-
Journal of Experimental & Clinical... Jun 2024Renal cell carcinoma (RCC) was historically considered to be less responsive to radiation therapy (RT) compared to other cancer indications. However, advancements in...
BACKGROUND
Renal cell carcinoma (RCC) was historically considered to be less responsive to radiation therapy (RT) compared to other cancer indications. However, advancements in precision high-dose radiation delivery through single-fraction and multi-fraction stereotactic ablative radiotherapy (SABR) have led to better outcomes and reduced treatment-related toxicities, sparking renewed interest in using RT to treat RCC. Moreover, numerous studies have revealed that certain therapeutic agents including chemotherapies can increase the sensitivity of tumors to RT, leading to a growing interest in combining these treatments. Here, we developed a rational combination of two radiosensitizers in a tumor-targeted liposomal formulation for augmenting RT in RCC. The objective of this study is to assess the efficacy of a tumor-targeted liposomal formulation combining the mTOR inhibitor everolimus (E) with the survivin inhibitor YM155 (Y) in enhancing the sensitivity of RCC tumors to radiation.
EXPERIMENTAL DESIGN
We slightly modified our previously published tumor-targeted liposomal formulation to develop a rational combination of E and Y in a single liposomal formulation (EY-L) and assessed its efficacy in RCC cell lines in vitro and in RCC tumors in vivo. We further investigated how well EY-L sensitizes RCC cell lines and tumors toward radiation and explored the underlying mechanism of radiosensitization.
RESULTS
EY-L outperformed the corresponding single drug-loaded formulations E-L and Y-L in terms of containing primary tumor growth and improving survival in an immunocompetent syngeneic mouse model of RCC. EY-L also exhibited significantly higher sensitization of RCC cells towards radiation in vitro than E-L and Y-L. Additionally, EY-L sensitized RCC tumors towards radiation therapy in xenograft and murine RCC models. EY-L mediated induction of mitotic catastrophe via downregulation of multiple cell cycle checkpoints and DNA damage repair pathways could be responsible for the augmentation of radiation therapy.
CONCLUSION
Taken together, our study demonstrated the efficacy of a strategic combination therapy in sensitizing RCC to radiation therapy via inhibition of DNA damage repair and a substantial increase in mitotic catastrophe. This combination therapy may find its use in the augmentation of radiation therapy during the treatment of RCC patients.
Topics: Carcinoma, Renal Cell; Animals; Survivin; Humans; Mice; Cell Line, Tumor; Kidney Neoplasms; DNA Repair; TOR Serine-Threonine Kinases; Xenograft Model Antitumor Assays; Mitosis; Imidazoles; DNA Damage; Everolimus; Naphthoquinones; Radiation-Sensitizing Agents; Liposomes; MTOR Inhibitors
PubMed: 38840237
DOI: 10.1186/s13046-024-03079-8 -
ESMO Open Jun 2024Most patients with pancreatic ductal adenocarcinoma (PDAC) do not benefit from immune checkpoint inhibitor treatment. However, the phase II study CheckPAC (NCT02866383)...
BACKGROUND
Most patients with pancreatic ductal adenocarcinoma (PDAC) do not benefit from immune checkpoint inhibitor treatment. However, the phase II study CheckPAC (NCT02866383) showed a clinical benefit (CB) rate of 37% and a response rate of 14% in patients with metastatic PDAC receiving stereotactic radiation therapy and nivolumab with or without ipilimumab. Translational studies were initiated to characterize the patients who would benefit from this treatment. Here, we evaluated the association between treatment outcome and 92 circulating immuno-oncology-related proteins in patients from the CheckPAC trial.
MATERIALS AND METHODS
The study included 78 patients with chemoresistant metastatic PDAC treated with nivolumab ± ipilimumab combined with radiotherapy. Proteins were measured in serum samples collected at baseline and on treatment with the use of the Olink Target 96 Immuno-Oncology panel. A cohort of 234 patients with metastatic PDAC treated with first-line chemotherapy were also included.
RESULTS
High levels of Fas ligand (FASLG) and galectin 1 (Gal-1) and low levels of C-C motif chemokine 4 were associated with CB. High FASLG and Gal-1 were associated with longer progression-free survival in univariable analysis. In the multivariable Cox regression analysis, the association was significant for Gal-1 (P < 0.001) but not significant for FASLG (P = 0.06). A focused unsupervised hierarchal clustering analysis, including T-cell activation and immune checkpoint-related proteins, identified clusters of patients with higher CB rate and higher tumor expression of leukocyte or T-cell markers (CD3, CD45, granzyme B). Thirty-six proteins increased significantly during immunotherapy. Several proteins (including FASLG, checkpoint proteins, and immune activation markers) increased independently of response during immunotherapy but did not increase in the cohort of patients treated with chemotherapy.
CONCLUSIONS
Circulating levels of immune-related proteins like FASLG and Gal-1 might be used to predict the efficacy of checkpoint inhibitors in patients with metastatic PDAC.
Topics: Humans; Carcinoma, Pancreatic Ductal; Male; Female; Immune Checkpoint Inhibitors; Pancreatic Neoplasms; Aged; Middle Aged; Biomarkers, Tumor; Ipilimumab; Treatment Outcome
PubMed: 38838501
DOI: 10.1016/j.esmoop.2024.103489 -
Investigative Ophthalmology & Visual... Jun 2024The purpose of this study was to analyze the extent of DNA breaks in primary uveal melanoma (UM) with regard to radiotherapy dose delivery (single-dose versus...
PURPOSE
The purpose of this study was to analyze the extent of DNA breaks in primary uveal melanoma (UM) with regard to radiotherapy dose delivery (single-dose versus fractionated) and monosomy 3 status.
METHODS
A total of 54 patients with UM were included. Stereotactic radiotherapy (SRT) was performed in 23 patients, with 8 undergoing single-dose SRT (sdSRT) treatment and 15 receiving fractionated SRT (fSRT). DNA breaks in the enucleated or endoresected tumors were visualized by a TUNEL assay and quantified by measuring the TUNEL-positive area. Protein expression was analyzed by immunohistochemistry. Co-detection of chromosome 3 with proteins was performed by immuno-fluorescent in situ hybridization.
RESULTS
The amount of DNA breaks in the total irradiated group was increased by 2.7-fold (P < 0.001) compared to non-irradiated tissue. Tumors treated with fSRT were affected more severely, showing 2.1-fold more DNA damage (P = 0.007) compared to the cases after single (high) dose irradiation (sdSRT). Monosomy 3 tumors showed less DNA breaks compared to disomy 3 samples (P = 0.004). The presence of metastases after radiotherapy correlated with monosomy 3 and less DNA breaks compared to patients with non-metastatic cancer in the combined group with fSRT and sdSRT (P < 0.05).
CONCLUSIONS
Fractionated irradiation led to more DNA damage than single-dose treatment in primary UM. As tumors with monosomy 3 showed less DNA breaks than those with disomy 3, this may indicate that they are less radiosensitive, which may influence the efficacy of irradiation.
Topics: Humans; Uveal Neoplasms; Melanoma; Female; Chromosomes, Human, Pair 3; Male; Middle Aged; Aged; DNA Damage; Adult; Aged, 80 and over; In Situ Hybridization, Fluorescence; In Situ Nick-End Labeling; Radiotherapy Dosage; Immunohistochemistry; Radiosurgery; Dose-Response Relationship, Radiation
PubMed: 38833258
DOI: 10.1167/iovs.65.6.7 -
World Neurosurgery May 2024Obtaining a definitive pathological diagnosis from brain tissue sampling was challenging due to the small, non-representative sample. This study introduced a novel...
OBJECTIVES
Obtaining a definitive pathological diagnosis from brain tissue sampling was challenging due to the small, non-representative sample. This study introduced a novel syringe technique for brain biopsy aimed at enhancing diagnostic accuracy by obtaining core tissue samples that better represent the targeted tissue.
METHODS
The ten patients with atypical brain lesions underwent the syringe biopsy. After meticulous preoperative planning with neuronavigation, a minimally invasive approach was used: a 3 cm skin incision and a 14 mm burr hole were created. A modified 3-cc syringe was used to create negative pressure and cannulate the brain tissue. The desired sample size (24 cm³) was obtained by controlling the syringe depth and withdrawal. Medical records were reviewed to assess sample analysis results and any complications RESULTS: The syringe technique successfully yielded adequate tissue samples in 9 out of 10 patients. In one case, the desired tissue could not be retrieved and required a microsurgical approach for removal. In all ten cases, a correct diagnosis was made without significant complications.
CONCLUSION
The preliminary findings suggest that the syringe technique is both safe and effective for obtaining substantial volumes of brain tissue, facilitating accurate pathological evaluation in cases of complex neurological disorders.
PubMed: 38825309
DOI: 10.1016/j.wneu.2024.05.153 -
The French Journal of Urology May 2024The incidence of localized renal cell carcinoma (RCC) is on the rise among individuals aged 70 and older. While the gold standard for treatment remains surgical...
INTRODUCTION
The incidence of localized renal cell carcinoma (RCC) is on the rise among individuals aged 70 and older. While the gold standard for treatment remains surgical resection, some elderly and frail patients with comorbidities are not eligible for this procedure. In selected cases, percutaneous thermal ablation, such as cryotherapy, microwave and radiofrequency, offers less invasive options. General anesthesia is sometimes necessary for such treatments, but most of the procedures can be conducted using mild or deep conscious sedation. This approach is preferably recommended for small cT1a tumors situated at a distance from the renal hilum and/or ureter. Active surveillance remains an alternative in the case of small low grade RCC although it may induce anxiety in certain patients. Recent research has highlighted the potentials of stereotactic ablative body radiotherapy (SABR) as a noninvasive, well-tolerated, and effective treatment for small renal tumors. This narrative review aims to explore recent advances in SABR for localized RCC, including appropriate patient selection, treatment modalities and administration, as well as efficacy and tolerance assessment.
MATERIAL AND METHODS
We conducted a literature review using the terms [kidney cancer], [renal cell carcinoma], [stereotactic radiotherapy], [SBRT], and [SABR] in the Medline, PubMed, and Embase databases, focusing on prospective and relevant retrospective studies published in English.
RESULTS
Studies report local control rates ranging from 70% to 100% with SABR, highlighting its efficacy in treating RCC. The decline in glomerular filtration rate (GFR) is approximately -5 to -17mL/min over the years following SABR. Common toxicities are rare, primarily CTCAE grade 1, include fatigue, nausea, chest or back pain, diarrhea, or gastritis.
CONCLUSION
Stereotactic ablative body radiotherapy (SABR) may be considered as a viable option for patients with localized RCC who are not suitable candidates for surgery with a high local control rate and a favorable safety profile. This approach should be discussed in a multidisciplinary meeting and results from ongoing clinical trials are awaited.
PubMed: 38823486
DOI: 10.1016/j.fjurol.2024.102660 -
World Neurosurgery May 2024To summarize the preliminary application experience of intraoperative ultrasound with burr hole probe in minimally invasive neurosurgery and to explore its application...
OBJECTIVE
To summarize the preliminary application experience of intraoperative ultrasound with burr hole probe in minimally invasive neurosurgery and to explore its application value.
METHODS
Thirty-one patients who underwent intraoperative ultrasound guided puncture with burr hole probe in our center from August 2018 to May 2024 were collected, including 16 cases of ventriculoperitoneal shunt operation, 6 cases of assisted stereotactic needle biopsy, 3 cases of intracranial pressure probe implantation in lateral ventricle, 3 cases of brain abscess puncture for external drainage, and 3 cases of intracranial cyst puncture and peritoneal drainage. During the procedures, the burr hole probe was used to locate the intracranial targets and guide the puncture. The postoperative computed tomography (CT) scans or combined postoperative pathological results could verify the accuracy of puncture. In addition, the intervention effect and recovery status of patients were also recorded.
RESULTS
The intraoperative ultrasound with burr hole probe could clearly display all the purposed targets and accurately guide the puncture procedures in all cases. All patients achieved satisfactory diagnostic and therapeutic results without new neurological dysfunction and serious complications.
CONCLUSIONS
The intraoperative ultrasound with burr hole probe is an effective device for demonstrating intracranial structures. It not only enables minimally invasive and precise diagnosis or treatment of many neurosurgical diseases, but also is simple and safe to operate, which has important promotional value in the neurosurgery.
PubMed: 38821403
DOI: 10.1016/j.wneu.2024.05.146 -
The Lancet. Oncology Jun 2024
Topics: Humans; Radiosurgery; Kidney Neoplasms; Treatment Outcome; Carcinoma, Renal Cell
PubMed: 38821091
DOI: 10.1016/S1470-2045(24)00276-6 -
The Lancet. Oncology Jun 2024
Topics: Humans; Radiosurgery; Kidney Neoplasms; Treatment Outcome; Carcinoma, Renal Cell
PubMed: 38821090
DOI: 10.1016/S1470-2045(24)00252-3 -
The Lancet. Oncology Jun 2024
Topics: Humans; Radiosurgery; Kidney Neoplasms; Treatment Outcome; Carcinoma, Renal Cell
PubMed: 38821089
DOI: 10.1016/S1470-2045(24)00181-5 -
Journal of Neurosurgery May 2024Targeting accuracy presents a key factor in achieving maximal safe ablation in laser interstitial thermal therapy (LITT). The VarioGuide system has proven precise for...
OBJECTIVE
Targeting accuracy presents a key factor in achieving maximal safe ablation in laser interstitial thermal therapy (LITT). The VarioGuide system has proven precise for brain biopsies, but data showing its accuracy in combination with LITT are limited. The aim of this study was to determine the phantom and in vivo accuracy of LITT probe placement using the VarioGuide system and to evaluate the effect of targeting error on maximum possible ablation volume.
METHODS
Stereotactic LITT probe placement was performed using the VarioGuide system in 3 phantom skulls. The same system was used in 10 patients treated with LITT, for which data were retrospectively analyzed. Target point error (TPE), target depth deviation (TDD), target lateral deviation (TLD), and angular deviation (AD) were derived from intraprocedural MRI scans of both the phantom and in vivo trajectories. In vivo, the effect of targeting error on the maximum reachable ablation was calculated as the difference between the planned maximal achievable tumor ablation (PTA) and the actual maximal achievable tumor ablation (ATA).
RESULTS
In total, 24 phantom and 16 in vivo trajectories were analyzed. In the phantom setting, the median TPE was 3.3 mm and median AD was 1.9°. Targeting accuracy significantly decreased for longer trajectories and those less perpendicular to the skull. In patients, the authors observed a comparable median TPE of 4.0 mm but significantly higher AD of 3.2°. In vivo, targeting inaccuracy resulted in a median decrease in maximum achievable ablation volume of 6% as compared to the planned trajectory.
CONCLUSIONS
The authors' study indicates that utilizing the VarioGuide system in combination with LITT yields an average targeting error as large as 4 mm, which was smaller for shorter and straighter trajectories. In patients, targeting inaccuracy resulted in a median 6% decrease of the planned tumor ablation volume. These are important factors that should be considered in optimal case planning and patient selection in LITT.
PubMed: 38820615
DOI: 10.3171/2024.3.JNS24193