SOX2 and OCT4 mediate radiation and drug resistance in pancreatic tumor organoids.

Pancreatic cancer has a five-year survival rate of only 10%, mostly due to late diagnosis and limited treatment options. In patients with unresectable disease, either FOLFIRINOX, a combination of 5-fluorouracil (5-FU), oxaliplatin and irinotecan, or gemcitabine plus nab-paclitaxel combined with radiation are frontline standard regimens. However, chemo-radiation therapy has shown limited success because patients develop resistance to chemotherapy and/or radiation. In this study, we evaluated the role of pancreatic cancer stem cells (CSC) using OCT4 and SOX2, CSC markers in mouse pancreatic tumor organoids. We treated pancreatic tumor organoids with 4 or 8 Gy of radiation, 10 µM of 5-FU (5-Fluorouracil), and 100 µM 3-Bromopyruvate (3BP), a promising anti-cancer drug, as a single treatment modalities, and in combination with RT. Our results showed significant upregulation of, OCT4, and SOX2 expression in pancreatic tumor organoids treated with 4 and 8 Gy of radiation, and downregulation following 5-FU treatment. The expression of CSC markers with increasing treatment dose exhibited elevated upregulation levels to radiation and downregulation to 5-FU chemotherapy drug. Conversely, when tumor organoids were treated with a combination of 5-FU and radiation, there was a significant inhibition in SOX2 and OCT4 expression, indicating CSC self-renewal inhibition. Noticeably, we also observed that human pancreatic tumor tissues exhibited heterogeneous and aberrant OCT4 and SOX2 expression as compared to normal pancreas, indicating their potential role in pancreatic cancer growth and therapy resistance. In addition, the combination of 5-FU and radiation treatment exhibited significant inhibition of the ß-catenin pathway in pancreatic tumor organoids, resulting in sensitization to treatment and organoid death. In conclusion, our study emphasizes the crucial role of CSCs in therapeutic resistance in PC treatment. We recommend using tumor organoids as a model system to explore the impact of CSCs in PC and identify new therapeutic targets.

The AAPM/ASTRO 2023 Core Physics Curriculum for Radiation Oncology Residents.

PURPOSE: The American Association of Physicists in Medicine Radiation Oncology Medical Physics Education Subcommittee (ROMPES) has updated the radiation oncology physics core curriculum for medical residents in the radiation oncology specialty. METHODS AND MATERIALS: Thirteen physicists from the United States and Canada involved in radiation oncology resident education were recruited to ROMPES. The group included doctorates and master's of physicists with a range of clinical or academic roles. Radiation oncology physician and resident representatives were also consulted in the development of this curriculum. In addition to modernizing the material to include new technology, the updated curriculum is consistent with the format of the American Board of Radiology Physics Study Guide Working Group to promote concordance between current resident educational guidelines and examination preparation guidelines. RESULTS: The revised core curriculum recommends 56 hours of didactic education like the 2015 curriculum but was restructured to provide resident education that facilitates best clinical practice and scientific advancement in radiation oncology. The reference list, glossary, and practical modules were reviewed and updated to include recent literature and clinical practice examples. CONCLUSIONS: ROMPES has updated the core physics curriculum for radiation oncology residents. In addition to providing a comprehensive curriculum to promote best practice for radiation oncology practitioners, the updated curriculum aligns with recommendations from the American Board of Radiology Physics Study Guide Working Group. New technology has been integrated into the curriculum. The updated curriculum provides a framework to appropriately cover the educational topics for radiation oncology residents in preparation for their subsequent career development.

Interstitial Brachytherapy for Lip Cancer: Technical Aspects to Individualize Treatment Approach and Optimize Outcomes.

Primary radiation therapy using interstitial brachytherapy (IBT) provides excellent local tumor control for early-stage squamous cell carcinoma of the lip. Technical aspects of treatment are important to optimize outcomes. In this report, we discuss patient selection criteria, procedural details, and dosimetric considerations for performing IBT for cancers of the lip. Catheters are inserted across the length of tumor entering and exiting approximately 5 mm beyond the palpable tumor extent. A custom mouthpiece is fabricated to facilitate normal tissue sparing. Patients undergo computed tomography imaging, the gross tumor volume is contoured based on physical examination and computed tomography findings, and an individualized brachytherapy plan is generated with the goals of achieving gross tumor volume D90% ≥ 90% and minimizing V150%. Ten patients with primary (n = 8) or recurrent (n = 2) cancers of the lip who received high-dose-rate lip IBT using 2.0- to 2.5-week treatment regimens are described (median prescription: 47.6 Gy in 14 fractions of 3.4 Gy). Local tumor control was 100%. There were no cases of acute grade ≥4 or late grade ≥2 toxicity, and cosmesis scores were graded as good to excellent in all patients. IBT represents an excellent treatment option for patients with lip squamous cell carcinoma. With careful attention to technical considerations furthered described in the present report, high rates of tumor control, low rates of toxicity, and favorable esthetic and functional outcomes can be achieved with IBT for lip cancer.

Proton Arc Therapy vs Interstitial HDR Brachytherapy in Gynecologic Cancer with Parametrial/pelvic Side Wall Extension.

Purpose: To investigate whether volumetric-modulated proton arc therapy (VPAT) plans generate comparable doses to organs at risk (OARs) compared with interstitial high-dose-rate (iHDR) brachytherapy for patients with gynecologic cancer with disease extension to parametrial/pelvic side wall, who are not eligible for the aggressive procedure. Materials and Methods: VPAT delivers proton arc beams by modulated energies at the beam nozzle while maintaining the same incident energy to the gantry during the arc rotation. Plans of 10 patients previously treated with iHDR brachytherapy for high-risk clinical treatment volumes (HRCTV; 31.8-110.6 cm3; lateral dimensions, 4.2-5.6 cm) were selected and compared with VPAT plans. VPAT plans for each patient were designed using a 152- to 245-MeV range of energy-modulated proton beams. Results: HRCTV coverage of the VPAT plans was comparable to that of the iHDR plans, with V150% showing no statistical differences. On average, the V100% and V90% of VPAT plans were higher than those of the iHDR plans, 95.0% vs 91.9% (P = .02) and 98.6% vs 97.5% (P = .02), respectively. D100 was also 17% higher for the VPAT plans (P = .03). On average, the D2cm3 of bladder, rectum, and small bowels in the VPAT plans were considerably lower than those in iHDR plans (by 17.4%, 35.2%, and 65.6%, respectively; P < .05 for all OARs). Conclusion: VPAT-generated plans were dosimetrically superior to those with HDR brachytherapy with interstitial needles for locally advanced gynecologic cancer with parametrial/pelvic side wall disease extension. Dosimetrically, VPAT provides a noninvasive alternative to iHDR brachytherapy with a superior dosimetric profile.

Pancreatic cancer derived 3D organoids as a clinical tool to evaluate the treatment response.

Background and purpose: Pancreatic cancer (PC) is the fourth leading cause of cancer death in both men and women. The standard of care for patients with locally advanced PC of chemotherapy, stereotactic radiotherapy (RT), or chemo-radiation-therapy has shown highly variable and limited success rates. However, three-dimensional (3D) Pancreatic tumor organoids (PTOs) have shown promise to study tumor response to drugs, and emerging treatments under in vitro conditions. We investigated the potential for using 3D organoids to evaluate the precise radiation and drug dose responses of in vivo PC tumors. Methods: PTOs were created from mouse pancreatic tumor tissues, and their microenvironment was compared to that of in vivo tumors using immunohistochemical and immunofluorescence staining. The organoids and in vivo PC tumors were treated with fractionated X-ray RT, 3-bromopyruvate (3BP) anti-tumor drug, and combination of 3BP + fractionated RT. Results: Pancreatic tumor organoids (PTOs) exhibited a similar fibrotic microenvironment and molecular response (as seen by apoptosis biomarker expression) as in vivo tumors. Untreated tumor organoids and in vivo tumor both exhibited proliferative growth of 6 folds the original size after 10 days, whereas no growth was seen for organoids and in vivo tumors treated with 8 (Gray) Gy of fractionated RT. Tumor organoids showed reduced growth rates of 3.2x and 1.8x when treated with 4 and 6 Gy fractionated RT, respectively. Interestingly, combination of 100 µM of 3BP + 4 Gy of RT showed pronounced growth inhibition as compared to 3-BP alone or 4 Gy of radiation alone. Further, positive identification of SOX2, SOX10 and TGFß indicated presence of cancer stem cells in tumor organoids which might have some role in resistance to therapies in pancreatic cancer. Conclusions: PTOs produced a similar microenvironment and exhibited similar growth characteristics as in vivo tumors following treatment, indicating their potential for predicting in vivo tumor sensitivity and response to RT and combined chemo-RT treatments.

Therapeutic Efficacy of Variable Biological Effectiveness of Proton Therapy in U-CH2 and MUG-Chor1 Human Chordoma Cell Death.

BACKGROUND: Chordoma is a cancer of spinal cord, skull base, and sacral area. Currently, the standard of care to treat chordoma is resection followed by radiation therapy. Since, chordoma is present in the spinal cord and these are very sensitive structures and often complete removal by surgery is not possible. As a result, chordoma has a high chance of recurrence and developing resistance to radiation therapy. In addition, treatment of chordoma by conventional radiation therapy can also damage normal tissues surrounding chordoma. Thus, current therapeutic options to treat chordoma are insufficient and novel therapies are desperately needed to treat locally advanced and metastatic chordoma. (2) Methods: In the present investigation, human chordoma cell lines of sacral origin MUG-Chor1 and U-CH2 were cultured and irradiated with Proton Beam Radiation using the clinical superconducting cyclotron and pencil-beam (active) scanning at Middle and End of the Spread-Out Bragg Peak (SOBP). Proton radiation was given at the following doses: Mug-Chor1 at 0, 1, 2, 4, and 8 Gy and U-CH2 at 0, 4, 8, 12, and 16 Gy. These doses were selected based on a pilot study in our lab and attempted to produce approximate survival fractions in the range of 1, 0.9, 0.5, 0.1, and 0.01, respectively, chosen for linear quadratic model fitting of the dose response. (3) Results: In this study, we investigated relative biological effectiveness (RBE) of proton radiation at the end of Spread Out Bragg Peak assuming that the reference radiation is a proton radiation in the middle of the SOBP. We observed differences in the survival of both Human chordoma cell lines, U-CH2 and MUG-Chor1. The data showed that there was a significantly higher cell death at the end of the Bragg peak as compared to middle of the Bragg peak. Based on the linear quadratic (LQ) fit for cell survival we calculated the RBE between M-SOBP and E-SOBP at 95% CI level and it was observed that RBE was higher than 1 at E-SOBP and caused significantly higher cell killing. Proton field at E-SOBP caused complex DNA damage in comparison to M-EOBP and the genes such as DNA topoisomerase 1, GTSE1, RAD51B were downregulated in E-SOBP treated cells. Thus, we conclude that there seems to be substantial variation in RBE (1.3-1.7) at the E-SOBP compared with the M-SOBP.

Conformal Radiation Therapy in Patients With Cardiovascular Implantable Electronic Devices: Proposed Practical Implementation of the 2019 American Association of Physicists in Medicine Task Group No. 203 Risk-Stratified Interrogation Schedule.

PURPOSE: Radiation therapy (RT) in patients with cardiac implantable electronic devices (CIED) carries a risk of device malfunction from radiation exposure. We sought to evaluate the incidence of CIED malfunction in a cohort of patients treated with modern RT techniques. METHODS AND MATERIALS: A retrospective analysis of 193 CIED patients treated with RT between 2000 and 2018 was conducted. All patients underwent pre-, intra-, and post-RT CIED interrogations. Patient demographics, CIED details, RT details, including total dose, modality, treatment site, CIED distance from RT field, treatment planning system maximum dose and in vivo dose estimates, and CIED malfunction data were analyzed. RESULTS: CIEDs in use were mainly pacemakers (single-chamber 10%, dual-chamber 49%) and defibrillators (35%). Patients received a median RT dose of 50 Gy (range, 7-80 Gy), treated with 3-dimensional CRT (47%), intensity modulated RT/volumetric modulated arc therapy (38%), and stereotactic body radiation therapy (10%). Neutron producing energies were used in 13% of the treatments. A strong correlation was noted between treatment planning system estimated maximum dose and in vivo estimated CIED dose when the CIED distance from the treatment field was >3 cm. However, in vivo measurements provide a lower estimated absorbed dose for CIED devices <3 cm from the RT field. During a median follow-up of 24 months (range, 7-64 months), 2 adverse CIED-related events were recorded: a spontaneous defibrillator discharge and a pacemaker malfunction subsequently causing ventricular tachycardia. Both patients received stereotactic body radiation therapy to the thorax, with CIED dose of 5 and 19.2 cGy, respectively. Both events occurred 2 years posttreatment without any intra- or post-RT CIED interrogations changes noted. CONCLUSIONS: In this series of patients treated with modern RT techniques, we observed a CIED malfunction rate of 1.04%. These low event rates establish the safety of delivering modern RT in CIED patients with the possibility of reducing the burden of intra- and posttreatment CIED monitoring.

Toward automation of initial chart check for photon/electron EBRT: the clinical implementation of new AAPM task group reports and automation techniques.

PURPOSE: The recently published AAPM TG-275 and the public review version of TG-315 list new recommendations for comprehensive and minimum physics initial chart checks, respectively. This article addresses the potential development and benefit of initial chart check automation when these recommendations are implemented for clinical photon/electron EBRT. METHODS: Eight board-certified physicists with 2-20 years of clinical experience performed initial chart checks using checklists from TG-275 and TG-315. Manual check times were estimated for three types of plans (IMRT/VMAT, 3D, and 2D) and for prostate, whole pelvis, lung, breast, head and neck, and brain cancers. An expert development team of three physicists re-evaluated the automation feasibility of TG-275 checklist based on their experience of developing and implementing the in-house and the commercial automation tools in our institution. Three levels of initial chart check automation were simulated: (1) Auto_UMMS_tool (which consists of in-house program and commercially available software); (2) Auto_TG275 (with full and partial automation as indicated in TG-275); and (3) Auto_UMMS_exp (with full and partial automation as determined by our experts' re-evaluation). RESULTS: With no automation of initial chart checks, the ranges of manual check times were 29-56 min (full TG-315 list) and 102-163 min (full TG-275 list), which varied significantly with physicists but varied little at different tumor sites. The 69 of 71 checks which were considered as "not fully automated" in TG-275 were re-evaluated with more automation feasibility. Compared to no automation, the higher levels of automation yielded a great reduction in both manual check times (by 44%-98%) and potentially residual detectable errors (by 15-85%). CONCLUSION: The initial chart check automation greatly improves the practicality and efficiency of implementing the new TG recommendations. Revisiting the TG reports with new technology/practice updates may help develop and utilize more automation clinically.

Immune checkpoint inhibition in patients treated with stereotactic radiation for brain metastases.

PURPOSE: Stereotactic radiation therapy (SRT) and immune checkpoint inhibitors (ICI) may act synergistically to improve treatment outcomes but may also increase the risk of symptomatic radiation necrosis (RN). The objective of this study was to compare outcomes for patients undergoing SRT with and without concurrent ICI. METHODS AND MATERIALS: Patients treated for BMs with single or multi-fraction SRT were retrospectively reviewed. Concurrent ICI with SRT (SRT-ICI) was defined as administration within 3 months of SRT. Local control (LC), radiation necrosis (RN) risk and distant brain failure (DBF) were estimated by the Kaplan-Meier method and compared between groups using the log-rank test. Wilcoxon rank sum and Chi-square tests were used to compare covariates. Multivariate cox regression analysis (MVA) was performed. RESULTS: One hundred seventy-nine patients treated with SRT for 385 brain lesions were included; 36 patients with 99 lesions received SRT-ICI. Median follow up was 10.3 months (SRT alone) and 7.7 months (SRT- ICI) (p = 0.08). Lesions treated with SRT-ICI were more commonly squamous histology (17% vs 8%) melanoma (20% vs 2%) or renal cell carcinoma (8% vs 6%), (p < 0.001). Non-small cell lung cancer (NSCLC) compromised 60% of patients receiving ICI (n = 59). Lesions treated with SRT-ICI had significantly improved 1-year local control compared to SRT alone (98 and 89.5%, respectively (p = 0.0078). On subset analysis of NSCLC patients alone, ICI was also associated with improved 1 year local control (100% vs. 90.1%) (p = 0.018). On MVA, only tumor size ≤2 cm was significantly associated with LC (HR 0.38, p = 0.02), whereas the HR for concurrent ICI with SRS was 0.26 (p = 0.08). One year DBF (41% vs. 53%; p = 0.21), OS (58% vs. 56%; p = 0.79) and RN incidence (7% vs. 4%; p = 0.25) were similar for SRT alone versus SRT-ICI, for the population as a whole and those patients with NSCLC. CONCLUSION: These results suggest SRT-ICI may improve local control of brain metastases and is not associated with an increased risk of symptomatic radiation necrosis in a cohort of predominantly NSCLC patients. Larger, prospective studies are necessary to validate these findings and better elucidate the impact of SRT-ICI on other disease outcomes.

Immunotherapies and Combination Strategies for Immuno-Oncology.

The advent of novel immunotherapies in the treatment of cancers has dramatically changed the landscape of the oncology field. Recent developments in checkpoint inhibition therapies, tumor-infiltrating lymphocyte therapies, chimeric antigen receptor T cell therapies, and cancer vaccines have shown immense promise for significant advancements in cancer treatments. Immunotherapies act on distinct steps of immune response to augment the body's natural ability to recognize, target, and destroy cancerous cells. Combination treatments with immunotherapies and other modalities intend to activate immune response, decrease immunosuppression, and target signaling and resistance pathways to offer a more durable, long-lasting treatment compared to traditional therapies and immunotherapies as monotherapies for cancers. This review aims to briefly describe the rationale, mechanisms of action, and clinical efficacy of common immunotherapies and highlight promising combination strategies currently approved or under clinical development. Additionally, we will discuss the benefits and limitations of these immunotherapy approaches as monotherapies as well as in combination with other treatments.

A multi-center analysis of single-fraction versus hypofractionated stereotactic radiosurgery for the treatment of brain metastasis.

BACKGROUND: Hypofractionated-SRS (HF-SRS) may allow for improved local control and a reduced risk of radiation necrosis compared to single-fraction-SRS (SF-SRS). However, data comparing these two treatment approaches are limited. The purpose of this study was to compare clinical outcomes between SF-SRS versus HF-SRS across our multi-center academic network. METHODS: Patients treated with SF-SRS or HF-SRS for brain metastasis from 2013 to 2018 across 5 radiation oncology centers were retrospectively reviewed. SF-SRS dosing was standardized, whereas HF-SRS dosing regimens were variable. The co-primary endpoints of local control and radiation necrosis were estimated using the Kaplan Meier method. Multivariate analysis using Cox proportional hazards modeling was performed to evaluate the impact of select independent variables on the outcomes of interest. Propensity score adjustments were used to reduce the effects confounding variables. To assess dose response for HF-SRS, Biologic Effective Dose (BED) assuming an α/ß of 10 (BED10) was used as a surrogate for total dose. RESULTS: One-hundred and fifty six patients with 335 brain metastasis treated with SF-SRS (n = 222 lesions) or HF-SRS (n = 113 lesions) were included. Prior whole brain radiation was given in 33% (n = 74) and 34% (n = 38) of lesions treated with SF-SRS and HF-SRS, respectively (p = 0.30). After a median follow up time of 12 months in each cohort, the adjusted 1-year rate of local control and incidence of radiation necrosis was 91% (95% CI 86-96%) and 85% (95% CI 75-95%) (p = 0.26) and 10% (95% CI 5-15%) and 7% (95% CI 0.1-14%) (p = 0.73) for SF-SRS and HF-SRS, respectively. For lesions > 2 cm, the adjusted 1 year local control was 97% (95% CI 84-100%) for SF-SRS and 64% (95% CI 43-85%) for HF-SRS (p = 0.06). On multivariate analysis, SRS fractionation was not associated with local control and only size ≤2 cm was associated with a decreased risk of developing radiation necrosis (HR 0.21; 95% CI 0.07-0.58, p < 0.01). For HF-SRS, 1 year local control was 100% for lesions treated with a BED10 ≥ 50 compared to 77% (95% CI 65-88%) for lesions that received a BED10 < 50 (p = 0.09). CONCLUSIONS: In this comparison study of dose fractionation for the treatment of brain metastases, there was no difference in local control or radiation necrosis between HF-SRS and SF-SRS. For HF-SRS, a BED10 ≥ 50 may improve local control.

Colorectal Cancer and Probiotics: Are Bugs Really Drugs?

Colorectal cancer (CRC) is one of the most common types of cancer worldwide. There are many factors that predispose a patient to the disease such as age, family history, ethnicity, and lifestyle. There are different genetic factors and diseases that also increase a person's risk for developing CRC. Studies have found associations between gut microbiome and the risk for developing versus protection against CRC. Normal gut microbiome aid in daily functions of the human body such as absorption, metabolism, detoxification, and regulation of inflammation. While some species of bacteria prevent CRC development and aid in therapeutic responses to various treatment regiments, other species seem to promote CRC pathogenesis. In this regard, many studies have been conducted to not only understand the biology behind these opposing different bacterial species; but also to determine if supplementation of these tumor opposing bacterial species as probiotics lends toward decreased risk of CRC development and improved therapeutic responses in patients with CRC. In this literature review, we aim to discuss the basics on colorectal cancer (epidemiology, risk factors, targets, treatments), discuss associations between different bacterial strains and CRC, and discuss probiotics and their roles in CRC prevention and treatment.

Multicriteria optimization: Site-specific class solutions for VMAT plans.

Multicriteria optimization (MCO), a novel commercially available optimization method for IMRT and VMAT has the potential to improve treatment planning techniques and workflows. MCO allows planners and physicians to assess in real time the impact and tradeoffs between all clinical goals and organ constraints. We investigate the feasibility of a universal set of objectives and constraints for VMAT plans in different anatomical sites and the impact of involving the Physician in the navigation of the generated Pareto plans. We randomly selected 20 prostate only, 14 whole pelvis, 10 advanced lung, 15 pancreas, and 7 head and neck plans planned with a VMAT technique. Using the clinically delivered isocenter and beam set-up, we retrospectively generated MCO plans with a universal set of constraints and objectives for each anatomical site. The MCO plan scores were compared with clinical plans or an independent plan generated with DMPO. For prostate only plans the TCP values for the clinical and MCO plans were similar and the rectum NTCP values and overall P+ were slightly better for the MCO plans. For whole pelvis, the resulting MCO plans were comparable in all the dosimetric measures to the clinical plans. For lung, the MCO dosimetric comparison also yielded comparable plans but when evaluating individual patients, there were 5 patients for which MCO plans had a clear advantage in reducing dose to lung and/or esophagus while improving/maintaining target coverage, 4 patients with comparable plans and 1 patient where MCO was worse. Allowing the physician to navigate independently produced a different selection of dosimetric trade-offs. Comparable MCO plans were also obtained for pancreas and head and neck. Based on our experience with many anatomical sites and a large number of patient plans, we have found that VMAT MCO plans are comparable to the clinical plans and can be produced with a universal set of objectives and constraints, even for a wide range of geometries and anatomies.

Improving TBI lung dose calculations: Can the treatment planning system help?

Lung toxicity is a serious concern during total body irradiation (TBI). Therefore, evaluation of accurate dose calculation when using lung blocks is of utmost importance. Existing clinical treatment planning systems can perform the calculation but there are large inaccuracies when calculating volumetric dose at extended distances in the presence of high atomic number materials. Percent depth dose and absolute dose measurements acquired at 400 cm SSD with a cerrobend block were compared with calculated values from the Eclipse treatment planning system using AAA and Acuros. The block was simulated in 2 ways; (1) manually drawing a contour to mimic the block and (2) creating a virtual block in the accessory tray. Although the relative dose distribution was accurately calculated, larger deviations of around 50% and 40% were observed between measured depth dose and absolute dose with AAA and Acuros, respectively. Deviations were reduced by optimizing the relative electron density in the contoured block or the transmission factor in the virtual block.

Novel Delivery Systems for Checkpoint Inhibitors.

Checkpoint inhibition (CPI) therapies have been proven to be powerful clinical tools in treating cancers. FDA approvals and ongoing clinical development of checkpoint inhibitors for treatment of various cancers highlight the immense potential of checkpoint inhibitors as anti-cancer therapeutics. The occurrence of immune-related adverse events, however, is a major hindrance to the efficacy and use of checkpoint inhibitors as systemic therapies in a wide range of patients. Hence, methods of sustained and tumor-targeted delivery of checkpoint inhibitors are likely to improve efficacy while also decreasing toxic side effects. In this review, we summarize the findings of the studies that evaluated methods of tumor-targeted delivery of checkpoint inhibitors, review their strengths and weaknesses, and discuss the outlook for therapeutic use of these delivery methods.

Checkpoint Inhibition: Will Combination with Radiotherapy and Nanoparticle-Mediated Delivery Improve Efficacy?

Checkpoint inhibition (CPI) has been a rare success story in the field of cancer immunotherapy. Knowledge gleaned from preclinical studies and patients that do not respond to these therapies suggest that the presence of tumor-infiltrating lymphocytes and establishment of immunostimulatory conditions, prior to CPI treatment, are required for efficacy of CPI. To this end, radiation therapy (RT) has been shown to promote immunogenic cell-death-mediated tumor-antigen release, increase infiltration and cross-priming of T cells, and decreasing immunosuppressive milieu in the tumor microenvironment, hence allowing CPI to take effect. Preclinical and clinical studies evaluating the combination of RT with CPI have been shown to overcome the resistance to either therapy alone. Additionally, nanoparticle and liposome-mediated delivery of checkpoint inhibitors has been shown to overcome toxicities and improve therapeutic efficacy, providing a rationale for clinical investigations of nanoparticle, microparticle, and liposomal delivery of checkpoint inhibitors. In this review, we summarize the preclinical and clinical studies of combined RT and CPI therapies in various cancers, and review findings from studies that evaluated nanoparticle and liposomal delivery of checkpoint inhibitors for cancer treatments.

Ethnic heterogeneity and prostate cancer mortality in Hispanic/Latino men: a population-based study.

BACKGROUND: Few studies focus on prostate cancer (PCa) outcomes in Hispanic/Latino men. Our study explores whether Hispanic/Latino subgroups demonstrate significantly different prostate cancer-specific mortality (PCSM) relative to Non-Hispanic White (NHW) and Non-Hispanic Black (NHB) men. METHODS: We extracted a population-based cohort of men diagnosed with local-regional PCa from 2000-2013 (n= 486,865). PCSM was measured in racial/ethnic groups: NHW (n=352,886), NHB (n= 70,983), Hispanic/Latino (n= 40,462), and Asian American/Pacific Islander (n= 22,534). PCSM was also measured in Hispanic/Latino subgroups: Mexican (n= 8,077), Puerto Rican (n= 1,284), South or Central American (n= 3,021), Cuban (n= 788), and Dominican (n= 300). We conducted univariable and multivariable analyses (MVA) to compare risk for PCSM. RESULTS: Compared to NHW men, results showed worse outcomes for NHB men with similar outcomes for Hispanic/Latino men. In MVA with NHW men as a reference, NHB (HR= 1.15, p <0.001) men had significantly worse PCSM and Hispanic/Latino (HR= 1.02, p= 0.534) men did not show a significant difference. In a second MVA, Puerto Rican (HR= 1.71, p <0.001) and Mexican (HR= 1.21, p= 0.008) men had significantly higher PCSM. With NHB men as a reference, the MVA showed Puerto Rican (HR= 1.50, p= 0.006) men with higher PCSM and Mexican (HR= 1.08, p= 0.307) men with no significant difference. CONCLUSIONS: Our findings indicate previously unknown disparities in PCSM for Puerto Rican and Mexican American men.