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Background: Tumor-immune interactions shape a developing tumor and its tumor immune microenvironment (TIME) resulting in either well-infiltrated, immunologically inflamed tumor beds, or immune deserts with low levels of infiltration. The pre-treatment immune make-up of the TIME is associated with treatment outcome; immunologically inflamed tumors generally exhibit better responses to radio- and immunotherapy than non-inflamed tumors. However, radiotherapy is known to induce opposing immunological consequences, resulting in both immunostimulatory and inhibitory responses. In fact, it is thought that the radiation-induced tumoricidal immune response is curtailed by subsequent applications of radiation. It is thus conceivable that spatially fractionated radiotherapy (SFRT), administered through GRID blocks (SFRT-GRID) or lattice radiotherapy to create areas of low or high dose exposure, may create protective reservoirs of the tumor immune microenvironment, thereby preserving anti-tumor immune responses that are pivotal for radiation success. Methods: We have developed an agent-based model (ABM) of tumor-immune interactions to investigate the immunological consequences and clinical outcomes after 2 Gy × 35 whole tumor radiation therapy (WTRT) and SFRT-GRID. The ABM is conceptually calibrated such that untreated tumors escape immune surveillance and grow to clinical detection. Individual ABM simulations are initialized from four distinct multiplex immunohistochemistry (mIHC) slides, and immune related parameter rates are generated using Latin Hypercube Sampling. Results: In silico simulations suggest that radiation-induced cancer cell death alone is insufficient to clear a tumor with WTRT. However, explicit consideration of radiation-induced anti-tumor immunity synergizes with radiation cytotoxicity to eradicate tumors. Similarly, SFRT-GRID is successful with radiation-induced anti-tumor immunity, and, for some pre-treatment TIME compositions and modeling parameters, SFRT-GRID might be superior to WTRT in providing tumor control. Conclusion: This study demonstrates the pivotal role of the radiation-induced anti-tumor immunity. Prolonged fractionated treatment schedules may counteract early immune recruitment, which may be protected by SFRT-facilitated immune reservoirs. Different biological responses and treatment outcomes are observed based on pre-treatment TIME composition and model parameters. A rigorous analysis and model calibration for different tumor types and immune infiltration states is required before any conclusions can be drawn for clinical translation. [ABSTRACT FROM AUTHOR]

Background: Tongue squamous cell carcinoma (TSCC) is a prevalent tumor that affects many people worldwide. Radiotherapy is a common treatment option, but its efficacy varies greatly. This study seeks to validate the identified gene signature associated with radiosensitivity in TSCC, and its potential in predicting radiotherapy response and prognosis. Methods: We analyzed 122 TSCC patients from TCGA database using the radiosensitivity signature and classified them into radiosensitive (RS) and radioresistant (RR) groups. Immune infiltration analysis methods were applied to investigate the immune status between different subgroups. Immunophenotype Score (IPS) and pRRophetic algorithm were employed to estimate the efficiency of treatment. A radioresistant TSCC cell line was established by gradually increasing radiation doses. Cell radiosensitivity was evaluated using the CCK-8 and colony formation assays. The expression of radiosensitivity-related genes was validated by qRT-PCR. Results: Our study validated the predictive capacity of a previously identified "31-gene signature" in the TCGA-TSCC cohort, which effectively stratified patients into RS and RR groups. We observed that the RS group exhibited superior overall survival and progression-free survival rates relative to the RR group when treated with radiotherapy. The RS group was significantly enriched in most immunerelated hallmark pathways, and may therefore benefit from immune checkpoint inhibitors. However, the RS group displayed lower sensitivity to first-line chemotherapy. A radioresistant TSCC cell line (CAL-27R) exhibited increased clonogenic potential and cell viability following irradiation, accompanied by downregulation of three radiosensitivity-related genes compared to its parental non-resistant cell (CAL-27). In addition, we constructed and validated a radiosensitivity-related prognostic index (PI) using 4 radiosensitivity-related genes associated with TSCC prognosis. Conclusion: We assessed the ability of the radiosensitivity gene signature to predict outcomes in TSCC patients. our research provided valuable insights into the molecular pathways associated with radiosensitivity in TSCC and offered clinicians a practical tool to predict patient radiotherapy effectiveness and prognosis. [ABSTRACT FROM AUTHOR]

Exosomes mediate cell-to-cell crosstalk involving a variety of biomolecules through an intricate signaling network. In recent years, the pivotal role of exosomes and their non-coding RNAs cargo in the development and progression of several cancer types clearly emerged. In particular, tumor bulk and its microenvironment co-evolve through cellular communications where these nanosized extracellular vesicles are among the most relevant actors. Knowledge about the cellular, and molecular mechanisms involved in these communications will pave the way for novel exosome-based delivery of therapeutic RNAs as well as innovative prognostic/diagnostic tools. Despite the valuable therapeutic potential and clinical relevance of exosomes, their role on sarcoma has been vaguely reported because the rarity and high heterogeneity of this type of cancer. Here, we dissected the scientific literature to unravel the multifaceted role of exosomal non-coding RNAs as mediator of cell-to-cell communications in the sarcoma subtypes. [ABSTRACT FROM AUTHOR]

Renal cell carcinoma (RCC) is considered radio- and chemo-resistant. Immune checkpoint inhibitors (ICIs) have demonstrated significant clinical efficacy in advanced RCC. However, the overall response rate of RCC to monotherapy remains limited. Given its immunomodulatory effects, a combination of radiotherapy (RT) with immunotherapy is increasingly used for cancer treatment. Heavy ion radiotherapy, specifically the carbon ion radiotherapy (CIRT), represents an innovative approach to cancer treatment, offering superior physical and biological effectiveness compared to conventional photon radiotherapy and exhibiting obvious advantages in cancer treatment. The combination of CIRT and immunotherapy showed robust effectiveness in preclinical studies of various tumors, thus holds promise for overcoming radiation resistance of RCC and enhancing therapeutic outcomes. Here, we provide a comprehensive review on the biophysical effects of CIRT, the efficacy of combination treatment and the underlying mechanisms involved in, as well as its therapeutic potential specifically within RCC. [ABSTRACT FROM AUTHOR]

This review provides a rationale for using the Food and Drug Administration (FDA)-approved antibody-drug conjugates (ADCs) for implementing as therapy in recurrent refractory germ cell tumors similar to their position in the treatment of other types of chemoresistant solid tumors. Germ cell tumors (GCTs) originate from germ cells; they most frequently develop in ovaries or in the testes, while being the most common type of malignancy in young men. GCTs are very sensitive to cisplatin-based chemotherapy, but therapeutic resistance occurs in a considerable number of cases, which is associated with disease recurrence and poor patient prognosis. ADCs are a novel type of targeted antitumor agents that combine tumor antigen-specific monoclonal antibodies with chemically linked chemotherapeutic drugs (payload) exerting a cytotoxic effect. Several FDA-approved ADCs use as targeting moieties the antigens that are also detected in the GCTs, offering a benefit of this type of targeted therapy even for patients with relapsed/refractory testicular GCTs (rrTGCT) unresponsive to standard chemotherapy. [ABSTRACT FROM AUTHOR]

Purpose: Bulky tumor remains as a challenge to surgery, chemotherapy and conventional radiation therapy. Hence, in efforts to overcome this challenge, we designed a novel therapeutic paradigm via strategy of Stereotactic Central/Core Ablative Radiation Therapy (SCART).), which is based on the principles of SBRT (stereotactic body radiation therapy and spatially fractionated radiation therapy (SFRT). We intend to safely deliver an ablative dose to the core of the tumor and with a low dose at tumor edge. The purpose of the phase 1 study was to determine dose-limiting toxicities (DLT)s and the Maximum Tolerated Dose (MTD) of SCART. Methods and materials: We defined a SCART-plan volume inside the tumor, which is proportional to the dimension of tumor. VMAT/Cyberknife technique was adopted. In the current clinical trial; Patients with biopsy proven recurrent or metastatic bulky cancers were enrolled. The five dose levels were 15 Gy X1, 15Gy X3, 18GyX3, 21GyX3 and 24GyX3, while keeping the whole tumor GTV's border dose at 5Gy each fraction. There was no restriction on concurrent systemic chemotherapy agents. Results: 21 patients were enrolled and underwent SCART. All 21 patients have eligible data for study follow-up. Radiotherapy was well tolerated with all treatment completed as scheduled. The dose was escalated for two patients to 24GyX3. No grade 3 or higher toxicity was observed in any of the enrolled patients. The average age of patients was 66 years (range: 14-85) and 13 (62%) patients were male. The median SCART dose was 18Gy (range: 15 - 24). Six out of the 18 patients with data for overall survival (OS) died, and the median time to death was 16.3 months (range: 1 - 25.6). The mean percent change for tumor shrinkage between first visit volumes and post-SCART volumes was 49.5% (SD: 40.89, p-value:0.009). Conclusion: SCART was safely escalated to 24 GyX 3 fractions, which is the maximum Tolerated Dose (MTD) for SCART. This regimen will be used in future phase II trials. [ABSTRACT FROM AUTHOR]

Cancer therapy, especially for tumors near sensitive areas, demands precise treatment. This review explores photodynamic therapy (PDT), a method leveraging photosensitizers (PS), specific wavelength light, and oxygen to target cancer effectively. Recent advancements affirm PDT's efficacy, utilizing ROS generation to induce cancer cell death. With a history spanning over decades, PDT's dynamic evolution has expanded its application across dermatology, oncology, and dentistry. This review aims to dissect PDT's principles, from its inception to contemporary medical applications, highlighting its role in modern cancer treatment strategies. [ABSTRACT FROM AUTHOR]

Aim: To assess rates of no systemic treatment (NST), attrition across lines of therapy, and factors influencing treatment selection in patients with locally advanced or metastatic urothelial cancer (la/mUC). Methods: Systematic literature review to identify real-world studies reporting NST or attrition rates in la/mUC from 2017–2022 (including data reported since 2015). Results: Of 2439 publications screened, 29 reported NST rates, ranging from 40–74% in eight European-based studies, 14–60% in 12 US-based studies, and 9–63% in nine studies in other locations (meta-analysis estimate, 39%). Factors associated with NST or no second-line therapy included older age, female sex, poor performance status, poor renal function and distant metastases. Conclusion: A substantial proportion of patients with la/mUC do not receive guideline-recommended treatment. Plain language summary A review of how patients with bladder cancer are treated or not treated with anti-cancer drugs People with advanced bladder cancer have a short survival. Bladder cancer is called advanced when it has spread outside of the urinary tract. Several drug treatments are available for people with advanced bladder cancer. However, sometimes people do not receive any drug treatment. We looked at published studies to see how many people with advanced bladder cancer did not receive any drug treatment and the reasons why. We also looked at how long people lived with or without drug treatment. We found that many people with advanced bladder cancer did not receive drug treatment. The number of people who received no drug treatment varied in studies from different countries. People who were older, were female, had poor health or kidney problems, or had cancer that had spread to other parts of the body were less likely to receive drug treatment. People who did not receive drug treatment lived for an average of 2 to 7 months, compared with 9 to 35 months for people who received drug treatment. More studies are needed to investigate the reasons why drug treatment is sometimes not used in people with advanced bladder cancer who could receive treatment, so that more people can benefit from available treatments. Summary points This systematic literature review assessed real-world evidence for undertreatment rates, attrition rates and factors influencing treatment selection in patients with locally advanced or metastatic urothelial carcinoma (la/mUC). Of 2439 studies reporting real-world evidence in la/mUC or bladder cancer that were screened, 29 reported the proportion of patients receiving no systemic treatment (NST), 47 reported the proportion of patients receiving no subsequent treatment after first-line (1L) treatment (ie, attrition rate) and six reported treatment rates after the approval of immunotherapy; in total, 66 studies reported either NST rates or attrition rates. Several regions and countries were represented, including the USA, the European Union, Asia, the Middle East, the UK and Russia. NST rates ranges from 40–74% in eight European-based studies, 14–60% in 12 US-based studies, and 9–63% in nine studies from other locations. Rates of receipt of second-line treatment were lower in cisplatin-ineligible versus -eligible patients, and in those who received 1L immunotherapy versus chemotherapy. Factors associated with NST or no subsequent treatment after 1L treatment included older age, female sex, poor performance status, poor renal function and distant metastases. Median overall survival for patients with NST ranged from 2.0 to 6.9 months, compared with 9.2 to 34.5 months for patients who received systemic treatment. Overall, our findings indicate that a substantial proportion of patients with la/mUC do not receive treatment according to guidelines, or at all. Additional studies are needed to explore the factors influencing treatment selection to support optimal treatment sequencing in the era of 1L maintenance and targeted therapies in later lines, and allow most patients to benefit from available treatments. [ABSTRACT FROM AUTHOR]

Objectives: There is no theory to quantitatively describe the complex tumor ecosystem. At the same time, cancer immunotherapy is considered a revolution in oncology, but the methods used to describe tumors and the criteria used to evaluate efficacy are not keeping pace. The purpose of this study is to establish a new theory for quantitatively describing the tumor ecosystem, innovating the methods of tumor characterization, and establishing new efficacy evaluation criteria for cancer immunotherapy. Methods: Based on the mathematization of immune equilibrium theory and the establishment of immunodynamics in a previous study, the method of reverse immunodynamics was used, namely, the immune braking force was regarded as the tumor ecological force and the immune force was regarded as the tumor ecological braking force, and the concept of momentum in physics was applied to the tumor ecosystem to establish a series of tumor ecodynamic equations. These equations were used to solve the fundamental and applied problems of the complex tumor ecosystem. Results: A series of tumor ecodynamic equations were established. The tumor ecological momentum equations and their component factors could be used to distinguish disease progression, pseudoprogression, and hyperprogression in cancer immunotherapy. On this basis, the adjusted tumor momentum equations were established to achieve the equivalence of tumor activity (including immunosuppressive activity and metabolic activity) and tumor volume, which could be used to calculate individual disease remission rate and establish new efficacy evaluation criteria (ieRECIST) for immunotherapy of solid tumor based on tumor ecodynamics. At the same time, the concept of moving cube-to-force square ratio and its expression were proposed to calculate the area under the curve of tumor ecological braking force of blood required to achieve an individual disease remission rate when the adjusted tumor ecological momentum was known. Conclusions: A new theory termed tumor ecodynamics emphasizing both tumor activity and tumor volume is established to solve a series of basic and applied problems in the complex tumor ecosystem. It can be predicted that the future will be the era of cancer immune ecotherapy that targets the entire tumor ecosystem. [ABSTRACT FROM AUTHOR]

Background: In vitro studies often use two-dimensional (2D) monolayers, but 3D cell organization, such as in spheroids, better mimics the complexity of solid tumors. To metastasize, cancer cells undergo the process of epithelial-tomesenchymal transition (EMT) to become more invasive and pro-angiogenic, with expression of both epithelial and mesenchymal markers. Aims: We asked whether EMMPRIN/CD147 contributes to the formation of the 3D spheroid structure, and whether spheroids, which are often used to study proliferation and drug resistance, could better model the EMT process and the metastatic properties of cells, and improve our understanding of the role of EMMPRIN in them. Methods: We used the parental mouse CT26 colon carcinoma (CT26-WT) cells, and infected them with a lentivirus vector to knock down EMMPRIN expression (CT26-KD cells), or with an empty lentivirus vector (CT26-NC) that served as a negative control. In some cases, we repeated the experiments with the 4T1 or LLC cell lines. We compared the magnitude of change between CT26-KD and CT26-WT/NC cells in different metastatic properties in cells seeded as monolayers or as spheroids formed by the scaffold-free liquid overlay method. Results: We show that reduced EMMPRIN expression changed the morphology of cells and their spatial organization in both 2D and 3D models. The 3D models more clearly demonstrated how reduced EMMPRIN expression inhibited proliferation and the angiogenic potential, while it enhanced drug resistance, invasiveness, and EMT status, and moreover it enhanced cell dormancy and prevented CT26-KD cells from forming metastatic-like lesions when seeded on basement membrane extract (BME). Most interestingly, this approach enabled us to identify that EMMPRIN and miR-146a-5p form a negative feedback loop, thus identifying a key mechanism for EMMPRIN activities. These results underline EMMPRIN role as a gatekeeper that prevents dormancy, and suggest that EMMPRIN links EMT characteristics to the process of spheroid formation. Conclusions: Thus, 3D models can help identify mechanisms by which EMMPRIN facilitates tumor and metastasis progression, which might render EMMPRIN as a promising target for anti-metastatic tumor therapy. [ABSTRACT FROM AUTHOR]

Purpose: The complex nature of breast cancer demands flexible and adaptable principles that can account for the diverse characteristics and evolving conditions of each patient. However, there are no common breast cancer treatment agility principles that can influence policies and direct breast cancer professionals and healthcare providers into enhancing the delivery of health outcomes to patients under these conditions along with continuous rapid improvements in breast cancer treatment plan design. The incorporation of agile principles from software engineering offers a promising avenue for enhancing patient care. This research is conducted to identify breast cancer treatment agility principles adopted from the software engineering field and to validate their conformance to agility through work reported from literature in breast cancer treatment context. Material and Methods: The authors applied a structured research methodology that involved interviews for eliciting and validating twelve agility principles from oncologists. Discussion of each principle is reflected using work reported from literature as a form of validation. Finally, a domain expert reviewed the literature-driven validation for each of the twelve identified breast cancer treatment agile principle to finally validate their conformance to agility and provide results. Results: This work resulted twelve validated agility principles for breast cancer treatment and classified whether they are meeting, partially-(hybrid), or not meeting agility. Seven out of the twelve agile principles resulted as meeting agility, where the remaining five principles resulted as partially meeting agility. None of them is recorded as not meeting agility. Conclusion: The work contributes to forming an agile mindset that can empower breast cancer professionals to optimize treatment plans, enhance patient experiences, and continuously improve the quality of care. The twelve identified agile principles are anticipated to contribute to driving more efficient oncology practices, policies, and protocols. It is concluded that the breast cancer treatment agility principles are not limited to twelve. [ABSTRACT FROM AUTHOR]

Background In the ARASENS trial (NCT02799602), darolutamide in combination with androgen-deprivation therapy (ADT) and docetaxel significantly reduced the risk of death by 32.5% (HR, 0.68; 95% CI, 0.57-0.80; P  < .0001) compared with placebo plus ADT with docetaxel in patients with metastatic hormone-sensitive prostate cancer (mHSPC). We present efficacy and safety of darolutamide versus placebo in Black patients from ARASENS. Patients and Methods Patients with mHSPC were randomized 1:1 to darolutamide 600 mg or placebo twice daily in combination with ADT and docetaxel. The primary endpoint was overall survival. Key secondary endpoints included time to castration-resistant prostate cancer (CRPC) and safety. Results In ARASENS, 54 Black patients received darolutamide (n  = 26) or placebo (n  = 28) plus ADT and docetaxel. In Black patients, overall survival favored darolutamide versus placebo (median, not reached vs. 38.7 months; stratified HR, 0.41; 95% CI, 0.17-1.02), with 4-year survival rates of 62% versus 41%. The darolutamide group also had longer time to CRPC compared with the placebo group (median, not reached vs.12.6 months; HR, 0.09; 95% CI, 0.02-0.30). The safety profile of darolutamide in Black patients was consistent with that observed for the overall ARASENS population (grade 3/4 treatment-emergent adverse events, TEAEs: 61.5% vs. 66.1%; serious TEAEs: 42.3% vs. 44.8%). Conclusion In this small population of Black patients with mHSPC from the ARASENS trial, darolutamide was associated with an improvement in survival and time to CRPC and was well tolerated. Efficacy and safety findings in Black patients were consistent with the overall ARASENS population. [ABSTRACT FROM AUTHOR]

During progression of rheumatoid arthritis (RA), angiogenesis provides oxygen and nutrients for the cells' increased metabolic demands and number. To turn on angiogenesis, pro-angiogenic factors must outweigh anti-angiogenic factors. We have previously shown that CD147/extracellular matrix metalloproteinase inducer (EMMPRIN) can induce the expression of the pro-angiogenic factors vascular endothelial growth factor (VEGF) and matrix metallopeptidase 9 (MMP-9) in a co-culture of the human HT1080 fibrosarcoma and U937 monocytic-like cell lines. However, whether CD147 influences anti-angiogenic factors was not known. We now show that relative to single cultures, the co-culture of these cells not only enhanced pro-angiogenic factors but also decreased the anti-angiogenic factors endostatin and thrombospondin-1 (Tsp-1), generally increasing the angiogenic potential as measured by a wound assay. Using anti-CD147 antibody, CD147 small interfering RNA (siRNA), and recombinant CD147, we demonstrate that CD147 hormetically regulates the generation of endostatin but has no effect on Tsp-1. Since endostatin is cleaved from collagen XVIII (Col18A), we applied different protease inhibitors and established that MMP-9 and proteasome 20S, but not cathepsins, are responsible for endostatin generation. MMP-9 and proteasome 20S collaborate to synergistically enhance endostatin generation, and in a non-cellular system, CD147 enhanced MMP-9 activity and hormetically regulated proteasome 20S activity. Serum samples obtained from RA patients and healthy controls mostly corroborated these findings, indicating clinical relevance. Cumulatively, these findings suggest that secreted CD147 mediates a possibly allosteric effect on MMP-9 and proteasome 20S activities and can serve as a switch that turns angiogenesis on or off, depending on its ambient concentrations in the microenvironment. [ABSTRACT FROM AUTHOR]

Objectives: The objective of this study was to compare the rate of post‐operative radiation therapy (PORT) initiation within 6 weeks for head and neck squamous cell carcinoma patients treated at a safety net, academic institutio between 2019 and 2021 versus those treated in 2022 after implementation of a new clinical pathway. Methods: A retrospective case–control study was performed at a single tertiary care, safety‐net, academic institution. Patient demographics, tumor characteristics, dates of surgery, and other treatment dates were collected from the electronic medical record. The time from surgery to PORT was calculated. Patients who started radiation treatment within 42 days of surgery were regarded as having started PORT on time. The demographics, tumor characteristics, and rate of timely PORT for the two cohorts of patients were compared. Results: From 2018 to 2021, our rate of PORT initiation within 6 weeks of surgery was 12% (n = 57). In 2022, our rate of timely PORT was 88% (n = 16), p < 0.5. Patient demographics and characteristics were similar with the exception of marital status and use of free‐flap reconstruction. The 2022 cohort was more likely to be single (p < 0.5), and all patients underwent free‐flap reconstruction in 2022 (p < 0.05). Conclusion: Early referrals, frequent communication, and use of a secure registry were the key to the success found by our group despite the socioeconomic challenges of our underserved, safety‐net hospital patient population. The changes made at our institution should serve as a template for other institutions seeking to improve the quality of care for their HNSCC patients. [ABSTRACT FROM AUTHOR]

Purpose: This study simulates a novel prostate SBRT intra-fraction reoptimization workflow in MRIgART to account for prostate intra-fraction motion and evaluates the dosimetric benefit of reducing PTV margins. Materials and methods: VMAT prostate SBRT treatment plans were created for 10 patients using two different PTV margins, one with a 5 mm margin except 3 mm posteriorly (standard) and another using uniform 2 mm margins (reduced). All plans were prescribed to 36.25 Gy in 5 fractions and adapted onto each daily MRI dataset. An intra-fraction adaptive workflow was simulated for the reduced margin group by synchronizing the radiation delivery with target position from cine MRI imaging. Intra-fraction delivered dose was reconstructed and prostate DVH metrics were evaluated under three conditions for the reduced margin plans: Without motion compensation (no-adapt), with a single adapt prior to treatment (ATP), and lastly for intra-fraction re-optimization during delivery (intra). Bladder and rectum DVH metrics were compared between the standard and reduced margin plans. Results: As expected, rectum V18 Gy was reduced by 4.4 ± 3.9%, D1cc was reduced by 12.2 ± 6.8% (3.4 ± 2.3 Gy), while bladder reductions were 7.8 ± 5.6% for V18 Gy, and 9.6 ± 7.3% (3.4 ± 2.5 Gy) for D1cc for the reduced margin reference plans compared to the standard PTV margin. For the intrafraction replanning approach, average intra-fraction optimization times were 40.0 ± 2.9 seconds, less than the time to deliver one of the four VMAT arcs (104.4 ± 9.3 seconds) used for treatment delivery. When accounting for intra-fraction motion, prostate V36.25 Gy was on average 96.5 ± 4.0%, 99.1 ± 1.3%, and 99.6 ± 0.4 for the non-adapt, ATP, and intra-adapt groups, respectively. The minimum dose received by the prostate was less than 95% of the prescription dose in 84%, 36%, and 10% of fractions, for the non-adapt, ATP, and intra-adapt groups, respectively. Conclusions: Intra-fraction re-optimization improves prostate coverage, specifically the minimum dose to the prostate, and enables PTV margin reduction and subsequent OAR sparing. Fast re-optimizations enable uninterrupted treatment delivery. [ABSTRACT FROM AUTHOR]

MYC oncogene rearrangements (MYC-R) negatively affect survival in patients with Ann Arbor stage III–IV diffuse large B-cell lymphoma (DLBCL), but their impact in limited stage (LS) I–II is unclear. Therefore, we assessed the impact of MYC-R on progression-free survival (PFS) and overall survival (OS) in LS DLBCL patients at the population level. We identified 1,434 LS DLBCL patients with known MYC-R status diagnosed between 2014 and 2020, who received R-CHOP(-like) regimens using the Netherlands Cancer Registry, with survival follow-up until February 2022. Stage I patients with (n = 83, 11%) and without (n = 650, 89%) a MYC-R had similar 2-years PFS (89% and 93%, p = 0.63) and OS (both 95%, p = 0.22). Conversely, stage II DLBCL patients with a MYC-R (n = 90, 13%) had inferior survival outcomes compared to stage II patients without a MYC-R (n = 611, 87%) (PFS 70% vs. 89%, p = 0.001; OS 79% vs. 94%, p < 0.0001). Both single MYC-R (single hit, n = 36) and concurrent BCL2 and/or BCL6 rearrangements (double/triple hit, n = 39) were associated with increased mortality and relapse risk. In conclusion, in stage II DLBCL a MYC-R is negatively associated with survival. In stage I DLBCL, however, survival outcomes are excellent irrespective of MYC-R status. This challenges the diagnostic assessment of MYC-R in stage I DLBCL patients. [ABSTRACT FROM AUTHOR]

Background: Although substantial efforts have been made to build molecular biomarkers to predict radiation sensitivity, the ability to accurately stratify the patients is still limited. In this study, we aim to leverage large-scale radiogenomics datasets to build genomic predictors of radiation response using the integral of the radiation dose–response curve. Methods: Two radiogenomics datasets consisting of 511 and 60 cancer cell lines were utilized to develop genomic predictors of radiation sensitivity. The intrinsic radiation sensitivity, defined as the integral of the dose–response curve (AUC) was used as the radioresponse variable. The biological determinants driving AUC and SF2 were compared using pathway analysis. To build the predictive model, the largest and smallest datasets consisting of 511 and 60 cancer cell lines were used as the discovery and validation cohorts, respectively, with AUC as the response variable. Results: Utilizing a compendium of three pathway databases, we illustrated that integral of the radiobiological model provides a more comprehensive characterization of molecular processes underpinning radioresponse compared to SF2. Furthermore, more pathways were found to be unique to AUC than SF2—30, 288 and 38 in KEGG, REACTOME and WIKIPATHWAYS, respectively. Also, the leading-edge genes driving the biological pathways using AUC were unique and different compared to SF2. With regards to radiation sensitivity gene signature, we obtained a concordance index of 0.65 and 0.61 on the discovery and validation cohorts, respectively. Conclusion: We developed an integrated framework that quantifies the impact of physical radiation dose and the biological effect of radiation therapy in interventional pre-clinical model systems. With the availability of more data in the future, the clinical potential of this signature can be assessed, which will eventually provide a framework to integrate genomics into biologically-driven precision radiation oncology. [ABSTRACT FROM AUTHOR]

Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths in the United States and compiles the most recent data on population‐based cancer occurrence and outcomes using incidence data collected by central cancer registries (through 2020) and mortality data collected by the National Center for Health Statistics (through 2021). In 2024, 2,001,140 new cancer cases and 611,720 cancer deaths are projected to occur in the United States. Cancer mortality continued to decline through 2021, averting over 4 million deaths since 1991 because of reductions in smoking, earlier detection for some cancers, and improved treatment options in both the adjuvant and metastatic settings. However, these gains are threatened by increasing incidence for 6 of the top 10 cancers. Incidence rates increased during 2015–2019 by 0.6%–1% annually for breast, pancreas, and uterine corpus cancers and by 2%–3% annually for prostate, liver (female), kidney, and human papillomavirus‐associated oral cancers and for melanoma. Incidence rates also increased by 1%–2% annually for cervical (ages 30–44 years) and colorectal cancers (ages <55 years) in young adults. Colorectal cancer was the fourth‐leading cause of cancer death in both men and women younger than 50 years in the late‐1990s but is now first in men and second in women. Progress is also hampered by wide persistent cancer disparities; compared to White people, mortality rates are two‐fold higher for prostate, stomach and uterine corpus cancers in Black people and for liver, stomach, and kidney cancers in Native American people. Continued national progress will require increased investment in cancer prevention and access to equitable treatment, especially among American Indian and Alaska Native and Black individuals. [ABSTRACT FROM AUTHOR]

Background: CD147, a transmembrane glycoprotein, has been implicated in various cancer-related processes but its role in breast cancer remains poorly understood. Herein, we investigated the expression of CD147 in different breast cancer cell lines and explored its functional roles, including migration, invasion, drug resistance and modulation of key proteins associated with cancer progression. Methods: The expression of CD147 was assessed in MCF-10 A, BT549, MDA-MB-231 and MCF-7 breast cancer cell lines using qRT-PCR and Western blotting, following which lyposome transfections were performed, leading overexpression of CD147 in BT549 cells and knockdown of CD147 in MCF-7 cells. Scratch assays and Transwell invasion and were performed to evaluate the cells' migration and invasion abilities. Sensitivity to 5-FU was determined via CCK-8 assays, and the expression of Snail1, E-cadherin, Vimentin, MMP-9 and the MAPK/ERK pathway were analyzed by qRT-PCR and Western blotting. Results: Compared with normal beast epithelial cells, CD147 was highly expressed in all breast cancer cell lines, with the highest overexpression observed in MCF-7 cells and the lowest overexpression observed in BT549 cells. Overexpression of CD147 in BT549 cells increased, migration, invasion, viability and resistance to 5-FU of BT549 cells, while CD147 knockdown in MCF-7 cells reduced these properties of MCF-7 cells. Furthermore, CD147 influenced the expression of Snail1, Vimentin, E-cadherin, and MMP-9, suggesting its involvement in epithelial-mesenchymal transition (EMT) regulation. The MAPK/ERK pathway was activated by CD147 in BT549 cells, as indicated by increased p-MEK/MEK ratio and p-ERK/ERK ratio. In contrast, CD147 silencing in MCF-7 cells resulted in reduced p-MEK/MEK ratio and p-ERK/ERK ratio. Conclusion: In summary, our findings suggest CD147 as a potential therapeutic target in breast cancer treatment, particularly in cases where drug resistance and metastasis are concerns, worthy of further explorations. [ABSTRACT FROM AUTHOR]

The technological developments associated with the branch of Radiation Oncology have been directed towards precise delivery of the dose, leading to improved survival in various solid malignancies. Radiation therapy as a treatment modality, is an integral component of more than half of the diagnosed malignancies. In spite of the role of adaptive radiation therapy evolving over the last decade, the fundamental question remains as to the difference in radiation response between individuals. Recently, the role of the radiosensitivity index has emerged, which has shown immense potential in the development of biologically driven tumor radiation therapy. The role of these novel methods of genome-based molecular assays needs to be explored to help in decision-making between radical treatment options for various malignancies and reduce the associated toxicity burden. In this article, we explore the current evidence available for various malignancy sites and provide a comprehensive review of the predictive values of various molecular markers available and their impact on the radiosensitivity index. [ABSTRACT FROM AUTHOR]

Objective: This study was conducted to determine whether higher doses of intensity-modulated radiotherapy(IMRT) could improve the survival rate in patients of cervical esophageal squamous cell carcinoma (CESCC), and lead to more severe treatment-related toxicity. Methods: The clinical records of stage I–IVA CESCC patients treated with definitive chemoradiotherapy (CRT) using IMRT between January 2013 and June 2018 were retrospectively analyzed. The patients in the high-dose (HD) group received ≥60 Gy and those in the standard-dose group received <60 Gy. A propensity score matching (PSM) was applied to balance the confounding factors between both groups. The primary endpoint was over-survival (OS). progression-free survival (PFS), loco-regional control (LRC), and treatment-related toxicity were also evaluated. Results: A total of 136 patients with CESCC were included. Patients with N1–3 nodal and stages III–IVA of the disease (P < 0.05) were included in the HD group. The differences in the OS, PFS, and LRC between the two groups were not statistically significant (P = 0.350, 0.063, and 0.099, respectively). After PSM, significantly longer PFS and LRC were observed in the HD group. The difference in OS between the two groups was not statistically significant. There was no significant difference in the incidence of treatment-related toxicity between the two groups. Conclusions: The results of this PSM analysis suggested that higher doses may improve PFS and LRC for CESCC patients receiving CRT using OMRT, but do not demonstrate any statistically significant advantage in improving OS. [ABSTRACT FROM AUTHOR]

Purpose: This study is aimed to explore risk factors affect the therapy outcomes of adrenal metastases (AM) for stereotactic body radiation therapy (SBRT) and guide clinical dose selection. Methods and materials: PubMed, Embase and Web of Science were searched in September 22, 2022 in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PRISMA). Subgroup analysis and meta-regression were used to search for sources of heterogeneity and identify risky outcomes factors. Publication bias test and sensitivity analysis were also conducted. Results: Thirty-three studies with full text from 2009 to 2022 about AM with SBRT on 1483 patients were included. Pooled 1- and 2-year local control (LC) and overall survival(OS) were 81.7% (95% confidence interval [CI], 75.6%-86.5%), 62.8% (95% CI, 53.8%-71.8%), 67.4% (95%CI, 61.8%-73.1%) and 46.5% (95%CI, 40.4%-52.6%), respectively. Biological effective dose (BED, α/β=10Gy) and dose per fraction affected 1-year LC (Qm=23.89, 15.10; P<0.0001, 0.0001). In the range of 60-80Gy (BED10), the group of dose per fraction = 9Gy achieved the excellent 1-year LC (< 9Gy: = 9Gy =78%, 91%; c2 = 10.16, P = 0.001). Tracking technology significantly affected 1- and 2-year OS (Qm = 5.73, 8.75; P = 0.017, 0.003) and high tracking adoption group showed excellent 1- and 2- year OS (78.7% [95%CI, 68.6%- 88.9%]; and 62.9% [95%CI, 53.1%-72.7%]). Conclusion: Increasing the dose per fraction appropriately may help control locally AM lesious. Tracking technology might contribute to improve survival of advanced patients with AM. But these results need prospective studies to verify them. [ABSTRACT FROM AUTHOR]

Objective: To characterize the supportive care (SC) needs and receipt of SC services among head and neck cancer (HNC) patients prior to oncologic treatment and to explore the influence of social determinants of health on these outcomes. Materials and Methods: Newly diagnosed HNC patients were surveyed via telephone prior to oncologic treatment between 10/2019 and 1/2021 using a prospective, cross-sectional, bi-institutional, pilot study design. The primary study outcome was unmet SC needs (Supportive Care Needs Survey-Short Form34 [SCNS-SF34]). Hospital type (university- vs county safety-net) was explored as an exposure. Descriptive statistics were performed using STATA16 (College Station, TX). Results: Among 158 potentially eligible patients, 129 were successfully contacted, 78 met the study criteria, and 50 completed the survey. The mean age was 61, 58% exhibited clinical stage III-IV disease, and 68% and 32% were treated at the university and county safety-net hospital, respectively. Patients were surveyed a median of 20 days after their first oncology visit and 17 days prior to initiation of oncology treatment. They had a median of 24 total needs (11 were met and 13 were unmet) and preferred to see a median of 4 SC services but received care from none. County safety-net patients had comparatively more unmet needs than university patients (14.5 vs 11.5, P =.04). Conclusion: Pretreatment HNC patients at a bi-institutional academic medical center report a high number of unmet SC needs with corollary poor receipt of available SC services. Novel interventions to address this significant gap in care are needed. [ABSTRACT FROM AUTHOR]

Technological development has increased the use of chemical elements that have hitherto received scant scientific attention as environmental contaminants. Successful management of these rare trace elements (RTEs) requires elucidation of their mobility in the soil–plant system. We aimed to determine the capacity of Lolium perenne (a common pasture species) to tolerate and accumulate the RTEs Be, Ga, In, La, Ce, Nd, and Gd in a fluvial recent soil. Cadmium was used as a reference as a well-studied contaminant that is relatively mobile in the soil–plant system. Soil was spiked with 2.5–283 mg kg−1 of RTE or Cd salts, representing five, 10, 20, and 40 times their background concentrations in soil. For Be, Ce, In, and La, there was no growth reduction, even at the highest soil concentrations (76, 1132, 10.2, and 874 mg kg−1, respectively), which resulted in foliar concentrations of 7.1, 12, 0.11, and 50 mg kg−1, respectively. The maximum no-biomass reduction foliar concentrations for Cd, Gd, Nd, and Ga were 0.061, 0.1, 7.1, and 11 mg kg−1, respectively. Bioaccumulation coefficients ranged from 0.0030–0.95, and increased Ce < In < Nd ≅ Gd < La ≅ Be ≅ Ga < Cd. Beryllium and La were the RTEs most at risk of entering the food chain via L. perenne, as their toxicity thresholds were not reached in the ranges tested, and the bioaccumulation coefficient (plant/soil concentration quotient) trends indicated that uptake would continue to increase at higher soil concentrations. In contrast, In and Ce were the elements least likely to enter the food chain. Further research should repeat the experiments in different soil types or with different plant species to test the robustness of the findings. [ABSTRACT FROM AUTHOR]

Cancer cells actively release lipid bilayer extracellular vesicles (EVs) that affect their microenvironment, favoring their progression and response to extracellular stress. These EVs contain dynamically regulating molecular cargos (proteins and nucleic acids) selected from their parental cells, representing the active biological functionality for cancer progression. These EVs are heterogeneous according to their size and molecular composition and are usually defined based on their biogenetic mechanisms, such as exosomes and ectosomes. Recent single EV detection technologies, such as nano-flow cytometry, have revealed the dynamically regulated molecular diversity within bulk EVs, indicating complex EV heterogeneity beyond classical biogenetic-based EV subtypes. EVs can be changed by internal oncogenic transformation or external stress such as chemotherapy. Among the altered combinations of EV subtypes, only a specific set of EVs represents functional molecular cargo, enabling cancer progression and immune modulation in the tumor microenvironment through their altered targeting efficiency and specificity. This review covers the heterogeneity of EVs discovered by emerging single EV analysis technologies, which reveal the complex distribution of EVs affected by oncogenic transformation and chemotherapy. Encouragingly, these unique molecular signatures in individual EVs indicate the status of their parental cancer cells. Thus, precise molecular profiling of circulating single EVs would open new areas for in-depth monitoring of the cancer microenvironment and shed new light on non-invasive diagnostic approaches using liquid biopsy. [ABSTRACT FROM AUTHOR]

Local therapy modalities such as radiation therapy, photodynamic therapy, photothermal therapy, and cryoablation have been used to treat localized tumors for decades. The discovery of the abscopal effect causes a paradigm shift where local therapy also causes systemic effects and leads to the remission of nonirradiated tumors. The abscopal effect of radiation therapy, alone or in combination with other treatments, has been extensively studied over the last six decades. However, the results are unsatisfactory in producing robust, reproducible, and long‐lasting systemic effects. Although immunotherapy and radiation therapy are promising in producing the abscopal effect, the abscopal effect's mechanism is still unclear, owing to various factors such as irradiation type and dose and cancer type. This article reviews the research progress, clinical and preclinical evidence of the abscopal effect by various local therapies alone and in combination with chemotherapy and immunotherapy, case reports, and the current challenges in producing the abscopal effect by various local therapies, focusing on radiotherapy, photodynamic therapy, cryoablation, and the prospects for obtaining a robust, reproducible, and long‐lasting abscopal effect. [ABSTRACT FROM AUTHOR]

Introduction: Radionecrosis is a consequence of SRS (stereotactic radiosurgery) for brain metastases in 34% of cases, and if symptomatic (8%-16%), it requires therapy with corticosteroids and bevacizumab and, less frequently, surgery. Oncological indications are increasing and appropriate stereotactic adapted LINACs (linear accelerators) are becoming more widely available worldwide. Efforts are being made to treat brain radionecrosis in order to relieve symptoms and spare the use of active therapies. Case presentation: Herein, we describe a 65-year-old female patient presenting with brain radionecrosis 6 months after stereotactic radiotherapy for two brain metastatic lesions. Being symptomatic with headache and slow cognitive-motor function, the patient received corticosteroids. Because of later lung progression, the patient took cabozantinib. An impressive reduction of the two brain radionecrosis areas was seen at the brain MRI 2 months after the initiation of the angiogenic drug. Discussion: The high incidence of radionecrosis (2/2 treated lesions) can be interpreted by the combination of SRS and previous ipilimumab that is associated with increased risk of radionecrosis. The molecular mechanisms of brain radionecrosis, and its exact duration in time, are poorly understood. We hypothesize that the antiangiogenic effect of cabozantinib may have had a strong effect in reducing brain radionecrosis areas. Conclusion: In this clinical case, cabozantinib is associated with a fast and significant volume reduction of brain radionecrosis appearing after SRS and concomitant immunotherapy. This drug seems to show, like bevacizumab clinical implications not only for its efficacy in systemic disease control but also in reducing brain radionecrosis. More research is needed to evaluate all molecular mechanisms of brain radionecrosis and their interaction with systemic therapies like third-generation TKIs. [ABSTRACT FROM AUTHOR]

Background: In situ tumor vaccine has been gradually becoming a hot research field for its advantage of achieving personalized tumor therapy without prior antigen identification. Various in situ tumor vaccine regimens have been reported to exert considerable antitumor efficacy in preclinical and clinical studies. However, the design of in situ tumor vaccines still needs further optimization and the underlying immune mechanism also waits for deeper investigation. Methods: A novel triple in situ vaccine strategy that combining local radiation with intratumoral injection of TLR9 agonist CpG and OX40 agonist was established in this sturdy. Local and abscopal antitumor efficacy as well as survival benefit were evaluated in the bilateral tumors and pulmonary metastasis model of B16F10 melanoma. In situ vaccine-induced immune responses and immune-associated variation in tumor environment were further investigated using multiparameter flow cytometry and RNA sequencing. Base on the analysis, the RT + CpG + αOX40 triple in situ vaccine was combined with checkpoint blockade therapy to explore the potential synergistic antitumor efficacy. Results: Enhanced tumor suppression was observed with minimal toxicity in both treated and untreated abscopal tumors after receiving RT + CpG + αOX40 triple vaccine. The introduction of local radiation and OX40 agonist benefit more to the inhibition of local and abscopal lesions respectively, which might be partially attributed to the increase of effector memory T cells in the tumor microenvironment. Further analysis implied that the triple in situ vaccine did not only activate the microenvironment of treated tumors, with the upregulation of multiple immune-associated pathways, but also enhanced systemic antitumor responses, thus achieved superior systemic tumor control and survival benefit. Moreover, the triple in situ vaccine synergized with checkpoint blockade therapy, and significantly improved the therapeutic effect of anti-programmed cell death protein (PD)-1 antibody. Conclusion: This triple combining in situ vaccine induced intensive antitumor responses, mediated effective systemic tumor control and survival benefit, and displayed impressive synergistic antitumor effect with checkpoint blockade therapy. These data preliminary confirmed the efficacy, feasibility and safety of the triple combining in situ vaccine, suggesting its great application potential as both monotherapy and a part of combined immunotherapeutic regimens in clinical scenario. [ABSTRACT FROM AUTHOR]

All lung tumors exhibit PCNE signatures, except LUAD02T and LUSC01T, forming one dominant group with minor clones under ten cells. One study limitation is subclone detection dependent on 10x scDNA-Seq cell profiling,[6] partially repenting subclone diversity in tumors. "LX" indicates subclone has loss of heterozygosity in chromosome X. The largest subclone populates 1,273 diploid cells (LUAD03T-D), whilst we detected 23 small cell populations, that is, subclones under 10 cells (Table S2). Our findings reflect lung tumors holding huge subclone diversity on copy number variations (CNVs) and complex structure variations (cSVs). [Extracted from the article]

Matrix metalloproteinases (MMPs) and their major source, endometrial stromal cells (ESCs), play important roles in menstruation. However, other mechanisms in endometrial shedding may be unexplored. This study focused on four proteins: S100A8 and S100A9 (alarmins) are binding partners and induce MMPs, MMP-3 cycle-dependently plays a key role in the proteolytic cascade, and CD147, which has S100A9 as its ligand, induces MMPs. Immunostaining for these proteins was performed on 118 resected specimens. The percentage and location of each positive reaction in ESCs were measured and compared using Image J. The influence of leukocytes on S100A8 or S100A9 immunopositivity was also examined. From the premenstrual phase, S100A8 and MMP-3 began to have overlapping expressions in ESCs of the superficial layer, and ESC detachment was found within these sites. S100A9 was expressed from the late secretory phase and CD147 already from earlier. Later, the expression sites of S100A9 and CD147 included those of S100A8. Before menstruation, S100A8 or S100A9 expression was not affected by leukocytes. These results suggest that the local formation of S100A8/S100A9 complex, which occurs specifically in ESCs upon progesterone withdrawal, induces the local expression of MMP-3 and serves as a switch to the lysis phase. [ABSTRACT FROM AUTHOR]

Oncogenic cell-surface membrane proteins contribute to the phenotypic and functional characteristics of cancer stem cells (CSCs). We employed a proximity-labeling proteomic approach to quantitatively analyze the cell-surface membrane proteins in close proximity to CD147 in CSCs. Furthermore, we compared CSCs to non-CSCs to identify CSC-specific cell-surface membrane proteins that are closely interact with CD147 and revealed that lateral interaction between CD147 and CD276 concealed within the lipid raft microdomain in CSCs, confers resistance to docetaxel, a commonly used chemotherapy agent for various cancer types, including metastatic breast cancer. Moreover, we investigated the clinical relevance of CD147 and CD276 co-expression in HER2+ breast cancer (BC) and triple-negative breast cancer patients who underwent chemotherapy. We observed poor disease-free survival and Overall survival rates in patients of CD147 and CD276 (p = 0.04 and 0.08, respectively). Subsequent immunohistochemical analysis in independent cohorts of HER2+ BC support for the association between co-expression of CD147 and CD276 and a poor response to chemotherapy. Collectively, our study suggests that the lateral interaction between CD147 and its proximal partners, such as CD276, may serve as a poor prognostic factor in BC and a predictive marker for the critical phenotypic determinant of BC stemness. [ABSTRACT FROM AUTHOR]

Ovarian cancer, especially high-grade serous type, is the most lethal gynecological malignancy. The lack of screening programs and the scarcity of symptomatology result in the late diagnosis in about 75% of affected women. Despite very demanding and aggressive surgical treatment, multiple-line chemotherapy regimens and both approved and clinically tested targeted therapies, the overall survival of patients is still unsatisfactory and disappointing. Research studies have recently brought some more understanding of the molecular diversity of the ovarian cancer, its unique intraperitoneal biology, the role of cancer stem cells, and the complexity of tumor microenvironment. There is a growing body of evidence that individualization of the treatment adjusted to the molecular and biochemical signature of the tumor as well as to the medical status of the patient should replace or supplement the foregoing therapy. In this review, we have proposed the principles of the novel regimen of the therapy that we called the "DEPHENCE" system, and we have extensively discussed the results of the studies focused on the ovarian cancer stem cells, other components of cancer metastatic niche, and, finally, clinical trials targeting these two environments. Through this, we have tried to present the evolving landscape of treatment options and put flesh on the experimental approach to attack the high-grade serous ovarian cancer multidirectionally, corresponding to the "DEPHENCE" system postulates. [ABSTRACT FROM AUTHOR]

Background: The CREST study showed that the addition of thoracic radiotherapy (TRT) could improve the survival rate in patients with extensive stage small cell lung cancer (ES-SCLC), but whether TRT can bring survival benefit in the era of immunotherapy remains controversial. This study aimed to explore the efficacy and safety of adding TRT to the combination of PD-L1 inhibitors and chemotherapy. Methods: The patients who received durvalumab or atezolizumab combined with chemotherapy as the first-line treatment of ES-SCLC from January 2019 to December 2021 were enrolled. They were divided into two groups, based on whether they received TRT or not. Propensity score matching (PSM) with a 1:1 ratio was performed. The primary endpoints were progression-free survival (PFS), overall survival (OS) and safety. Results: A total of 211 patients with ES-SCLC were enrolled, of whom 70 (33.2%) patients received standard therapy plus TRT as first-line treatment, and 141 (66.8%) patients in the control group received PD-L1 inhibitors plus chemotherapy. After PSM, a total of 57 pairs of patients were enrolled in the analysis. In all patients, the median PFS (mPFS) in the TRT and non-TRT group was 9.5 and 7.2 months, respectively, with HR = 0.59 (95%CI 0.39–0.88, p = 0.009). The median OS (mOS) in the TRT group was also significantly longer than that in the non-TRT group (24.1 months vs. 18.5 months, HR = 0.53, 95%CI 0.31–0.89, p = 0.016). Multivariable analysis showed that baseline liver metastasis and the number of metastases ≥ 3 were independent prognostic factors for OS. Addition of TRT increased the incidence of treatment-related pneumonia (p = 0.018), most of which were grade 1–2. Conclusions: Addition of TRT to durvalumab or atezolizumab plus chemotherapy significantly improves survival in ES-SCLC. Although it may leads to increased incidence of treatment-related pneumonia, a majority of the cases can be relieved after symptomatic treatment. [ABSTRACT FROM AUTHOR]

Although immunotherapy has been broadly successful in the treatment of hematologic malignancies and a subset of solid tumors, its clinical outcomes for glioblastoma are still inadequate. The results could be due to neuroanatomical structures such as the bloodbrain-barrier, antigenic heterogeneity, and the highly immunosuppressive microenvironment of glioblastomas. The antitumor efficacy of endogenously activated effector cells induced by peptide or dendritic cell vaccines in particular has been insufficient to control tumors. Effector cells, such as T cells and natural killer (NK) cells can be expanded rapidly ex vivo and transferred to patients. The identification of neoantigens derived from tumor-specific mutations is expanding the list of tumor-specific antigens for glioblastoma. Moreover, recent advances in gene-editing technologies enable the effector cells to not only have multiple biological functionalities, such as cytokine production, multiple antigen recognition, and increased cell trafficking, but also relieve the immunosuppressive nature of the glioblastoma microenvironment by blocking immune inhibitory molecules, which together improve their cytotoxicity, persistence, and safety. Allogeneic chimeric antigen receptor (CAR) T cells edited to reduce graft-versushost disease and allorejection, or induced pluripotent stem cell-derived NK cells expressing CARs that use NK-specific signaling domain can be a good candidate for off-the-shelf products of glioblastoma immunotherapy. We here discuss current progress and future directions for T cell and NK cell therapy in glioblastoma. [ABSTRACT FROM AUTHOR]