Significant Increase In Survival Research Articles

Pembrolizumab as first-line treatment for recurrent and metastatic head and neck cancer - real-world single-centre data.

The randomised clinical trial KEYNOTE-048 has demonstrated a significant increase in survival for patients with head and neck cancer treated with pembrolizumab with or without chemotherapy. The purpose of the present retrospective study was to investigate whether survival in a group of consecutive patients treated at our department was comparable to the results from KEYNOTE-048. Seventy-six patients initiated treatment with pembrolizumab ± platinum/5-FU between July 2020 and May 2022. Baseline characteristics were collected, response rates and survival times were calculated and compared to those published from KEYNOTE-048. Fifty-one percent of patients had locoregional recurrence and 47% had distant metastases. Median progression-free survival was 5.5 months, and median overall survival (OS) was 12.3 months in the total cohort. OS was significantly higher for patients with combined positive score (CPS) ≥20 (14.6 months) than for patients with CPS 1-19 (7.3 months) (p = 0.04). There was no significant difference in survival times between patients ± 65 years of age or between patients with locoregional disease versus distant metastases. In conclusion, the results from KEYNOTE-048 were corroborated in a consecutive cohort of patients treated at Rigshospitalet, Copenhagen, Denmark.

Main aspects of personalized approach to the treatment of patients with chemotherapy resistant metastatic colorectal cancer

Purpose of the study. To improve the results of treatment of patients with unresectable metastases of colorectal cancer in the liver that are not controlled by systemic chemotherapy.Materials and methods. The study includes clinical data on the treatment of 76 patients with metachronous metastases of colorectal cancer in the liver that are not controlled by systemic chemotherapy. Patients underwent removal of the primary tumor according to urgent indications at the first stage of complex treatment, followed by systemic chemotherapy in an adjuvant mode. After 24.5 ± 0.2 months, patients were diagnosed with metastatic liver damage, and therefore systemic chemotherapy was initiated. After changing two lines of drug therapy with a registered progression of the oncological process, liver metastases were recognized as uncontrolled by systemic chemotherapy. After that patients were included in the given study and divided into two groups. The study group included 40 patients who underwent regional chemotherapy. The control group included 36 patients who continued systemic chemotherapy with subsequent line changes. The effectiveness was evaluated according to the RECIST 1.1 and mRECIST scales, as well as the overall one-year, two- and three-year survival rates.Results. The median overall survival of patients in the control and study groups was 30.0 ± 0.8 and 41.5 ± 0.5 months, respectively, p < 0.05. The total one-year, two- and three-year survival of patients in the control and study groups was 94.4 %, 69.4 %, 33.3 % and 100 %, 82.5 %, 57.5 %, respectively, p < 0.05. The median life expectancy of deceased patients in the control and study groups was 22.5 ± 0.4 and 27.0 ± 0.4 months.Conclusions. As a result of a comparative analysis of the detection of adverse events and complications of the treatment, patients of the study group underwent treatment much easier than patients of the control group – in patients in the group of systemic chemotherapy, moderate and severe complications were detected in 44.4 % of cases, in the study group – in 2.5 % of cases. According to the results of a clinical study, regional chemotherapy is an effective method of treating patients with colon cancer metastases in the liver that are not controlled by systemic chemotherapy and is associated with a statistically significant increase in overall survival (p < 0.05). For a more detailed study of the benefits of regional chemotherapy in this category of patients, further prospective clinical studies are necessary.

EPID-18. PATTERNS OF CARE AND CLINICAL OUTCOMES OF PATIENTS WITH GLIOBLASTOMA FROM 2005-2020: A REAL-WORLD ANALYSIS

Abstract BACKGROUND Survival for glioblastoma (GBM) remains low, with disparities affecting outcomes. Standard of care (SoC) includes surgery and adjuvant chemoradiation. This study explores demographics, treatment patterns, and outcomes of GBM patients in the United States. METHODS A retrospective study was conducted on patients with GBM in the National Cancer Database for GBM patients between 2005-2020 according to ESMO Guidance for Reporting Oncology Real-World (GROW). Trends were analyzed with descriptive statistics and X2-test between time periods: 2005-08, 2009-12, 2013-16, and 2017-20. Predictors of SoC receipt were analyzed with multivariate logistic regression. Median overall survival (mOS) estimated using Kaplan-Meier and Cox regression models. Adjustment made using demographic, socioeconomic, and clinical factors. Outcomes reported as (Odds Ratio [OR]/Hazard Ratio [HR] 95% Confidence Interval) per STROBE guidelines. RESULTS Of 104,697 GBM patients, 42.5% were female. 91.2% White, 5.7% Black, and 2.0% were Asian. 5.3% were Hispanic. Median age was 65 years (IQR:57-73). Percentage of patients ≥65 years increased from 48.8% in 2005-08 to 54.0% in 2017-20. 56.5% of patients received SoC. SoC usage increased over time: 2009-12 (OR:1.26, 1.21-1.31, P<0.001) vs 2013-16 (OR:1.36, 1.31-1.41, P<0.001) vs 2017-20 (OR:1.51, 1.45-1.57 P<0.001). Females (OR:0.91, 0.89-0.93 P<0.001), Black (OR:0.81, 0.77-0.86 P<0.001), and Hispanics (OR:0.92, 0.86-0.97, P=0.004) were less likely to receive SoC than males, White, and non-Hispanics. Privately insured were more likely to receive SoC than Medicare (OR:0.83, 0.80-0.87, P<0.001), Medicaid (OR:0.68, 0.64-0.71, P<0.001), and uninsured patients (OR:0.60, 0.55-0.64, P<0.001). SoC recipients had mOS of 14.6 months (14.5-14.8) vs 4.8 (4.7-4.9) for non-recipients (P<0.001). Compared to 2005-08, survival improved over time: 2017-20 (HR:0.83, 0.82-0.85, P<0.001) vs 2013-16 (HR:0.88, 0.86-0.89, P<0.001) vs 2009-12 (HR:0.93, 0.91-0.94, P<0.001). CONCLUSIONS Receipt of SoC has risen with significant increase in survival. However, female, Black, and Hispanic patients were less likely to receive SoC. Targeted efforts are warranted to mitigate disparities.

CSIG-04. ANTI-TUMOR RESPONSE OF ONCOMAGNETIC MONOTHERAPY IN GLIOBLASTOMA

Abstract BACKGROUND Glioblastoma (GBM) is the most lethal primary malignant brain tumor with a median survival of 15–20 months. Concurrent temozolomide (TMZ) chemotherapy and radiation (XRT) remain the current standard of care (SOC) treatment for newly diagnosed GBM. The addition of tumor treating fields (TTFs) improves median survival for newly diagnosed GBM from 16 to 20.9 months. This modest improvement underscores the urgent need to identify a new treatment modality as a safe and effective therapy. PURPOSE The noninvasive Oncomagnetic device developed in our laboratory selectively kills glioblastoma (GBM) in vitro. We studied the cellular and molecular effects of Oncomagnetic monotherapy (OMT) on GBM cell lines and investigated immune response in a syngeneic mouse model. RESULTS OMT significantly reduces cell proliferation and cell survival in vitro. OMT induces persistent ROS primarily by increasing superoxide level in cancer cells and reduces mitochondrial-membrane potential in GBM cells. It also induces DNA damage and arrests cells in G1-phase of the cell cycle. Whole-body Oncomagnetic stimulation caused a substantial retardation of tumor growth and reduction of the contrast-enhanced tumor volume in 9.4T MRI scans. OMT showed significant increase in overall survival in treated mice. We also observed upregulated immune response indicated by RNA sequencing data obtained from OMT-treated GBM cells as well as in treated GBM mouse tumor sections by imaging mass cytometry analysis. The tSNE analysis of various immune clusters suggests significant increase in immune response by activating CD4+, CD8+, murine-macrophages and M1-macrophages located at tumor site in the treated group. CONCLUSION The obtained data indicate significant anti-tumor response by inhibiting cancer signaling pathways and an increased immune response. Our findings suggest unique mechanism of action for OMT stimulation and provide a strong rationale for standalone OMT for GBM.

CTNI-18. RESULTS FROM A PHASE 1 STUDY OF SONODYNAMIC THERAPY WITH WHOLE HEMISPHERIC LOW INTENSITY NON-ABLATIVE ULTRASOUND IN PATIENTS WITH RECURRENT HIGH GRADE GLIOMA

Abstract We report the first use of a novel device that delivers non-ablative low intensity diffuse ultrasound (LIDU) across the entire hemisphere in combination with the oral sonosensitizing agent 5-ALA for the treatment of recurrent high grade glioma. LIDU in combination with 5-ALA focally targets tumor cells with sonodynamic therapy (SDT), causing selective tumor cell death across the entire hemisphere via 1) direct tumor targeting and 2) stimulation of immunogenic cell death. In this 3x3 clinical trial designed for safety (n=12, NCT05362409), two patients were enrolled after multiple recurrences and seven patients had multifocal or multicentric disease. Treatments were delivered monthly for a minimum of four sessions. A treatment duration of 120 minutes was established after dose escalation and expansion. SDT delivered via a novel device and in conjunction with 5-ALA was well tolerated, with no duration-limiting toxicities or serious related adverse events. Compared to historical data, we observed a significant increase in overall survival (mOS of 14.0+ months, with 7 of 12 patients still alive at the time of this submission and final median OS not yet achieved). A Phase 2b randomized, multicenter, double-blind, placebo-controlled study has been planned to commence in 2025 to assess the safety and efficacy of LIDU with sonosensitization in patients with newly diagnosed GBM.

Alginate-Bentonite Encapsulation of Extremophillic Bacterial Consortia Enhances Chenopodium quinoa Tolerance to Metal Stress.

This study explores the encapsulation in alginate/bentonite beads of two metal(loid)-resistant bacterial consortia (consortium A: Pseudomonas sp. and Bacillus sp.; consortium B: Pseudomonas sp. and Bacillus sp.) from the Atacama Desert (northern Chile) and Antarctica, and their influence on physiological traits of Chenopodium quinoa growing in metal(loid)-contaminated soils. The metal(loid) sorption capacity of the consortia was determined. Bacteria were encapsulated using ionic gelation and were inoculated in soil of C. quinoa. The morphological variables, photosynthetic pigments, and lipid peroxidation in plants were evaluated. Consortium A showed a significantly higher biosorption capacity than consortium B, especially for As and Cu. The highest viability of consortia was achieved with matrices A1 (3% alginate and 2% bentonite) and A3 (3% alginate, 2% bentonite and 2.5% LB medium) at a drying temperature of 25 °C and storage at 4 °C. After 12 months, the highest viability was detected using matrix A1 with a concentration of 106 CFU g-1. Further, a greenhouse experiment using these consortia in C. quinoa plants showed that, 90 days after inoculation, the morphological traits of both consortia improved. Chemical analysis of metal(loid) contents in the leaves indicated that consortium B reduced the absorption of Cu to 32.1 mg kg-1 and that of Mn to 171.9 mg kg-1. Encapsulation resulted in a significant increase in bacterial survival. This highlights the benefits of using encapsulated microbial consortia from extreme environments, stimulating the growth of C. quinoa, especially in soils with metal(loid) levels that can be a serious constraint for plant growth.

HPV16 mutant E6/E7 construct is protective in mouse model

BackgroundHuman papillomavirus type 16 (HPV-16) infection is strongly associated with considerable parts of cervical, neck, and head cancers. Performed investigations have had moderate clinical success, so research to reach an efficient vaccine has been of great interest. In the present study, the immunization potential of a newly designed HPV-16 construct was evaluated in a mouse model.ResultsInitially, a construct containing HPV-16 mutant (m) E6/E7 fusion gene was designed and antigen produced in two platforms (i.e., DNA vaccine and recombinant protein). Subsequently, the immunogenicity of these platforms was investigated in five mice) C57BL/6 (groups based on several administration strategies. Three mice groups were immunized recombinant protein, DNA vaccine, and a combination of them, and two other groups were negative controls. The peripheral blood mononuclear cells (PBMCs) proliferation, Interleukin-5 (IL-5) and interferon-γ (IFN-γ) cytokines, IgG1 and IgG2a antibody levels were measured. After two weeks, TC-1 tumor cells were injected into all mice groups, and subsequently further analysis of tumor growth and metastasis and mice survival were performed according to the schedule.Overall, the results obtained from in vitro immunology and tumor cells challenging assays indicated the potential of the mE6/E7 construct as an HPV16 therapeutic vaccine candidate. The results demonstrated a significant increase in IFN-γ cytokine (P value < 0.05) in the Protein/Protein (D) and DNA/Protein (E) groups. This finding was in agreement with in vivo assays. Control groups show a 10.5-fold increase (P value < 0.001) and (C) DNA/DNA group shows a 2.5-fold increase (P value < 0.01) in tumor growth compared to D and E groups. Also, a significant increase in survival of D and E (P value < 0.001) and C (P value < 0.01) groups were observed.ConclusionsSo, according to the findings, the recombinant protein could induce stronger protection compared to the DNA vaccine form. Protein/Protein and DNA/Protein are promising administration strategies for presenting this construct to develop an HPV-16 therapeutic vaccine candidate.

Customizable Lyophilized Agent for Radiotherapy Imaging and TherapY (CLARITY).

Smart radiotherapy biomaterials (SRBs) include seed and liquid biomaterials designed to be employed as fiducial markers during radiotherapy while also delivering therapeutic drug payloads to enhance treatment outcomes. In this study, we investigate a novel Customizable Lyophilized Agent for Radiotherapy Imaging and TherapY (CLARITY) biomaterial, which can be loaded with immunoadjuvants (anti-CD40 monoclonal antibody or Caflanone (FBL-03G)) at the point of care. The CLARITY biomaterial was investigated in an animal model of pancreatic cancer using C57BL6 mice. Mice were imaged before and at different points of time post-treatment to evaluate the potential of CLARITY biomaterial to provide imaging contrast similar to fiducials. This study also used cadavers to assess CLARITY's potential to provide imaging contrast in humans. Results showed imaging contrast from computed tomography (CT) and magnetic resonance imaging (MRI) modalities for up to 30 days post-treatment, demonstrating potential for use as fiducials. A significant increase in survival (***, p = 0.0006) was observed for mice treated with CLARITY biomaterial loaded with immunoadjuvant for up to 10 weeks post-treatment compared to those without treatment. These initial results demonstrate the potential of CLARITY biomaterial to serve as a smart multifunctional radiotherapy biomaterial and provide the impetus for further development and optimization as a point-of-care technology for combination radiotherapy and immunotherapy.

Long-term effect of supporting immunotherapy in a patient with metastatic small cell lung cancer

About 15 % of lung tumors are small cell lung cancer. Because of its extremely poor prognosis with a median overall survival of 10 months, and the long absence of new treatment options beyond the combination of platinum and etoposide (EP), the introduction of immunotherapy has been a significant development in the treatment of this disease. IMpower133 was the first phase III trial demonstrated a statistically significant increase in median overall survival in the atezolizumab group from 10.3 to 12.3 months. Our clinical case demonstrates the efficacy of an EP with atezolizumab. The patient got 6 courses of EP with atezolizumab and 29 courses of atezolizumab maintenance immunotherapy, indicating the efficacy and tolerability of this combination.

Abstract C071: Transcription factor switching drives progression of the classical subtype of pancreatic cancer

Abstract Despite recent advances in the treatment of pancreatic adenocarcinoma (PDAC), the median survival remains &amp;lt;12 months. Patients typically present with late-stage disease and are often unable to tolerate drug combination regimens. Large-scale genomic approaches categorise PDAC into two distinct molecular subtypes, based on transcriptomic signatures, and these are termed the classical and squamous (or basal) subtypes. Although it is well-described that PDAC harbours gene mutations (i.e. KRAS G12D, p53 R172H) that initiate the disease, little is known about the influence of lineage-defining Transcription Factors (TF) on PDAC subtypes and their contribution to tumor progression. We took an unbiased approach to discover driving TFs in PDAC, we performed ChIP-seq of the active enhancer mark H3K27Ac from surplus tissue following resection of primary PDAC tumors (n=6) and normal adjacent tissue (n=4). Analysis of the H3K27Ac sites showed that the most enriched motifs within all experimentally mapped enhancer elements were HNF motifs (HNF4G &amp; HNF4A) and Forkhead (i.e., FOXA1), confirming that these two classes of TFs constitute the lineage-defining factors in these clinical samples. Investigation of publicly available clinical datasets revealed HNF4G to be amplified in 9% of PDAC patients. Using Rapid Immunoprecipitation and Mass Spectrometry of Endogenous protein complexes (RIME), our method for unbiased discovery of endogenous protein complexes, we investigated the fundamental differences in the FOXA1 interactome between models of classical and squamous subtypes. HNF4A and HNF4G were only seen as FOXA1-interactors in models of the classical subtype. HNF4G Knockout (KO) clones injected orthotopically into the pancreas of mice, showed a significant increase (p-value&amp;lt;0.0006) in median survival and slower tumor growth compared to Control (Cas-9) (p-value &amp;lt;0.0001). HNF4G-KO dependent genes were specifically expressed in primary tumors (with decreased EMT signalling) versus metastatic samples (PanCRux dataset), implying that the HNF4G target genes were mostly limited to primary tumor contexts. We found Protein Arginine Methylate Transferase (PRMT1) to be a significant and reproducible interactor of FOXA1 and HNF4G. We observed a significant global reduction in PRMT1 chromatin binding in both the HNF4G-KO and FOXA1 depleted cells compared to the control. This data suggests a dependency on both HNF4G and FOXA1 for recruitment of PRMT1 to chromatin. We find HNF4G to be the key driver of classical subtype primary disease, in part by recruiting the methyltransferase PRMT1 to regulatory regions revealing a therapeutically exploitable opportunity. A molecular switch occurs in advanced disease, whereby HNF4G expression decreases, unmasking FOXA1’s transcriptional activity. De-repressed FOXA1 drives late-stage disease, by orchestrating metastasis-specific enhancer-promoter loops to direct metastatic gene regulation. We suggest the existence of stage-dependent TF activity, triggered by molecular compartmentalisation that mediates multistage progression of PDAC. Citation Format: Shalini Vasudev Rao, Lisa V Young, Danya Cheeseman, Stephanie V Mack, Dominique-Laurent Couturier, Sean V Flynn, Rebecca Brias, Amy Smith, Jill Temple, Duncan Jodrell, Alasdair Russell V Russell, Igor Chernukhin, Jason Carroll. Transcription factor switching drives progression of the classical subtype of pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr C071.

Analysis of budget planning specifics in providing targeted therapy to patients with breast cancer

The article is devoted to the analysis of the specifics of budget planning when using CDK4/6 inhibitors (ribociclib, palbociclib, and abemaciclib) for the treatment of HER2-negative metastatic breast cancer in postmenopausal patients. Based on clinical trial data and cost analysis, ribociclib was found to be advantageous in terms of efficacy and cost-effectiveness. According to randomized clinical trial data, not all the CDK4/6 inhibitors demonstrated a statistically significant increase in overall survival in combination with aromatase inhibitors. Ribociclib in combination with aromatase inhibitors has a statistically significant difference in overall survival compared to aromatase inhibitor monotherapy and reduces the risk of death by 24%. More than 30% of patients receiving CDK 4/6 inhibitors therapy require dose reduction, which is accomplished in a variety of ways depending on the dosage forms. Dose reduction has an impact on the cost per CDK4/6 inhibitors treatment cycle: before dose reduction, the cost per cycle of therapy with palbociclib and abemaciclib is lower compared to ribociclib. At the first dose reduction, the cost per cycle of therapy for all CDK 4/6 inhibitors is comparable. At the second dose reduction, the cost of a cycle of therapy on ribociclib is half that of palbociclib and abemaciclib. When planning the budget for providing CDK4/6 inhibitors to patients with metastatic cancer, it is necessary to consider a number of key characteristics of drugs that affect the costs and organization of the treatment process. An important aspect of budget planning is forecasting the need for drugs, considering the need for dose reduction. For ribociclib, the calculation of annual need is simplified by the possibility of reducing the number of tablets taken, which allows the use of a single dosage form, whereas for palbociclib and abemaciclib it is necessary to purchase several dosage forms with different dosages, which complicates planning, reduces the predictability of consumption, and requires additional administrative measures.

Survival impact of [225Ac]Ac-DOTATOC alpha-therapy in a preclinical model of pancreatic neuroendocrine tumor liver micrometastases.

A mouse model of liver metastases of pancreatic NETs was developed by intraportal injection of AR42J cells and explored using [68Ga]Ga-DOTATOC and [18F]F-FDG PET/MRI. Biodistribution study and radiation dosimetry of [225Ac]Ac-DOTATOC were determined in subcutaneous tumor-bearing NMRI-nude mice. Efficacy and toxicity were determined by intravenous injection of increasing activities of [225Ac]Ac-DOTATOC 10days after intraportal graft. Liver tumors showed a high uptake of [68Ga]Ga-DOTATOC and no uptake of [18F]F-FDG confirming the well-differentiated phenotype. All groups treated with [225Ac]Ac-DOTATOC showed a significant increase in overall survival compared with DOTATOC-treated mice, especially those treated with the highest activities: 53days with 240kBq (p = 0.0001), and 58days with 2 × 120kBq (p < 0.0001) vs 28days with non-radiolabeled DOTATOC. On blood tests, a transient and moderate decreased in white blood cells count after treatment and no severe hepatic or renal toxicity were observed after treatment which was consistent with pathological and radiation dosimetry findings. [225Ac]Ac-DOTATOC exhibit a favorable efficacy and toxicity profile in a mouse model of liver micrometastatic pancreatic NET.

Omega 3 Fatty Acids Attenuate the Acute Kidney Injury to CKD Transition and Renal Fibrosis: Identification of Antifibrotic Metabolites.

AKI is an established risk factor for developing CKD. Recently, the renoprotective effect of omega-3 polyunsaturated fatty acids (ω3PUFAs) has attracted attention. This study aimed to evaluate the effect of ω3PUFAs on the transition of AKI to CKD, and to identify fatty acid active metabolites in renal tissue. Two mice models of AKI to CKD (7-week, male) and unilateral ureteral obstruction (UUO)-induced renal fibrosis (11-week, male) were fed linseed oil, rich in ω3PUFAs (Lin group), or with soybean oil, low in ω3PUFAs (Soy group). Renal fatty acids and metabolites composition in mice were measured by liquid chromatography-mass spectrometry. Rat renal fibroblast cells (NRK-49F cells) were used for in vitro study. At day 14 after 35 min bilateral renal ischemia reperfusion (IR), significant increase in survival was observed in the Lin group compared to the Soy group. Using the 30 min bilateral renal IR model (AKI to CKD model), the Lin group showed attenuated renal tissue damage and fibrosis. In addition, the antifibrotic effect of Lin group was also observed in UUO renal fibrosis model. In the two mice models, levels of eicosapentaenoic acid (EPA) and its metabolites were significantly elevated in renal tissue of mice fed with Lin. Cultured NRK-49F incubated with EPA and its metabolites 18-hydroxyeicosapentaenoic acid (18-HEPE), 17,18-epoxyeicosatetraenoic acid (17,18-EpETE) and 17,18-dihydroxyeicosatetraenoic acid (17,18-diHETE) displayed suppressed TGF-β1-stimulated α-smooth muscle actin protein expression. These effects were suppressed in the presence of an inhibitor of a cytochrome P450 involved in EPA metabolism. This observation suggests that the EPA metabolites have antifibrotic effects. ω3PUFAs prevents AKI to CKD and renal fibrosis. Moreover, the EPA metabolites 18-HEPE, 17,18-EpETE and 17,18-diHETE were found to have antifibrotic effects.

Impact of an Etoposide Chemotherapy Shortage on Patients With Extensive-Stage Small-Cell Lung Cancer: Results of a Natural Experiment.

A shortage of essential intravenous (IV) etoposide lasted from 2018 until 2020 in Ontario, Canada, allowing for a natural experiment in which external factors (IV etoposide availability) dictated patients' treatment assignment. The purpose of this study was to evaluate the impact of this IV etoposide shortage (IVES) on patient care outcomes. Individuals with extensive-stage small-cell lung cancer (ES-SCLC) treated during a pre-IVES (November 2017-October 2018) and IVES (November 2018-October 2019) time intervals were retrospectively reviewed at the Verspeeten Family Cancer Centre. We investigated the association of the shortage on health care utilization and survival using a time-to-event analysis, Cox proportional hazards and logistic regression modeling. A total of 119 patients with ES-SCLC were assessed, 49 in the pre-IVES interval and 70 in the IVES interval. The median age was 68 (IQR, 62-74) years, 48% (n = 57) were male, 33% (n = 39) had CNS metastases, and 69% (n = 82) received first-line systemic therapy. Alternate regimens used for IVES cohort included IV platinum-oral (PO) etoposide, IV platinum-IV irinotecan, and PO etoposide monotherapy. An adjusted multivariable model demonstrated a significant increase in hospitalization (odds ratio, 2.30 [95% CI, 1.01 to 5.24]; P = .047) and shorter progression-free survival (PFS; hazard ratio, 1.79 [95% CI, 1.19 to 2.68]; P = .005) during the IVES. This study demonstrated increased hospitalization, and decreased PFS, among patients with ES-SCLC treated with alternate chemotherapy regimens during an IVES. The impact of cancer drug shortages can be harmful, and optimizing a more secure drug supply with mitigation strategies is warranted.

Cushion sea-star removal enhances coral restoration practices and limits background mortality on recovering reefs

The capacity for natural coral reef recovery and the effectiveness of active restoration efforts are often contingent upon uncertain and understudied background variables, such as chronic predation for example. In the Maldives, small coral colonies (< 10 cm), primarily from the genera Pocillopora and Acropora (often found recolonising degraded reefs) are frequently predated on by the spiny cushion sea-star (Culcita schmideliana). Incidentally, these same corals (especially Acroporids) are often prioritised in active reef restoration practices. However, the level of risk these corallivores pose on restoration success has not yet been assessed. Here, we aimed to initially document the population densities of C. schmideliana on a degraded reef system in the Maldives (Kunfunadhoo, Baa Atoll). We then assessed their associated predatory effects on coral recruits and transplants, and explored the benefits of C. schmideliana removal on the survival of these corals. Population densities ranged between 1.2 and 3.3 individuals per 100 m2, which resulted in high predation rates on coral recruits (4 – 20%) and transplants (11 – 43%). Culcita schmideliana predation accounted for the majority of the documented mortality (85%). Where C. schmideliana were removed, a significant increase in survival for recruits (9% higher) and transplants (24% higher) was shown. Further observations linked a cessation of C. schmideliana removal to a significant rise in predation instances for previously protected corals (up to 52%). Our study therefore highlights the severe impacts of C. schmideliana predation and shows Culcita spp. population management as a viable passive solution for effective reef restoration.

Impact of adjuvant treatments and risk factors on survival in 2023 FIGO stage IIB endometrial cancer patients: Turkish Gynecologic Oncology Group Study

ObjectiveThe aim of this study was to investigate the impact of adjuvant treatments, factors influencing recurrence, and survival data in patients with 2023 International Federation of Gynecology and Obstetrics (FIGO)...

Functional prediction of response to therapy prior to therapeutic intervention is associated with improved survival in patients with high-grade glioma

Patients with high-grade glioma (HGG) have an extremely poor prognosis compounded by a lack of advancement in clinical care over the past few decades. Regardless of classification, most newly diagnosed patients receive the same treatment, radiation and temozolomide (RT/TMZ). We developed a functional precision oncology test that prospectively identifies individual patient’s response to this treatment regimen. Tumor tissues isolated from patients with newly diagnosed HGG enrolled in 3D PREDICT REGISTRY were evaluated for response to chemotherapeutic agents using the 3D Predict™ Glioma test. Patients receiving RT/TMZ were followed for 2 years. Clinical outcomes including imaging, assessments, and biomarker measurements were compared to patient matched test-predicted therapy response. Median survival between test-predicted temozolomide responders and test-predicted temozolomide non-responders revealed a statistically significant increase in progression-free survival when using the test to predict response across multiple subgroups including HGG (5.8 months), glioblastoma (4.7 months), and MGMT unmethylated glioblastoma (4.7 months). Overall survival was also positively separated across the subgroups at 7.6, 5.1, and 6.3 months respectively. The strong correlation of 3D Predict Glioma test results with clinical outcomes demonstrates that this functional test is prognostic in patients treated with RT/TMZ and supports aligning clinical treatment to test-predicted response across varying HGG subgroups.

Theranostic GPA33-Pretargeted Radioimmunotherapy of Human Colorectal Carcinoma with a Bivalent 177Lu-Labeled Radiohapten.

Radiolabeled small-molecule DOTA-haptens can be combined with antitumor/anti-DOTA bispecific antibodies (BsAbs) for pretargeted radioimmunotherapy (PRIT). For optimized delivery of the theranostic γ- and β-emitting isotope 177Lu with DOTA-based PRIT (DOTA-PRIT), bivalent Gemini (DOTA-Bn-thiourea-PEG4-thiourea-Bn-DOTA, aka (3,6,9,12-tetraoxatetradecane-1,14-diyl)bis(DOTA-benzyl thiourea)) was developed. Methods: Gemini was synthesized by linking 2 S-2-(4-isothiocyanatobenzyl)-DOTA molecules together via a 1,14-diamino-PEG4 linker. [177Lu]Lu-Gemini was prepared with no-carrier-added 177LuCl3 to a molar-specific activity of 123 GBq/μmol and radiochemical purity of more than 99%. The specificity of BsAb-177Lu-Gemini was verified invitro. Subsequently, we evaluated biodistribution and whole-body clearance for [177Lu]Lu-Gemini and, for comparison, our gold-standard monovalent [177Lu]Lu-S-2-(4-aminobenzyl)-DOTA ([177Lu]Lu-DOTA-Bn) in naïve (tumor-free) athymic nude mice. For our proof-of-concept system, a 3-step pretargeting approach was performed with an established DOTA-PRIT regimen (anti-GPA33/anti-DOTA IgG-scFv BsAb, a clearing agent, and [177Lu]Lu-Gemini) in mouse models. Results: Initial invivo studies showed that [177Lu]Lu-Gemini behaved similarly to [177Lu]Lu-DOTA-Bn, with almost identical blood and whole-body clearance kinetics, as well as biodistribution and mouse kidney dosimetry. Pretargeting [177Lu]Lu-Gemini to GPA33-expressing SW1222 human colorectal xenografts was highly effective, leading to absorbed doses of [177Lu]Lu-Gemini for blood, tumor, liver, spleen, and kidneys of 3.99, 455, 6.93, 5.36, and 14.0 cGy/MBq, respectively. Tumor-to-normal tissue absorbed-dose ratios (i.e., therapeutic indices [TIs]) for the blood and kidneys were 114 and 33, respectively. In addition, we demonstrate that the use of bivalent [177Lu]Lu-Gemini in DOTA-PRIT leads to improved TIs and augmented [177Lu]Lu-Gemini tumor uptake and retention in comparison to monovalent [177Lu]Lu-DOTA-Bn. Finally, we established efficacy in SW1222 tumor-bearing mice, demonstrating that a single injection of anti-GPA33 DOTA-PRIT with 44 MBq (1.2 mCi) of [177Lu]Lu-Gemini (estimated tumor-absorbed dose, 200 Gy) induced complete responses in 5 of 5 animals and a histologic cure in 2 of 5 (40%) animals. Moreover, a significant increase in survival compared with nontreated controls was noted (maximum tolerated dose not reached). Conclusion: We have developed a bivalent DOTA-radiohapten, [177Lu]Lu-Gemini, that showed improved radiopharmacology for DOTA-PRIT application. The use of bivalent [177Lu]Lu-Gemini in DOTA-PRIT, as opposed to monovalent [177Lu]Lu-DOTA-Bn, allows curative treatments with considerably less administered 177Lu activity while still achieving high TIs for both the blood (>100) and the kidneys (>30).

Improved Survival of Advanced-Stage Anaplastic Thyroid Cancer With Systemic Therapy.

Anaplastic thyroid cancer (ATC) is the most aggressive and fatal thyroid malignancy. Currently, there still exists a paucity of literature studying the relationship between available ATC-targeted therapy, immunotherapy, and survival. We aim to investigate how systemic therapies affect survival outcomes in ATC. A single-tertiary-institution chart review of patients diagnosed with advanced-stage ATC, and who underwent surgery as part of their treatment, was performed between 2000 and 2023, with 41 patients included. Demographics, clinical characteristics, and survival data were collected and analyzed via Kaplan-Meier and Cox proportional hazards analyses. 54% of patients were female, and average age was 67.4 years old. The most common mutations identified were BRAF (15 patients), p53 (9 patients), and p63 (2 patients). A total of 18 patients utilized targeted or immunotherapy, with Trametinib and Dabrafenib (9 patients) as the most common agents used. Two-year overall survival was 24%, and 5-year overall survival was 23%, with median survival time of 7.6 months. Kaplan-Meier analysis demonstrated improved survival in patients who received chemotherapy (p = 0.048). Cox proportional hazards analysis demonstrated that patients treated with immunotherapy or targeted therapy had a statistically significant increase in survival compared with patients who did not receive these therapies (p = 0.016). Additionally, females and those with a p63 mutation demonstrated improved survival outcomes (p = 0.010, p = 0.001). Targeted therapy and immunotherapy use should be strongly considered when treating patients with ATC. Further studies into novel drugs targeting immune checkpoints and combination therapy are needed to better optimize treatment of patients with ATC. 3 Laryngoscope, 135:478-484, 2025.

Strong binding between nanoplastic and bacterial proteins facilitates protein corona formation and reduces nanoplastics toxicity

The interaction and combination of nanoplastics with microorganisms, enzymes, plant proteins, and other substances have garnered considerable attention in current research. This study specifically examined the interaction and biological effects of NPs and proteins. The findings indicated that the presence of externally wrapped proteins alters the original morphology and surface roughness of nanoplastics, leading to the formation of unevenly distributed coronas on the surface. This confirms that nanoplastics can interact with proteins to form protein coronas. The study characterized the adsorption behavior of bacterial proteins on unmodified, amino-modified, and carboxyl-modified nanoplastics using Langmuir and Freundlich isotherm models, showing that the adsorption process of the three nanoplastics on bacterial proteins was mainly controlled by chemisorption. Fluorescence spectroscopy revealed a higher binding affinity of unmodified nanoplastics. Nearly 40 % of the proteins in the protein corona of unmodified NPs are involved in metabolite production and electron transport processes. Nearly 50 % of the proteins in the protein corona of amino-modified NPs are involved in cellular metabolic processes, followed by enzymes that carry out redox reactions. The protein corona of carboxyl-modified NPs has the highest number of proteins involved in metabolic pathways, followed by proteins involved in energy-electron transfer. The formation of protein coronas on NPs with different surface modifications can reduce the toxicity of nanoplastics to bacteria to a certain extent compared to pure nanoplastics, especially amino-modified NPs, which show a significant increase in bacterial survival. The formation of protein coronas on NPs leads to varying degrees of decrease in bacterial ROS and MDA generation, with amino-modified NPs showing the most reduction; SOD and CAT exhibit varying degrees of increase and decrease. These findings not only advance our understanding of the biological impacts of NPs but also provide a basis for future in-depth investigations into the pathways of NP contamination in real environments.