.8-73.2; 95% CI) in 2000-2007 to 72.4 months (57.5-98.2; 95% CI) in 2008-2015 and has not yet been determined in the 2016-2022 cohort (p = 0.008). OS improved in all age groups, even in older patients. The median OS in patients not undergoing autologous stem cell transplantation (ASCT) was 38.8 months (31.5-51.6; 95% CI) compared with 132.66 months (110.5-150.9; 95% CI) in those who underwent this procedure (p < 0.0001). The introduction of novel drug classes in first-line treatment significantly improved OS compared with traditional chemotherapy (56.7 months). The median OS increased to 78.8 months (95% CI: 68.8-113.3; p = 0.03) with proteasome inhibitors (PIs), 99.4 months (95% CI: 99.4-NA; < 0.0001) with immunomodulatory drugs (IMIDs), and was not determined for anti-CD38 monoclonal antibodies (p = 0.02). Survival outcomes for MM have significantly improved over the past two decades, particularly among younger and ASCT-eligible patients. However, according to all studies, disparities persist across healthcare settings, underscoring the need for equitable access to modern therapies and optimized management strategies.

Characterizing the Natural History of Pediatric Brain Tumors Presenting with Metastasis

Background: The natural history of pediatric patients with metastasis of primary brain tumors within and outside the central nervous system is poorly understood, as too are possible clinical correlates with outcome. Correspondingly, the aim of this study was to interrogate a national database to characterize this diagnosis and its clinical course in pediatric patients. Methods: The U.S. National Cancer Database (NCDB) was interrogated between the years 2005–2016 for all patients aged 18 years and younger with a primary brain tumor diagnosis, as well as evidence of disease metastasis at initial diagnosis. Data were summarized and overall survival (OS) was modeled using Kaplan–Meier and Cox regression analyses. Results: Out of a total of 8615 pediatric brain tumor patients, 356 (4%) had evidence of metastasis at initial diagnosis. Compared to patients without metastasis, patients with metastasis were statistically younger, more often male, and less likely to have private health insurance (all p &lt; 0.050). With respect to clinical characteristics, the primary tumors of patients with metastasis were statistically more likely to be located in the cerebellum; be of higher histologic grading, with a higher proportion of medulloblastoma diagnoses and lower proportion of malignant glioma and pilocytic astrocytoma diagnoses; and were more likely to be treated by subtotal surgical resection, chemotherapy and radiation therapy (all p &lt; 0.050) when compared to patients without metastasis. Five-year OS for those with metastasis was significantly lower than those without (48% vs. 75%, p &lt; 0.001), with the median overall survival for patients with metastasis being 53 months (95% CI 29–86). Multivariate analysis indicated that a shorter OS was independently associated with the primary diagnoses of malignant glioma (HR 27.7, p = 0.020) and Atypical Teratoid/Rhabdoid Tumor (ATRT, HR 41.1, p = 0.041) and with WHO grades 3 (HR 20.1, p = 0.012) and 4 (HR 11.5, p &lt; 0.001). Longer OS was significantly and independently associated with surgery (HR 0.49, p &lt; 0.001), chemotherapy (HR 0.53, p = 0.041), and radiation therapy (HR 0.57, p = 0.026). Conclusions: Although uncommon, pediatric brain tumors with evidence of metastasis at initial diagnosis will present with a distinct socioeconomic and clinical profile compared to patients without metastasis. Multiple predictors are independently associated with overall prognosis, and understanding these features should be validated in prospective efforts to identify vulnerable patients earlier in order to maximize the impact of treatment.

Artemin promotes proliferation and invasion of malignant peripheral nerve sheath tumor cells through the PI3K/Akt pathway

Objective: To investigate the expression of Artemin (ARTN) in malignant peripheral nerve sheath tumor (MPNST), its effect on the malignant behavior of MPNST cells, and its signaling pathway. Methods: Fifty-one MPNST paraffin embedded tissues through surgical resection at Tianjin Medical University Cancer Hospital from January 1995 to November 2011 were collected, the expression of the ARTN protein was detected by immunohistochemistry, and the relationship between the ARTN protein expression and the clinical pathological characteristics and prognosis were analyzed. In human MPNST cell lines ST-8814 (NF-1) and STS26T(sporadic), ARTN overexpression and low expression cell lines were constructed by transfecting ARTN overexpression plasmids and ARTN small interfering RNA (siRNA), respectively. The expression of ARTN mRNA was detected by real time quantitative polymerase chain reaction (RT-qPCR), the expression of the ARTN protein and Phosphoinositide 3-kinase(PI3K)/Akt signaling pathway related proteins were detected by Western blot. CCK-8 assay was used to detect cell proliferation ability, and cell invasion assay was used to detect cell invasion ability. The pathway proteins that interacted with ARTN were searched in the STRING database, and the functional pathways were clarified by Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. The PI3K/Akt pathway specific inhibitor LY294002 was used to block the PI3K/Akt pathway of ST-8814 and STS26T cells to observe the changes in cell proliferation and invasion. Results: Among the 51 MPNST tissue specimens, 22 cases showed a high expression of the ARTN protein and 29 cases showed a low expression of the protein. Higher expressions of the ARTN protein was associated with larger tumor diameters and disease progression (recurrence or metastasis) (both P＜0.05). The median disease-free survival (DFS) of patients with a low expression of the ARTN protein was 26.2 months, and the median overall survival (OS) was 66.9 months. The median DFS and median OS of patients with a high expression of the ARTN protein were 10.7 months and 53.8 months, respectively. The log rank test results showed that the progression free survival rate of patients with a high expression of the ARTN protein was worse than that of patients with a low expression (P=0.027), but the difference in overall survival rate between the two groups was not statistically significant (P=0.790), which was also confirmed by Cox regression analysis. The CCK-8 assay results showed that after 48 hours of transfection, the absorbance (A) values of ST-8814 and STS26T cells in the ARTN overexpression group were 1.35±0.01 and 1.10±0.02, respectively, which were higher than those in the empty plasmid control group (1.05±0.01 and 0.78±0.01, both P＜0.01), while the A values of ST-8814 and STS26T cells in the ARTN siRNA group were 0.35±0.01 and 0.61±0.01, respectively, which were lower than those in the control siRNA group (0.74±0.01 and 1.10±0.04, both P＜0.01). The results of cell invasion assay showed that the number of transmembrane cells in ST-8814 and STS26T cells overexpressing ARTN was (29.67±2.08) and (31.67±2.08), respectively, which were higher than those in the empty plasmid control group [(20.00±1.00) and (24.33±1.15), both P＜0.01]. The number of transmembrane cells in ST-8814 and STS26T cells in the ARTN siRNA group were (14.00±2.00) and (19.33±1.53), respectively, which were lower than those in the control siRNA group [(19.33±2.52) and (23.33±0.58), both P＜0.05].The KEGG results showed that ARTN is associated with multiple tumor signaling pathways, especially the PI3K/Akt signaling pathway. Western blot results showed that overexpression of ARTN upregulated the expression of p-PI3K and p-Akt proteins in ST-8814 and STS26T cells (both P＜0.01).After knocking down ARTN expression, the expression of p-PI3K and p-Akt proteins was significantly down regulated (both P＜0.01). LY294002 could significantly inhibit the effect of ARTN overexpression on ST-8814 and STS26T cells after blocking the PI3K/Akt pathway. The A values of ST-8814 and STS26T cells in the ARTN overexpression+LY294002 group were 1.09±0.06 and 0.82±0.01, respectively, which were lower than those in the ARTN overexpression group (1.50±0.01 and 1.29±0.01, respectively, both P＜0.01). The numbers of transmembrane cells in the cell invasion assay were 16.67±3.21 and 19.67±2.31, respectively, which were also lower than those in the ARTN overexpression group (29.67±2.08 and 31.67±2.08, respectively, both P＜0.01). Conclusions: In MPNST, a high expression of the ARTN protein was associated with larger tumor size, disease progression, and worse DFS. ARTN promotes the proliferation and invasion of MPNST cells through the PI3K/Akt signaling pathway.

Valproic acid and celecoxib enhance the effect of temozolomide on glioblastoma cells

Objective. To evaluate the survival of patients with recurrent glioblastoma receiving valproic acid and to study its impact in combination with temozolomide and celecoxib on tumor cells. Materials and methods. A retrospective analysis was conducted on data from patients diagnosed with glioblastoma (ICD-10 – C71) who received valproic acid as part of their comprehensive treatment and were reoperated on with recurrent glioblastoma. Tumor cells of the C6, U87 and T98G lines were used for the experimental study. Glioblastoma modeling was performed using Wistar rats. The study was approved by the ethics committee. Results. The median overall survival of patients with glioblastoma receiving valproic acid accounted for 22 months, compared to 13 months for patients not receiving valproic acid. In in vitro experiments, the half-maximal inhibitory concentration (IC50) of temozolomide for various tumor cell lines ranged from 435.3 to 844 μM; the IC50 of valproic acid for U87MG, T98G, and C6 cell lines comprised 1510, 3900, and 3600 μM, respectively; the IC50 of celecoxib for these tumor cell lines amounted to 30.1, 41.07, and 48.4 μM, respectively. Valproic acid significantly enhanced the antiglioma effect of temozolomide on U87 cell lines; the highest sensitivity to the action of celecoxib in combination with temozolomide was observed in C6 and T98G cell lines. The combination of valproic acid with celecoxib enhanced the antiglioma action of temozolomide both in vitro and in vivo, which was accompanied by a reduction in tumor volume (p &lt; 0.05) and increased survival of experimental animals. Conclusion. The high antiglioma potential of the combination of valproic acid and celecoxib with temozolomide opens up prospects for optimizing existing treatment approaches for recurrent glioblastoma, thereby highlighting the need for further research. Valproic acid and celecoxib enhance the effects of temozolomide on glioblastoma cells.

New treatment options for generalized HER2-positive breast cancer in higher-line systemic palliative therapy.

HER2-positive breast cancer occurs in about 15-20 % of all breast cancers. It is both a prognostic and predictive biomarker and the introduction of anti-HER2 therapy over the last 20 years has significantly improved outcomes in this subset of patients, so that they are now comparable to or better than those of patients with HER2-negative tumors. Approximately 5-10% of patients are diagnosed with metastatic breast cancer. It was good news for these patients when, on April 17, 2020, the FDA approved tucatinib in combination with trastuzumab and capecitabine for adult patients with advanced unresectable or metastatic HER2-positive breast cancer who had received one or more prior anti-HER2-based regimens in the metastatic setting. The efficacy of the regimen was demonstrated in the HER2CLIMB trial, which enrolled 612 patients with HER2-positive metastatic breast cancer who had previously been treated with trastuzumab, pertuzumab, and/or trastuzumab emtansine. Median overall survival for patients in the tucatinib arm was 21.9 months (95% CI 18.3-31.0) compared with 17.4 months (95% CI 13.6-19.9) for patients in the control arm (HR 0.66; 95% CI 0.50-0.87; P = 0.00480). Our patient is a middle-aged woman without visceral metastatic involvement, but with extensive nodal involvement, skeletal metastatic involvement and left breast almost completely consumed by tumor. This woman had a more or less successful three lines of anti-HER2 therapy and the fourth line of one-year-long systemic treatment with the cytostatic eribulin. The inclusion of tucatinib with trastuzumab and capecitabine in the fifth line of systemic therapy achieved a very nice partial regression of the primary tumor without significant toxicity. In this case report, we describe the case of a highly pretreated patient with HER-2 positive metastatic breast cancer.

Outcomes with first-line ipilimumab and nivolumab for patients with metastatic renal cell carcinoma by number of doses.

540 Background: Ipilimumab (IPI) and nivolumab (NIVO) are standard first-line systemic therapy for patients with metastatic renal cell carcinoma (RCC). The regimen is administered in combination once every 3 weeks for 4 doses, followed by NIVO maintenance. The dose and frequency of IPI appears to correlate with treatment safety and tolerability across cancer types. Further, studies in advanced melanoma have demonstrated that the efficacy of IPI + NIVO is largely driven by the first two doses in many patients (Postow MA et al., J Clin. Oncol. 2022). We assessed outcomes with IPI + NIVO by number of doses given in patients with metastatic RCC. Methods: We conducted a retrospective study of patients with metastatic RCC at Memorial Sloan Kettering Cancer Center treated with first-line IPI + NIVO. Baseline characteristics and treatment outcomes were obtained from electronic health record review. We calculated overall survival (OS) by the Kaplan-Meier method starting at 12 weeks after initiation of combination therapy, including all patients who were still alive and being followed at that time point and excluding those who had disease progression prior to completing 4 doses. We compared survival rates at 12 and 18 months and median OS for patients who received 4 doses versus those who received fewer than 4 doses. Results: Patients with metastatic RCC treated with first-line IPI + NIVO were included (N=222); 77% were male, 85% had clear cell RCC, 48% had sarcomatoid and/or rhabdoid features, and 87% had IMDC intermediate or poor risk disease. Regarding IPI + NIVO, 145 patients (65%) received all 4 doses, 30 (14%) received 3 doses, 21 (9%) received 2 doses, and 26 (12%) received 1 dose. The most common reasons for not completing all 4 doses (77, 35%) were toxicity (57%) and disease progression (21%). All 145 patients who received 4 doses and 44 who received fewer than 4 doses for reasons other than early progression or death were included in the analysis. OS in the 4 dose and &lt;4 dose group at 18 months was 83% (95% CI: 76%, 89%) and 79% (95% CI: 63%, 88%), respectively. Conclusions: In this observational analysis, we found comparable OS rates in those patients who received all 4 doses of IPI + NIVO compared to those who received fewer than 4 doses for reasons other than disease progression, primarily toxicity. Four Doses of IPI + NIVO (N=145) Fewer Than Four Doses of IPI + NIVO, Excluding Early Disease Progression (N=44) 12-month OS (95% CI) 89% (82%, 93%) 86% (72%, 94%) 18-month OS (95% CI) 83% (76%, 89%) 79% (63%, 88%) Median OS, months (95% CI) 67.1 (40.1, NR) 82.5 (27.1, 109.3) Log-rank p value = 0.595

Development and regulatory approval of a new systemic targeted therapy for advanced hepatocellular carcinoma.

613 Background: There are no commercially available devices for the treatment of patients with advanced hepatocellular carcinoma who have failed 1st line and 2nd line therapy. We have identified tumor-specific modulation frequencies in patients with advanced hepatocellular carcinoma. We exposed patients to radiofrequency electromagnetic fields, which are amplitude-modulated from 0.1 Hz to 100 kHz and measured changes in pulse pressure. Frequencies eliciting measurable changes in pulse pressure were selected as tumor-specific frequencies. Methods: Treatment is administered to patients with advanced hepatocellular carcinoma by means of a battery-operated portable device emitting 27 MHz radiofrequency electromagnetic fields, which are amplitude-modulated at hepatocellular carcinoma frequencies. The device is connected to a coaxial cable ending with a spoon-shaped antenna placed on the anterior part of the patient's tongue during treatment. Treatment is administered three times a day for one hour. Results: A total of 69 patients with advanced hepatocellular carcinoma received treatment with the TheraBionic device until progression or death. The median overall survival of patients who received treatment with the TheraBionic device after failing 1st line and 2nd line therapy was 9.15 (95% CI 1.6-34.8) months and the median overall survival of Child-Pugh A patients was 9.5 months, which are comparatively longer than the 7.8 months pooled estimated medians of the placebo arms of 11 randomized 1st line and 2nd line placebo-controlled studies assessing the safety and efficacy of new agents for the treatment of Child-Pugh A advanced HCC (Llovet, Montal et al., J Hepatol 2019). We also analyzed the survival of patients who had received two lines of systemic therapy and did not receive any additional cancer treatment while and after receiving treatment with the TheraBionic device. The median OS of these patients was 9.8 months and the median OS of the Child-Pugh A patients was 17.2 months, which are comparatively longer than the 7.74 months pooled estimated medians of the placebo arms of the above cited 11 randomized studies. To assess unknown device-related adverse events, we assessed patient reported symptoms using the same scale in the SHARP and Asian Pacific Sorafenib studies. The incidence of any grade adverse events among Child-Pugh A who received treatment with the TheraBionic device was not different from the Placebo group of the SHARP and Asian Pacific Sorafenib studies. There were no NCI Grade 2, 3 or 4 toxicities. One patient developed grade 1 mucositis and one patient developed grade 1 fatigue. Conclusions: The data presented here provide reasonable assurance of safety and probable benefit in patients with advanced hepatocellular carcinoma who have failed 1st line and 2nd line therapy: https://www.fda.gov/medical-devices/recently-approved-devices/therabionic-p1-h220001 .

A Nomogram Based on Circulating Inflammatory Factors for Predicting Prognosis of Newly Diagnosed Multiple Myeloma Patients.

The growth and survival of multiple myeloma (MM) cells depend heavily on bone marrow microenvironment, where inflammation emerges as a significant feature and is commonly associated with unfavorable prognosis in MM. Our previous study and other published studies have shown that MM patients with higher neutrophil-to-lymphocyte ratio (NLR) or interleukin (IL)-10 (IL-10), lower lymphocyte-to-monocyte ratio (LMR) or platelet-to-lymphocyte ratio (PLR) frequently have inferior overall survival (OS) independent of current risk- stratification markers. Nevertheless, whether specific inflammation-related markers have prognostic value for MM patients remains elusive. We retrospectively analyzed the clinical data of 452 newly diagnosed MM (NDMM) patients treated in our center from May 2013 to June 2022. Cox regression analysis and least absolute shrinkage and selector operation (LASSO)were performed to establish the predictive nomograms for survival outcomes in the training cohort, and the nomograms were validated by calibration curves in the validation cohort. The best cutoff values of NLR, LMR, PLR, and IL-10 were 4.44, 4.0, 100, and 1.42pg/mL, respectively. We established a nomogram model after LASSO Cox and multivariate Cox regression analysis. The nomogram model exhibited acceptable discrimination, with C-index values of 0.777, 0.714, and 0.71 in the training cohort, validation cohort, and entire cohort, respectively, which was significantly higher than the C-indices of the three most extensively used staging systems for NDMM (D-S, ISS, and R-ISS). All calibration curves revealed good consistency between the predictive and actual survival outcomes.Patients were divided into high-risk and low-risk groups based on their total nomogram scores, with a threshold of 106.2, where the median OS of patients in the high-risk group was significantly shorter than that of patients in the low-risk group. The proposed nomogram based on circulating inflammatory factors is an inexpensive, widely available, and easily interpretable risk-stratification tool for NDMM patients.

Analysis of risk and prognostic factors for pulmonary metastasis in gastric cancer: a study based on the Surveillance, Epidemiology, and End Results database.

Pulmonary metastasis in patients with gastric cancer (GC) is closely associated with adverse clinical outcomes and reduced survival rates. This study aimed to investigate the incidence, risk factors, and prognostic factors of pulmonary metastasis in GC patients. A retrospective cohort study was conducted using data from the Surveillance, Epidemiology, and End Results (SEER) database (2010-2021), involving 48,474 GC patients, of whom 2,694 (5.56%) had pulmonary metastasis. Descriptive statistics, multivariable logistic regression, and Cox regression analyses were performed using R software, complemented by Kaplan-Meier survival curves and receiver operating characteristic curve construction. Logistic regression revealed that the risk of pulmonary metastasis was significantly higher in patients with squamous cell carcinoma than adenocarcinoma [adjusted odds ratio (aOR) 1.575, 95% confidence interval (CI): 1.152-2.120], while other pathological types showed a lower risk (aOR 0.269, 95% CI: 0.214-0.333). Stage T4 patients had a significantly higher risk than T1 (aOR 1.487, 95% CI: 1.130-1.954). Surgical intervention (aOR 0.198, 95% CI: 0.145-0.265) and clearance of four or more lymph nodes (aOR 0.489, 95% CI: 0.330-0.725) were associated with reduced pulmonary metastasis risks. Conversely, patients with liver, brain, and bone metastases exhibited significantly increased risks of pulmonary metastasis (aOR 3.888, 95% CI: 3.568-4.238; aOR 4.434, 95% CI: 3.480-5.631; and aOR 2.883, 95% CI: 2.568-3.234, respectively). Multivariate Cox regression analysis of overall survival (OS) and cancer-specific survival (CSS) demonstrated that patients with other epithelial tumors had significantly higher mortality risks [hazard ratio (HR) 1.194, 95% CI: 1.019-1.399; HR 1.191, 95% CI: 1.006-1.409]. Conversely, surgical treatment significantly reduced mortality risks (HR 0.632, 95% CI: 0.473-0.843; HR 0.659, 95% CI: 0.486-0.894), as did chemotherapy (HR 0.322, 95% CI: 0.295-0.351; HR 0.336, 95% CI: 0.307-0.369). Single patients (never married) exhibited higher mortality risks (HR 1.142, 95% CI: 1.020-1.278; HR 1.159, 95% CI: 1.030-1.305), as did patients with liver metastasis (HR 1.240, 95% CI: 1.144-1.344; HR 1.275, 95% CI: 1.171-1.388). Patients with primary lesions located in the lower stomach showed increased mortality risk (HR 1.289, 95% CI: 1.110-1.496; HR 1.203, 95% CI: 1.026-1.410), and those with bone metastases also increased OS mortality risk (HR 1.183, 95% CI: 1.071-1.307). The median OS for patients with pulmonary metastasis was 2 months, compared to 14 months for those without (P<0.001). Surgical treatment and chemotherapy significantly prolonged OS and CSS. Pulmonary metastasis in GC is associated with extremely poor survival rates. Comprehensive screening for high-risk patients, combined with detailed clinical and pathological evaluations, is essential to improve survival outcomes.

The Impact of Body Mass Index (BMI) on Clinical Outcomes for Patients Receiving Systemic Anti-Cancer Therapies for Advanced Clear Cell Renal Carcinoma.

IntroductionObesity is a risk factor for the development of renal cell carcinoma (RCC), however observational studies have suggested patients with RCC receiving systemic anti-cancer therapy (SACT) and BMI ≥25kg/m2 may have a better prognosis than patients with a normal or low BMI, a phenomenon often referred to as the obesity paradox.MethodsThe impact of BMI on survival outcomes in patients with advanced clear cell RCC receiving SACT within the National Health Service (NHS) in England between 2010 and 2018 was investigated. A retrospective analysis was performed using the SACT dataset from NHS-England.ResultsA total of 1034 patients were included. The majority of patients commenced treatment with oral SACT, pazopanib (53.3%) and sunitinib (43.7%). Median overall survival for patients with BMI ≤25kg/m2 was 12.6months (95% CI; 10.1-14.4) and 17.9months (15.4-20.0) for patients with BMI ≥25kg/m2 (P < .001). The association between BMI and improved survival was greatest in the first year of commencing SACT with the adjusted mortality rate of 68.9% for patients with BMI less than 25kg/m2 compared to 48.6% for patients with BMI greater than 25kg/m2 (rate ratio .77, .63 to .93).ConclusionA high BMI compared to a normal or low BMI was associated with improved survival in patients with metastatic RCC who were predominantly treated with oral SACT. Improved survival in obese patients with advanced RCC may be associated with improved response to systemic targeted therapies.

Comparative efficacy of TAS-102 and chemotherapy rechallenge in the third-line setting and beyond in patients with advanced colorectal cancer: A retrospective study.

78 Background: The optimal approach to third line therapy for patients with metastatic colorectal cancer remains a subject of debate. Options include Trifluridine/Tipiracil (TAS-102), TAS-102 with bevacizumab, regorafenib, chemotherapy rechallenge with or without an anti-EGFR agent, or fruquintinib. This study aims to evaluate the efficacy of standard of care TAS-102, TAS-102 with bevacizumab, or regorafenib versus chemotherapy rechallenge in patients with metastatic colorectal cancer in the third line setting and beyond. Methods: We conducted a retrospective analysis of patients with metastatic colorectal cancer who received either TAS-102 with or without bevacizumab, regorafenib or chemotherapy rechallenge with or without an anti-EGFR agent between 2018 and 2023, at the Ministry of National Guard for Health Affairs in Riyadh, Saudi Arabia. Patients received such agents in the third line setting and beyond. Results: A total of 75 patients were included in this study, with 39 patients receiving TAS-102 with or without bevacizumab, or regorafenib, and 36 receiving chemotherapy rechallenge. The median patient age was 58 years (range 28-81), with the majority being males at 55%. Among the chemotherapy rechallenge group, 31% were treated with cetuximab and 6% had panitumumab rechallenge, some of which were guided by cell free DNA liquid biopsy testing. In the other group, 66% received regorafenib, 26% TAS-102 alone, and 8% TAS-102 with bevacizumab. At the time of analysis, 56% of patients had passed away. Median overall survival for patients who received TAS-102 with our without bevacizumab, and regorafenib in the third line setting was found to be 13.1 months. Whereas for patients who received chemotherapy rechallenge, their median overall survival was 19.5 months. Conclusions: Patients with metastatic colorectal cancer who received chemotherapy rechallenge in the third line setting survived longer compared with patients who received TAS-102 with or without bevacizumab, or regorafenib.

Regorafenib combined with immunotherapy and prognosis of unresectable hepatocellular carcinoma.

541 Background: To investigate the prognosis and influencing factors of patients with unresectable hepatocellular carcinoma (uHCC) receiving regorafenib in different treatment modes. Methods: A total of 227 patients with uHCC who received at least 2 cycles of regorafenib treatment in the Affiliated Hospital of Qingdao University between June 2018 and August 2022 were retrospectively collected through the Hospital Information System (HIS). 204 patients were finally enrolled by inclusion and exclusion criteria after screening. Results: The median follow-up was 25.9 (4.5-69.7) months. The median overall survival (OS) of 204 patients with uHCC was 27.7 (95%CI 21.98-33.42) months. The 1, 2, 3 and 5-year OS were 80.9%, 55.9%, 41.4% and 26.7%, respectively. Univariate analysis showed that combination with immune checkpoint inhibitor (ICI) and metabolic-associated complications were independent factors for survival benefit of regorafenib, while the Eastern Cooperative Oncology Group Performance Status (ECOG‐PS) scale = 2, undecreased Alpha-fetoprotein (AFP), macrovascular invasion and extrahepatic metastasis were independent risk factors for poor prognosis (P&lt;0.05). Compared with 60 patients receiving regorafenib alone, 144 patients receiving regorafenib combined with ICI had a significant survival benefit (median OS, 16.9 vs. 31.5 months, respectively, P=0.006). The median OS of 153 patients receiving second-line therapy with regorafenib was 30.3 months. Among 51 patients receiving third or more lines of therapy with regorafenib, compared with 4 patients receiving regorafenib alone, 47 patients receiving regorafenib combined with ICI had a significant survival benefit (median OS, 9.4 vs. 24.1 months, respectively, P=0.000). Among 148 patients receiving local treatment, the median OS of patients with regorafenib combined with ICI (n=115) or without ICI (n=33) was 33.2 and 16.5 months, respectively (P=0.005). Conclusions: Regorafenib has a good prognosis in second-line treatment of uHCC. The OS of patients with regorafenib combined with ICI were significantly better than that of patients without ICI. The OS benefit of regorafenib combined with ICI was also equivalent in patients with third or more lines. The benefit of regorafenib combined with ICI was better for patients receiving local treatment.

Effect of SMARCA4 mutations on the outcomes of patients with advanced EGFR mutant lung adenocarcinoma

Objective: To investigate the impact of SMARCA4 mutations on the outcomes of patients with advanced lung adenocarcinoma with epidermal growth factor receptor (EGFR) mutations. Methods: In the Memorial Sloan Kettering Cancer Center (MSK) MetTropism study, 960 patients with advanced EGFR-mutated lung adenocarcinoma were screened and included in the MSK cohort, composing of 313 males and 647 females, with a median [M(Q1, Q3)] age of 64 (56, 72) years. A retrospective analysis was conducted on the data of 178 patients with advanced EGFR-mutated lung adenocarcinoma who received EGFR tyrosine kinase inhibitors (TKIs) treatment in the Department of Oncology, the First Affiliated Hospital of Nanjing Medical University, from January 2018 to December 2022. Among these patients, 69 were males and 109 were females, with a median age of 63 (54, 69) years. The follow-up of patients from the First Affiliated Hospital of Nanjing Medical University was conducted up to December 31, 2023, with a median follow-up time of 26.6 (95%CI: 24.6-28.6) months for the entire cohort, and 29 patients were lost to follow-up. Survival curves were plotted using the Kaplan-Meier method, and the log-rank test was used to compare the relationship between SMARCA4 gene alternations and prognosis. Results: In the 960 patients of the MSK cohort with advanced EGFR-mutated lung adenocarcinoma, the SMARCA4 gene alternations rate was 4.2% (40/960). The median overall survival (OS) for patients without SMARCA4 gene alternations was 41.5 (95%CI: 35.6-47.3) months, which was superior to that of patients with SMARCA4 gene alternations [15.6 (95%CI: 7.9-23.4) months, P<0.001]. Patients with SMARCA4 gene alternations had a higher risk of mortality, with an HR (95%CI) of 1.97 (1.35 to 2.88). Among the 178 patients with advanced EGFR-mutated lung adenocarcinoma from the First Affiliated Hospital of Nanjing Medical University, the SMARCA4 gene alternations rate was 4.5% (8/178). The median progression-free survival (PFS) for patients without SMARCA4 gene alternations was 16.1 (95%CI: 12.2-20.0) months, which was superior to the median PFS of patients with SMARCA4 gene alternations [6.0 (95%CI: 1.3-10.7) months, P<0.001]. The median OS for patients without SMARCA4 gene alternations was 50.1 (95%CI: 28.1-72.1) months, which was also superior to the median OS of patients with SMARCA4 gene alternations [17.6 (95%CI: 15.4-19.8) months, P=0.001]. Conclusion: SMARCA4 alternation is an important factor associated with poor prognosis in patients with advanced EGFR-mutant lung adenocarcinoma.

Surgery lengthens survival for collecting duct carcinoma: analysis of hospital-based cancer registry data in Japan

BackgroundTo identify the prognosis of Japanese patients with collecting duct carcinoma (CDC).MethodsWe used a hospital-based cancer registry data in Japan to extract CDC cases that were diagnosed in 2013, histologically confirmed, and determined the first course of treatment. We further investigated treatment modalities and estimated overall survival (OS) by the Kaplan–Meier method.ResultsA total of 61 CDC patients were identified. The 5-year OS rate for all CDC patients who were diagnosed in Japan during 2013 was 23.6% (95% CI: 15.0–37.4), with a median OS of 14 months (95% CI: 12–24). The 5-year OS rate for CDC patients at stages I, III, and IV were 53.0% (95% CI: 29.9–94.0), 35.7% (95% CI: 19.8–64.4), and 3.4% (95% CI: 0.5–23.7), respectively. Noteworthy, the 1-year OS for stage IV patients was 27.6% (95% CI: 0.5–23.7) and the median OS was only 5 months (95% CI: 4–12). We further examined the OS for advanced disease according to treatment modalities. The median OS of patients who undertook chemotherapy alone was significantly shorter than patients who undertook surgery alone for advanced disease (4 months [95% CI: 4-NA] vs. 15 months [95% CI: 13–68]; p < 0.001) and surgery-only patients had a similar median OS as surgery-plus-chemotherapy patients (19 months [95% CI: 13-NA]; p < 0.001). Moreover, a multivariable analysis for the OS in advanced disease revealed that surgery-plus-chemotherapy patients had significantly more favorable prognoses (HR 0.21, 95% CI: 0.07–0.57).ConclusionsJapanese CDC patients face poor prognoses similar to Western countries, especially in advanced cases that receive only chemotherapy. Surgery appears necessary for advanced disease.

Efficacy and safety of first-line nivolumab plus ipilimumab treatment in elderly patients (aged ≥ 75 years) with non-small cell lung cancer

PurposeNivolumab plus ipilimumab (Nivo-Ipi) combination therapy is an effective first-line treatment for advanced non-small cell lung cancer (NSCLC). However, its effectiveness and feasibility in elderly patients (aged ≥ 75 years) remain unclear. This study aimed to investigate the efficacy and safety of first-line Nivo-Ipi therapy in elderly patients with NSCLC.MethodsThis retrospective study included 57 patients with NSCLC (52 men and 5 women), aged ≥ 75 years (range: 75–86) who received first-line Nivo-Ipi therapy from December 2020 to November 2022 at four institutes in Japan. Patient characteristics, therapeutic efficacy, and the incidence and severity of adverse events (AE) were assessed.ResultsThe overall response rate was 42.1%, the disease control rate was 73.6%, the median progression-free survival (PFS) was 7.1 months, and the median overall survival (OS) was 14.1 months. Common Grade ≥ 3 AEs included pneumonitis, elevated aspartate transaminase, elevated alanine transaminase, adrenal insufficiency, and colitis. No treatment-related deaths were reported. PFS and OS were longer in patients who experienced treatment-related AEs. Patients with and without AEs had a median PFS of 11.7 and 2.8 months, respectively. Similarly, the median OS of patients with and without AEs was 20.4 and 9.0 months, respectively.ConclusionFirst-line Nivo-Ipi therapy is effective in elderly patients with NSCLC. Although there was an increased incidence of pneumonitis, the treatment was manageable and presented as a viable treatment option. Notably, the occurrence of treatment-related AEs was associated with improved clinical outcomes, suggesting a potential prognostic value of AEs in this population.

First-line cadonilimab plus chemotherapy in HER2-negative advanced gastric or gastroesophageal junction adenocarcinoma: a randomized, double-blind, phase 3 trial.

Programmed cell death protein-1 (PD-1) inhibitors plus chemotherapy have been the standard of care in the first-line treatment of advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma; however, the survival benefits are modest in patients with low programmed death ligand 1 (PD-L1) expression. Here we investigated the efficacy and safety of cadonilimab (PD-1/cytotoxic T lymphocyte antigen-4 (CTLA-4) bispecific antibody) plus chemotherapy as first-line treatment in G/GEJ adenocarcinoma. The prespecified interim analysis is reported here. This was a randomized, double-blind, placebo-controlled phase 3 study. Eligible patients were adults with untreated, unresectable, locally advanced or metastatic G/GEJ adenocarcinoma. Patients were randomized 1:1 to receive cadonilimab (10 mg kg-1 every 3 weeks) or placebo plus chemotherapy (every 3 weeks). The primary endpoint was overall survival (OS) in the intention-to-treat population (one-sided significance level, P = 0.025). Secondary endpoints included OS in patients with a PD-L1 combined positive score ≥5, progression-free survival, objective response rate, duration of response and safety. As of 18 August 2023, 610 patients from 75 study centers were randomized to cadonilimab (n = 305) or placebo (n = 305). With a median follow-up of 18.7 months, the cadonilimab group had a significantly longer median OS (14.1 versus 11.1 months; hazard ratio (HR) 0.66; 95% confidence interval (CI) 0.54-0.81; P < 0.001) than the placebo group. The primary endpoint was met. The median progression-free survival was 7.0 months versus 5.3 months (HR 0.53, 95% CI 0.44-0.65). The median OS in patients with a PD-L1 combined positive score ≥5 was 15.3 months versus 10.9 months (HR 0.58, 95% CI 0.41-0.82). The objective response rate was 65.2% versus 48.9% with a median duration of response of 8.8 months versus 4.4 months. Grade ≥3 treatment-related adverse events occurred in 65.9% of the cadonilimab group and 53.6% of the placebo group, and the most common were decreased platelet count, decreased neutrophil count and anemia. Most of the immune-related adverse events were grade 1 or 2. No new safety signals were observed. Cadonilimab plus chemotherapy significantly improved OS with a manageable safety profile in patients with advanced G/GEJ adenocarcinoma. ClinicalTrials.gov registration: NCT05008783 .

Primary Effusion Lymphoma Prognostic Score (PEL-PS): A Validated International Prognostic Score in HIV-Associated Primary Effusion Lymphoma.

Primary effusion lymphoma (PEL) is an HIV-associated B-cell non-Hodgkin lymphoma (NHL) caused by Kaposi sarcoma herpesvirus (KSHV). There is no validated prognostic model in PEL, and prognosis is thought to be poor compared to other HIV-associated NHL. We derived the PEL-Prognostic score (PEL-PS) from an international real-world training set of 59 patients with HIV-associated PEL who received first-line anthracycline-containing chemotherapy from the HIV and AIDS Malignancy Branch at the National Cancer Institute (NCI) in the United States and the National Center for HIV Malignancy at the Chelsea and Westminster Hospital (CWH) in England from 2000 to 2022. We identified prognostic factors associated with overall survival (OS). In a multivariable Cox model, ECOG ≥ 3 (p = 0.007; hazard ratio [HR] = 4.0 [95% CI: 1.5-11.1]) and hemoglobin < 8 g/dL (p = 0.006; HR = 3.8 [95% CI: 1.5-9.7]) were jointly associated with lower survival probability. The resulting PEL-PS separated patients with no negative prognostic factors (score 0: hemoglobin ≥ 8 g/dL and ECOG ≤ 2, 48.1% of patients) with median OS of 10.6 years versus patients with 1-2 negative prognostic factors (score 1-2: hemoglobin < 8 g/dL and/or ECOG ≥ 3, 51.9% of patients) with median OS of 0.8 years (p < 0.0001). The PEL-PS was then validated in 58 patients with HIV-associated PEL treated with first-line anthracycline-containing chemotherapy at Hôpital Saint-Louis in France over the same period: median OS in patients with PEL-PS 0 was 16.9 years versus 0.6 years in patients with PEL-PS score of 1-2 (p < 0.0001). The PEL-PS identifies patients with good and poor prognosis. Patients with poor prognosis may benefit from novel therapies.

Fedratinib combined with ropeginterferon alfa-2b in patients with myelofibrosis (FEDORA): study protocol for a multicentre, open-label, Bayesian phase II trial

BackgroundMyelofibrosis (MF) is a clonal haematopoietic disease, with median overall survival for patients with primary MF only 6.5 years. The most frequent gene mutation found in patients is JAK2V617F, causing constitutive activation of the kinase and activation of downstream signalling. Fedratinib is an oral selective JAK2 inhibitor. It has shown activity in MF and is well-tolerated, but combination with other therapies is likely needed to achieve clonal remission. Combining a JAK2 inhibitor with an interferon may be synergistic, as haematopoietic cells are activated from quiescence (a typical kinase resistance mechanism) rendering them more sensitive to inhibition.Ropeginterferon alfa-2b is a next generation pegylated interferon-α-2b with high tolerability and clinical activity in patients with MF, however, evidence of tolerability and activity in combination with fedratinib is lacking in this setting. The aim of the FEDORA trial is to assess tolerability, safety, and activity of fedratinib with ropeginterferon alfa-2b in patients with MF who require treatment to justify further investigation in a phase III trial.MethodsFEDORA is a single arm, multicentre, open-label, Bayesian phase II trial to assess tolerability, safety, and activity of fedratinib with ropeginterferon alfa-2b aiming to recruit 30 patients. Patients with JAK2V617F positive primary or secondary MF, who are aged ≥ 18 years, have intermediate-1 with palpable splenomegaly of > 5cm, intermediate-2, or high-risk disease according to the Dynamic International Prognostic Scoring System (DIPSS), and who require treatment are eligible. The primary outcome is tolerability, whereby the combination is deemed intolerable in a patient if drug-related toxicities in the first four months of treatment lead to: either drug being discontinued; delays in treatment exceeding 28 consecutive days; or death. FEDORA uses a within-patient dose escalation regimen to ensure each patient reaches a personalised dose combination that is acceptable.DiscussionFEDORA is using a Bayesian trial design and aims to provide evidence of the tolerability, safety, and activity of combining fedratinib with ropeginterferon alfa-2b upon which the decision as to whether a phase III trial is warranted will be based.Trial registrationEudraCT number: 2021–004056-42.ISRCTN: 88,102,629.

Impact of re-operation on progression-free survival in patients with recurrent GBM: Experience in a tertiary referral center.

Reoperation for patients with recurrent glioblastoma multiforme (GBM) is a highly debated topic within the medical community. GBM is known for its aggressive nature and poor prognosis, with most patients experiencing tumor recurrence despite initial treatments. Some studies suggest a survival benefit from a second surgery, while others do not. The aim of this study is to assess whether reoperation for recurrent GBM offers a survival benefit compared to patients who do not undergo re-resection and to identify the prognostic factors influencing patient selection for reoperation. This study retrospectively reviewed medical records from the American University of Beirut Medical Center over a ten-year period, from 01/01/2012 to 01/01/2023. It included patients with recurrent GBM after initial surgical resection. Patients were categorized into two groups: those who underwent reoperation and those who received only medical management upon recurrence. Inclusion criteria included histologically confirmed GBM with previous tumor resection; patients who only had a biopsy were excluded. Time to progression and time to death were analyzed using the Kaplan-Meier curve, with differences between groups assessed by the log-rank test. Age categorization (≤50 vs. >50 years) and gender distribution did not significantly impact reoperation likelihood (p = 0.306 and p = 0.616, respectively). However, a notable association was observed with Charlson comorbidity index (CCI) ≤3, indicating higher reoperation rates (p = 0.022). Tumor size grouping (≤5 vs. >5 cm) showed no significant association with reoperation status (p = 0.175). Similarly, whether the tumor was unifocal or multifocal and the extent of initial tumor resection (GTR vs. subtotal) did not demonstrate significant associations with reoperation (p = 0.086 and p = 0.351, respectively). Remarkably, complications following the initial surgery emerged as a significant factor associated with the decision not to undergo reoperation (p = 0.018). The most common complications following both initial and subsequent surgeries included DVT, weakness, seizures, and wound leakage and infection. The progression-free survival for patients who underwent reoperation was 15.9 months, whereas for those who did not undergo reoperation, it was 6.7 months (log-rank p < 0.001) The median post progression survival for patients who underwent reoperation upon recurrence was 5.9 months, compared to 5.1 months for those who did not undergo reoperation. (log-rank p = 0.065). The median overall survival for patients who did not undergo reoperation was 11 months, compared to 21 months for those who underwent reoperation (log-rank p < 0.001). In conclusion, reoperation for recurrent Glioblastoma Multiforme (GBM) appears to offer a survival benefit, as indicated by significantly longer disease-free intervals and higher progression-free and overall survival rates compared to patients who did not undergo reoperation.