Krishnan, Sunil

Surgical treatment of pelvic sarcoma involving the bone is the standard of care but is associated with several sequelae and reduced functional quality of life (QOL). Treatment with photon and proton radiotherapy is associated with relapse. Carbon ion radiotherapy (CIRT) may reduce both relapse rates and treatment sequelae. The PROSPER study is a tricontinental, nonrandomized, prospective, three-arm, pragmatic trial evaluating treatments of pelvic sarcoma involving the bone. Patients aged at least 15 years are eligible for inclusion. Participants must have an Eastern Cooperative Oncology Group Performance Status score of two or less, newly diagnosed disease, and histopathologic confirmation of pelvic chordoma, chondrosarcoma, osteosarcoma, Ewing sarcoma with bone involvement, rhabdomyosarcoma (RMS) with bone involvement, or non-RMS soft tissue sarcoma with bone involvement. Treatment arms include (1) CIRT (n = 30) delivered in Europe and Asia, (2) surgical treatment with or without adjuvant radiotherapy (n = 30), and (3) proton therapy (n = 30). Arms two and three will be conducted at Mayo Clinic campuses in Arizona, Florida, and Minnesota. The primary end point is to compare the 1-year change in functional QOL between CIRT and surgical treatment. Additional comparisons among the three arms will be made between treatment sequelae, local control, and other QOL measures.

489 Background: To determine if SBRT followed by sorafenib (SBRT/S) improves overall survival (OS), progression free survival (PFS) and quality of life (QOL) vs. sorafenib alone (S), in patients (pts) with HCC. Methods: Eligible pts had new or recurrent HCC, unsuitable for surgery, ablation or TACE, with Zubrod performance status (PS) 0-2, Child-Pugh (CP) A, BCLC stage B or C, ≤ 5 HCCs, sum of hepatic HCCs ≤ 20 cm, and distant metastases ≤ 3 cm. Pts were randomized 1:1 to S 400 mg BID vs. SBRT (27.5-50 Gy in 5 fractions) followed by S 200 mg BID, increased to 400 mg BID after 28 days. Primary endpoint was OS; reported secondary endpoints - PFS, adverse events (AEs - CTCAEv4), and QOL (improvement in FACT-Hep score by ≥ 5 points from baseline to 6 months). Planned sample size was 292 pts (238 OS events, HR=0.72, 80% power, 1-sided α=0.05). Accrual closed early, due to a change in HCC standard of care. Statistics were amended to report as of 7/1/2022, projecting 155 OS events, with 65% power and the same α. OS and PFS were estimated by Kaplan-Meier and arms compared using log-rank test. Cox proportional hazards models were used to analyze treatment effect. Secondary endpoints were tested with 2-sided α=0.05. Results: Of 193 pts accrued from April 2013 to March 2021 from 23 sites, 177 eligible pts were randomized to S (n=92) vs. SBRT/S (n=85). Median age was 66 yrs (27-84); 41% had Hep. C; 19% had Hep. B or B/C. 82% were BCLC stage C. 74% had macrovascular invasion (MVI), 63% with VP3 or VP4 MVI. 4% had metastases. Median sum of max diameter of HCCs was 8.2 cm for S and 6.7 cm for SBRT/S; 40% had a single HCC. Median follow-up for all and alive pts was 13.2 and 33.7 mo. 22% of S pts received SBRT after discontinuing S. With 153 OS events, median OS was improved from 12.3 mo. (90% CI 10.6, 14.3) with S to 15.8 mo. (90% CI 11.4-19.2) with SBRT/S (HR=0.77, 1-sided p=0.0554). After adjusting for PS, M stage, CP A5 vs. 6, and degree of MVI, OS was statistically significantly improved for SBRT/S (HR=0.72, 95% CI 0.52-0.99, 2-sided Cox p=0.042). Median PFS was improved from 5.5 mo. (95% CI 3.4-6.3) with S to 9.2 months (95% CI 7.5-11.9) with SBRT/S (HR=0.55, 95% CI 0.40-0.75, 2-sided p=0.0001). 8 grade (G) 3+ bleeds were seen: 5 in S arm (1 G3 variceal, 2 G3 upper GI, 1 G3 hepatic, and 1 G4 abdominal) and 3 post SBRT/S (2 G3 upper GI, 1 G3 lower GI). Treatment-related G3+ AEs were not significantly different (S - 42%; SBRT/S - 47%; p=0.52), with 3 G5 AEs (S - 1 hepatic failure, 1 death NOS; SBRT/S - 1 lung infection). 83 (47%) pts consented to QoL. Of 20 S and 17 SBRT/S pts with QoL assessments at baseline and 6 months, 10% on S improved in FACT-Hep score vs 35% on SBRT/S. Conclusions: Compared to S alone, SBRT improved OS & PFS in patients with HCC, with no observed increase in AEs, and a strong suggestion for QOL benefit at 6 months. Supported by U10CA180868 (NRG Onc. Op., U10CA180822 (NRG Onc. SDMC), UG1CA189867 (NCORP), and U24CA180803 (IROC) from the NCI. Clinical trial information: NCT01730937 .

Coating nanoparticles with stealth epilayers increases circulation time by evading opsonization, macrophage phagocytosis, and reticuloendothelial sequestration. However, this also reduces internalization by cancer cells upon reaching the tumor. We designed gold nanorods (GNRs) with an epilayer that retains stealth properties in circulation but transforms spontaneously in the acidotic tumor microenvironment to a cell-penetrating particle. We used a customized stoichiometric ratio of l -glutamic acid and l -lysine within an amphiphilic polymer of poly( l -glutamic acid-co- l -lysine), or P(Glu-co-Lys), to effect this transformation in acidotic environments. P(Glu-co-Lys)-GNRs were internalized by cancer cells to facilitate potent in vitro radiosensitization. When administered intravenously in mice, they accumulate in the periphery and core of tumors without any signs of serum biochemical or hematological alterations, normal organ histopathological abnormalities, or overt deterioration in animal health. Furthermore, P(Glu-co-Lys)-GNRs penetrated the tumor microenvironment to accumulate in the hypoxic cores of tumors to potently radiosensitize heterotopic and orthotopic pancreatic cancers in vivo.

AbstractRadioenhancing nanoparticles (NPs) are being evaluated in ongoing clinical trials for various cancers including head and neck, lung, esophagus, pancreas, prostate, and soft tissue sarcoma. Supported by decades of preclinical investigation and recent randomized trial data establishing clinical activity, these agents are poised to influence future multimodality treatment paradigms involving radiotherapy. Although the physical interactions between NPs and ionizing radiation are well characterized, less is known about how these agents modify the tumor microenvironment, particularly regarding tumor immunogenicity. In this review, we describe the key multidisciplinary considerations related to radiation, surgery, immunology, and pathology for designing radioenhancing NP clinical trials.This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease

Abstract Background Pancreatic cancer is one of the leading causes of cancer deaths worldwide. Current chemoradiation therapy suffers from normal tissue toxicity. To overcome this problem, we are proposing incorporating nanoparticles as radiosensitizers and as drug delivery vehicles into current chemoradiation regimes. Gold nanoparticles (GNPs) and Docetaxel (DTX) have shown very promising synergetic radiosensitization effects despite DTX toxicity to normal tissues. Here, we explored the effect of DTX prodrug encapsulated in lipid nanoparticles (LNPDTX−P) on GNP uptake in pancreatic cancer models in vitro and in vivo. Methods For the in vitro experiment, pancreatic cancer cell line, MIA PaCa-2, were cultured and dosed with 7.5 µg/mL of GNPs (of ~ 11 nm in diameter functionalized with PEG and RGD peptide) and with 45 nM of free DTX or equivalent dose of LNPDTX−P. For the in vivo experiment, MIA PaCa-2 were implanted subcutaneously in NRG mice and the mice were dosed with 2 mg/kg of GNPs and 6 mg/kg of DTX or equivalent dose of LNPDTX−P. GNPs content in mice and in cells were measured using Inductively Coupled Plasma–Mass Spectrometry (ICP–MS). Results The results show that LNPDTX−P treated tumour samples have no less than 191% increase in GNPs uptake compared to control samples in both in vitro and in vivo. The results also show that LNPDTX−P treated tumour samples have retained over 160% of GNPs compared to control samples in both in vitro and in vivo. No significant difference was found in GNP uptake or retention between free DTX and LNPDTX−P in tumour treated samples in vivo. Conclusions The results are very promising as LNPDTX−P have superior targeting of tumour tissues compared to free DTX due to their nano size and their ability to be functionalized. Because of their minimal toxicity to normal tissues, both GNPs and LNPDTX−P can be ideal radiosensitization candidates in radiotherapy and would produce very promising synergistic therapeutic outcome. Current radiotherapy treatments can hugely benefit from the effects of these two radiosensitizers boosting the radiation dose to the tumour while reducing the normal tissue dose. This in return will improve patient outcome and quality of life.

Radiotherapy (RT) of colorectal cancer (CRC) can prime adaptive immunity against tumor-associated antigen (TAA)–expressing CRC cells systemically. However, abscopal tumor remissions are extremely rare, and the postirradiation immune escape mechanisms in CRC remain elusive. Here, we found that irradiated CRC cells used ATR-mediated DNA repair signaling pathway to up-regulate both CD47 and PD-L1, which through engagement of SIRPα and PD-1, respectively, prevented phagocytosis by antigen-presenting cells and thereby limited TAA cross-presentation and innate immune activation. This postirradiation CD47 and PD-L1 up-regulation was observed across various human solid tumor cells. Concordantly, rectal cancer patients with poor responses to neoadjuvant RT exhibited significantly elevated postirradiation CD47 levels. The combination of RT, anti-SIRPα, and anti–PD-1 reversed adaptive immune resistance and drove efficient TAA cross-presentation, resulting in robust TAA-specific CD8 T cell priming, functional activation of T effectors, and increased T cell clonality and clonal diversity. We observed significantly higher complete response rates to RT/anti-SIRPα/anti–PD-1 in both irradiated and abscopal tumors and prolonged survival in three distinct murine CRC models, including a cecal orthotopic model. The efficacy of triple combination therapy was STING dependent as knockout animals lost most benefit of adding anti-SIRPα and anti–PD-1 to RT. Despite activation across the myeloid stroma, the enhanced dendritic cell function accounts for most improvements in CD8 T cell priming. These data suggest ATR-mediated CD47 and PD-L1 up-regulation as a key mechanism restraining radiation-induced immune priming. RT combined with SIRPα and PD-1 blockade promotes robust antitumor immune priming, leading to systemic tumor regressions.

Domestic violence is highly prevalent in Australia and has serious and complex impacts. This study aimed to analyse research outputs on domestic violence in Australia from the period of 1984 to 2019. Articles relevant to domestic violence in Australia that met specified inclusion criteria were retrieved using the Scopus database. Bibliometric analysis of the output was conducted to examine trends in publications. A trend of an increase in publications relating to domestic violence in Australia over time was identified, with the majority published in institutions located in densely populated capital cities. Significant diversity was found in the subject matter of highly cited articles, reflecting the far-reaching impacts of domestic violence. The increase in social attention to domestic violence over time was reflected in an increase in publications. Future research would benefit from examining trends in the reporting of domestic violence, and analysing the effectiveness of interventions for perpetrators and victims.

Background: The most often diagnosed malignancy in women worldwide is cancer of the cervix. It is also the most prevalent kind of gynecological cancer in women. This cancer originates in the opening of the cervix and spreads through sexual contact. Even though human papillomavirus (HPV) may not cause cancer immediately, it does develop over time as a result of the virus’s lengthy persistence to cause dysplastic changes overtime, particularly in high-risk kinds. The primary objective of this research is to see if miRNAs are dysregulated as a result of treatment resistance in cervical cancer (CC). The aim is to see if these microRNAs may be utilized as biomarkers for detecting chemoresistance in CC, particularly for clinical applications. Methods: The recommended protocol for comprehensive study and meta-analysis (PRISMA-P) standards will be utilized for the analysis and data interpretation. The bibliographic databases will be methodically searched using a combination of search keywords. Based on established inclusion and exclusion criteria, the acquired findings will be reviewed, and data retrieved from the selected scientific papers for systematic review. We will then construct a forest from the pooled Hazard ratio (HR) and 95% C.I. values, data obtained using the random-effects model. Discussion: The focus of this study is to identify the function of miRNAs as a chemoresistance regulator and determine if they have the potential scope to be considered as biomarkers for cervical cancer. Through this systematic review and meta-analysis, the goal is to collect, compare, and analyze the data pertaining to the role of miRNAs in cervical cancer, thereby, enabling us to understand the role they play in chemosensitivity.

miRNAs biomarkers are emerging as an essential part of clinical oncology. Their oncogenic and tumour suppressor properties playing a role in malignancy has generated interest in their potential for use in disease prognosis. While several studies on miRNA have been carried out across the globe, evaluating the clinical implications of miRNAs in cancer diagnosis and prognosis research has currently not been attempted. A study delineating the area of miRNA research, including the topics presently being focused on, the seminal papers in this field, and the direction of research interest, does not exist. This study aims to conduct a large-scale, global data analysis and bibliometric profiling analysis of studies to evaluate the research output of clinical implications of miRNAs in cancer diagnosis and prognosis listed in the SCOPUS database. A systematic search strategy was followed to identify and extract all relevant studies, subsequently analysed to generate a bibliometric map. SPSS software (version 27) was used to calculate bibliometric indicators or parameters for analysis, such as year and country of affiliation with leading authors, journals, and institutions. It is also used to analyse annual research outputs, including total citations and the number of times it has been cited with productive nations and H-index. The number of global research articles retrieved for miRNA-Cancer research over the study period 2003 to 2019 was 18,636. Between 2012 and 2019, the growth rate of global publications is six times (n = 15,959; 90.71 percent articles) that of 2003 to 2011. (2704; 9.29 per cent articles). China published the most publications in the field of miRNA in cancer (n = 7782; 41%), while the United States had the most citations (n = 327,538; 48%) during the time span. Of these journals, Oncotarget has the highest percentage of article publications. The journal Cancer Research had the most citations (n = 41,876), with 6.20 per cent (n = 41,876). This study revealed a wide variety of journals in which miRNA-Cancer research are published; these bibliometric parameters exhibit crucial clinical information on performance assessment of research productivity and quality of research output. Therefore, this study provides a helpful reference for clinical oncologists, cancer scientists, policy decision-makers and clinical data researchers.