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American Society of Clinical Oncology... Jun 2024Clinical investigation of immune checkpoint inhibitors (ICIs) has expanded from indications in metastatic non-small cell lung cancer (NSCLC) to add to the treatment of... (Review)
Review
Clinical investigation of immune checkpoint inhibitors (ICIs) has expanded from indications in metastatic non-small cell lung cancer (NSCLC) to add to the treatment of early-stage or resectable NSCLC. Although completed randomized trials supported the approvals of some ICIs as perioperative therapies (ie, adjuvant, neoadjuvant, or neoadjuvant followed by adjuvant), ongoing trials are evaluating other anti-PD-(L)1 antibodies for similar indications, or in combination with stereotactic body radiotherapy (SBRT). The incorporation of immunotherapy brings potential to improve outcomes of patients with resectable NSCLC, but these advances have also increased the complexity of the treatment landscape and created important knowledge gaps. This article reviews the current standards for local therapies in NSCLC, describes the clinical trials exploring the combination of ICIs to SBRT, and explains the recent approvals of ICIs as perioperative therapies. A discussion follows to highlight three important areas of uncertainty: (1) the contribution of ICIs given in each treatment phase (neoadjuvant and adjuvant) to the overall effect of neoadjuvant chemoimmunotherapy followed by adjuvant ICIs; (2) the selection of regimens to serve as comparators in future randomized trials of perioperative therapies; and (3) the role of pathologic complete response as an intermediate end point and aid for selection of patients for adjuvant therapy. Moving forward, stakeholders will need to engage in concerted research efforts to address the relevant clinical questions regarding the optimal management of resectable NSCLC.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Immunotherapy; Immune Checkpoint Inhibitors; Combined Modality Therapy; Neoadjuvant Therapy; Treatment Outcome
PubMed: 38788177
DOI: 10.1200/EDBK_432500 -
International Journal of Oncology Jul 2024The prognosis for patients with non‑small cell lung cancer (NSCLC), a cancer type which represents 85% of all lung cancers, is poor with a 5‑year survival rate of... (Review)
Review
The prognosis for patients with non‑small cell lung cancer (NSCLC), a cancer type which represents 85% of all lung cancers, is poor with a 5‑year survival rate of 19%, mainly because NSCLC is diagnosed at an advanced and metastatic stage. Despite recent therapeutic advancements, ~50% of patients with NSCLC will develop brain metastases (BMs). Either surgical BM treatment alone for symptomatic patients and patients with single cerebral metastases, or in combination with stereotactic radiotherapy (RT) for patients who are not suitable for surgery or presenting with fewer than four cerebral lesions with a diameter range of 5‑30 mm, or whole‑brain RT for numerous or large BMs can be administered. However, radioresistance (RR) invariably prevents the action of RT. Several mechanisms of RR have been described including hypoxia, cellular stress, presence of cancer stem cells, dysregulation of apoptosis and/or autophagy, dysregulation of the cell cycle, changes in cellular metabolism, epithelial‑to‑mesenchymal transition, overexpression of programmed cell death‑ligand 1 and activation several signaling pathways; however, the role of the Hippo signaling pathway in RR is unclear. Dysregulation of the Hippo pathway in NSCLC confers metastatic properties, and inhibitors targeting this pathway are currently in development. It is therefore essential to evaluate the effect of inhibiting the Hippo pathway, particularly the effector yes‑associated protein‑1, on cerebral metastases originating from lung cancer.
Topics: Humans; Brain Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Radiation Tolerance; Hippo Signaling Pathway; Protein Serine-Threonine Kinases; Signal Transduction; Radiosurgery; Epithelial-Mesenchymal Transition; Molecular Targeted Therapy
PubMed: 38785155
DOI: 10.3892/ijo.2024.5656 -
Brain Research Bulletin Jul 2024The medial prefrontal cortex (mPFC) forms output pathways through projection neurons, inversely receiving adjacent and long-range inputs from other brain regions....
INTRODUCTION
The medial prefrontal cortex (mPFC) forms output pathways through projection neurons, inversely receiving adjacent and long-range inputs from other brain regions. However, how afferent neurons of mPFC are affected by chronic stress needs to be clarified. In this study, the effects of chronic restraint stress (CRS) on the distribution density of mPFC dendrites/dendritic spines and the projections from the cortex and subcortical brain regions to the mPFC were investigated.
METHODS
In the present study, C57BL/6 J transgenic (Thy1-YFP-H) mice were subjected to CRS to establish an animal model of depression. The infralimbic (IL) of mPFC was selected as the injection site of retrograde AAV using stereotactic technique. The effects of CRS on dendrites/dendritic spines and afferent neurons of the mPFC IL were investigaed by quantitatively assessing the distribution density of green fluorescent (YFP) positive dendrites/dendritic spines and red fluorescent (retrograde AAV recombinant protein) positive neurons, respectively.
RESULTS
The results revealed that retrograde tracing virus labeled neurons were widely distributed in ipsilateral and contralateral cingulate cortex (Cg1), second cingulate cortex (Cg2), prelimbic cortex (PrL), infralimbic cortex, medial orbital cortex (MO), and dorsal peduncular cortex (DP). The effects of CRS on the distribution density of mPFC red fluorescence positive neurons exhibited regional differences, ranging from rostral to caudal or from top to bottom. Simultaneously, CRS resulted a decrease in the distribution density of basal, proximal and distal dendrites, as well as an increase in the loss of dendritic spines of the distal dendrites in the IL of mPFC. Furthermore, varying degrees of red retrograde tracing virus fluorescence signals were observed in other cortices, amygdala, hippocampus, septum/basal forebrain, hypothalamus, thalamus, mesencephalon, and brainstem in both ipsilateral and contralateral brain. CRS significantly reduced the distribution density of red fluorescence positive neurons in other cortices, hippocampus, septum/basal forebrain, hypothalamus, and thalamus. Conversely, CRS significantly increased the distribution density of red fluorescence positive neurons in amygdala.
CONCLUSION
Our results suggest a possible mechanism that CRS leads to disturbances in synaptic plasticity by affecting multiple inputs to the mPFC, which is characterized by a decrease in the distribution density of dendrites/dendritic spines in the IL of mPFC and a reduction in input neurons of multiple cortices to the IL of mPFC as well as an increase in input neurons of amygdala to the IL of mPFC, ultimately causing depression-like behaviors.
Topics: Animals; Prefrontal Cortex; Mice, Inbred C57BL; Stress, Psychological; Mice, Transgenic; Mice; Restraint, Physical; Depression; Male; Dendritic Spines; Disease Models, Animal; Afferent Pathways; Dendrites; Neurons, Afferent; Brain
PubMed: 38777132
DOI: 10.1016/j.brainresbull.2024.110981 -
Cureus Apr 2024A 60-year-old male presented with an elevated prostate-specific antigen (PSA) of 10 ng/ml. A transrectal ultrasound-guided prostate biopsy showed prostate adenocarcinoma...
A 60-year-old male presented with an elevated prostate-specific antigen (PSA) of 10 ng/ml. A transrectal ultrasound-guided prostate biopsy showed prostate adenocarcinoma GS 4+3 (grade 3) with 5 out of 12 cores positive for malignancy. He initially planned to have prostate stereotactic body radiation therapy (SBRT) with SpaceOAR gel insertion in his rectoprostatic space to reduce radiation to the rectum. Magnetic resonance imaging (MRI) two months after SpaceOAR insertion showed evidence of infiltration of the SpaceOAR within the anterior rectal wall. This delayed his treatment and he was started on a short course of androgen deprivation therapy with Leuprolide while waiting for absorption of the gel. After completion of androgen deprivation therapy, the patient was treated with external beam radiation therapy (EBRT) to the prostate, seminal vesicles, and pelvis to a total dose of 6000 centigray (cGy) in 20 fractions at a dose per fraction of 300 cGy. He did well after treatment with minimal side effects.
PubMed: 38765433
DOI: 10.7759/cureus.58485 -
Cureus Apr 2024Lung cancer with brain metastasis has a high morbidity and mortality worldwide. Neurocysticercosis is a parasitic infection commonly found in regions with poor...
Lung cancer with brain metastasis has a high morbidity and mortality worldwide. Neurocysticercosis is a parasitic infection commonly found in regions with poor sanitation. We present a case with the coexistence of lung cancer and neurocysticercosis. A 57-year-old Caucasian female, with a history of secondhand smoke exposure, presented with a cough. Further evaluation revealed a lesion in the right upper lobe of the lung on a CT scan, a frontal lobe lesion on brain MRI, and hypermetabolic lymph nodes on a PET scan. Biopsies confirmed invasive moderately differentiated adenocarcinoma, indicating stage 4 lung cancer with a solitary brain metastasis. The patient underwent stereotactic radiosurgery for the brain lesion and subsequently received chemoradiation therapy. Upon completion of therapy, the patient showed improvement in both lung and brain lesions. Durvalumab maintenance therapy was initiated. However, a follow-up MRI of the brain revealed a new lesion in the right lateral ventricle. Stereotactic radiosurgery was performed to target this lesion. Five months later, a repeat MRI showed growth of the brain lesion. Given the atypical image finding, a biopsy of the right lateral ventricle lesion was performed, revealing an unexpected diagnosis of calcified parenchymal neurocysticercosis. The patient was referred to an infectious disease specialist who started the patient on dexamethasone without antiparasitic treatment. The co-occurrence of metastatic lung cancer to the brain and neurocysticercosis presents significant diagnostic and therapeutic complexities. Despite stereotactic radiosurgery, the patient's neurologic symptoms failed to improve, and subsequent radiographic assessments yielded inconclusive results. Consequently, a brain biopsy was performed, deviating from the usual practice in cancer management, revealing the unexpected presence of neurocysticercosis. This unforeseen diagnosis underscores the critical significance of contemplating alternative etiologies in patients exhibiting atypical clinical manifestations, particularly in regions devoid of prevalent parasitic infections. This case highlights the challenges in identifying and managing complex cases involving lung cancer and neurocysticercosis, where treatment decisions must balance the need for oncologic control and the management of parasitic infection.
PubMed: 38765376
DOI: 10.7759/cureus.58456 -
Nature Communications May 2024After contracting COVID-19, a substantial number of individuals develop a Post-COVID-Condition, marked by neurologic symptoms such as cognitive deficits, olfactory...
After contracting COVID-19, a substantial number of individuals develop a Post-COVID-Condition, marked by neurologic symptoms such as cognitive deficits, olfactory dysfunction, and fatigue. Despite this, biomarkers and pathophysiological understandings of this condition remain limited. Employing magnetic resonance imaging, we conduct a comparative analysis of cerebral microstructure among patients with Post-COVID-Condition, healthy controls, and individuals that contracted COVID-19 without long-term symptoms. We reveal widespread alterations in cerebral microstructure, attributed to a shift in volume from neuronal compartments to free fluid, associated with the severity of the initial infection. Correlating these alterations with cognition, olfaction, and fatigue unveils distinct affected networks, which are in close anatomical-functional relationship with the respective symptoms.
Topics: Humans; COVID-19; Cognitive Dysfunction; Male; Fatigue; Female; Magnetic Resonance Imaging; Middle Aged; Olfaction Disorders; Adult; SARS-CoV-2; Brain; Post-Acute COVID-19 Syndrome; Aged
PubMed: 38762609
DOI: 10.1038/s41467-024-48651-0 -
PLoS Medicine May 2024Preclinical studies have demonstrated that tumour cell death can be enhanced 10- to 40-fold when radiotherapy is combined with focussed ultrasound-stimulated microbubble...
BACKGROUND
Preclinical studies have demonstrated that tumour cell death can be enhanced 10- to 40-fold when radiotherapy is combined with focussed ultrasound-stimulated microbubble (FUS-MB) treatment. The acoustic exposure of microbubbles (intravascular gas microspheres) within the target volume causes bubble cavitation, which induces perturbation of tumour vasculature and activates endothelial cell apoptotic pathways responsible for the ablative effect of stereotactic body radiotherapy. Subsequent irradiation of a microbubble-sensitised tumour causes rapid increased tumour death. The study here presents the mature safety and efficacy outcomes of magnetic resonance (MR)-guided FUS-MB (MRgFUS-MB) treatment, a radioenhancement therapy for breast cancer.
METHODS AND FINDINGS
This prospective, single-center, single-arm Phase 1 clinical trial included patients with stages I-IV breast cancer with in situ tumours for whom breast or chest wall radiotherapy was deemed adequate by a multidisciplinary team (clinicaltrials.gov identifier: NCT04431674). Patients were excluded if they had contraindications for contrast-enhanced MR or microbubble administration. Patients underwent 2 to 3 MRgFUS-MB treatments throughout radiotherapy. An MR-coupled focussed ultrasound device operating at 800 kHz and 570 kPa peak negative pressure was used to sonicate intravenously administrated microbubbles within the MR-guided target volume. The primary outcome was acute toxicity per Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Secondary outcomes were tumour response at 3 months and local control (LC). A total of 21 female patients presenting with 23 primary breast tumours were enrolled and allocated to intervention between August/2020 and November/2022. Three patients subsequently withdrew consent and, therefore, 18 patients with 20 tumours were included in the safety and LC analyses. Two patients died due to progressive metastatic disease before 3 months following treatment completion and were excluded from the tumour response analysis. The prescribed radiation doses were 20 Gy/5 fractions (40%, n = 8/20), 30 to 35 Gy/5 fractions (35%, n = 7/20), 30 to 40 Gy/10 fractions (15%, n = 3/20), and 66 Gy/33 fractions (10%, n = 2/20). The median follow-up was 9 months (range, 0.3 to 29). Radiation dermatitis was the most common acute toxicity (Grade 1 in 16/20, Grade 2 in 1/20, and Grade 3 in 2/20). One patient developed grade 1 allergic reaction possibly related to microbubbles administration. At 3 months, 18 tumours were evaluated for response: 9 exhibited complete response (50%, n = 9/18), 6 partial response (33%, n = 6/18), 2 stable disease (11%, n = 2/18), and 1 progressive disease (6%, n = 1/18). Further follow-up of responses indicated that the 6-, 12-, and 24-month LC rates were 94% (95% confidence interval [CI] [84%, 100%]), 88% (95% CI [75%, 100%]), and 76% (95% CI [54%, 100%]), respectively. The study's limitations include variable tumour sizes and dose fractionation regimens and the anticipated small sample size typical for a Phase 1 clinical trial.
CONCLUSIONS
MRgFUS-MB is an innovative radioenhancement therapy associated with a safe profile, potentially promising responses, and durable LC. These results warrant validation in Phase 2 clinical trials.
TRIAL REGISTRATION
clinicaltrials.gov, identifier NCT04431674.
Topics: Humans; Breast Neoplasms; Female; Microbubbles; Middle Aged; Aged; Prospective Studies; Adult; Treatment Outcome; Magnetic Resonance Imaging; Aged, 80 and over
PubMed: 38758967
DOI: 10.1371/journal.pmed.1004408 -
NeuroImage. Clinical 2024The intricate relationship between deep brain stimulation (DBS) in Parkinson's disease (PD) and cognitive impairment has lately garnered substantial attention. The...
BACKGROUND AND OBJECTIVES
The intricate relationship between deep brain stimulation (DBS) in Parkinson's disease (PD) and cognitive impairment has lately garnered substantial attention. The presented study evaluated pre-DBS structural and microstructural cerebral patterns as possible predictors of future cognitive decline in PD DBS patients.
METHODS
Pre-DBS MRI data in 72 PD patients were combined with neuropsychological examinations and follow-up for an average of 2.3 years after DBS implantation procedure using a screening cognitive test validated for diagnosis of mild cognitive impairment in PD in a Czech population - Dementia Rating Scale 2.
RESULTS
PD patients who would exhibit post-DBS cognitive decline were found to have, already at the pre-DBS stage, significantly lower cortical thickness and lower microstructural complexity than cognitively stable PD patients. Differences in the regions directly related to cognition as bilateral parietal, insular and cingulate cortices, but also occipital and sensorimotor cortex were detected. Furthermore, hippocampi, putamina, cerebellum and upper brainstem were implicated as well, all despite the absence of pre-DBS differences in cognitive performance and in the position of DBS leads or stimulation parameters between the two groups.
CONCLUSIONS
Our findings indicate that the cognitive decline in the presented PD cohort was not attributable primarily to DBS of the subthalamic nucleus but was associated with a clinically silent structural and microstructural predisposition to future cognitive deterioration present already before the DBS system implantation.
Topics: Humans; Deep Brain Stimulation; Parkinson Disease; Male; Female; Subthalamic Nucleus; Middle Aged; Cognitive Dysfunction; Aged; Magnetic Resonance Imaging; Neuropsychological Tests
PubMed: 38749145
DOI: 10.1016/j.nicl.2024.103617 -
Cureus Apr 2024We report a rare case of an extremely old colorectal cancer (CRC) patient who had complete remission after liver metastasectomy and stereotactic body radiotherapy (SBRT)...
We report a rare case of an extremely old colorectal cancer (CRC) patient who had complete remission after liver metastasectomy and stereotactic body radiotherapy (SBRT) to lung oligometastases (OM), with good quality of life and no evidence of recurrence 12 years after the initial diagnosis. An 83-year-old male patient had a right hemicolectomy for stage pT3 pN0 adenocarcinoma of the colon. Soon he was found to have liver metastasis treated with radiofrequency ablation and then liver metastasectomy with clear margins, followed by chemotherapy in the form of FOLFIRI for six months. Six years later, positron emission tomography (PET) showed 1.6 cm OM in the left upper lobe lung. He was not considered a good candidate for surgery. We offered him SBRT 48 Gy in four fractions every other day. The lesion disappeared with no recurrence in the same location on PET and serial computed tomography (CT) scans. Three years later, PET-CT found a new OM in the left lingular lung measuring 1.2 cm. A CT-guided lung biopsy confirmed invasive adenocarcinoma favoring OM from the CRC. SBRT planning failed due to its proximity to the heart. He accepted the longer course of conventional volumetric modulated arc therapy at 60 Gy in 15 fractions with daily cone-beam CT guidance. Again, he tolerated treatment very well with no significant side effects, despite his age. He did not require any chemotherapy or other systemic treatment in the last 11 years, so he did not experience any toxicities related to such treatment. This case is important to show that old age alone should not be considered a contraindication for metastasectomy and SBRT for CRC with liver and lung OM.
PubMed: 38741816
DOI: 10.7759/cureus.58135 -
JHEP Reports : Innovation in Hepatology Jun 2024Inoperable hepatocellular carcinoma (HCC) can be treated by stereotactic body radiotherapy. However, carbon ion radiotherapy (CIRT) is more effective for sparing...
BACKGROUND & AIMS
Inoperable hepatocellular carcinoma (HCC) can be treated by stereotactic body radiotherapy. However, carbon ion radiotherapy (CIRT) is more effective for sparing non-tumorous liver. High linear energy transfer could promote therapy efficacy. Japanese and Chinese studies on hypofractionated CIRT have yielded excellent results. Because of different radiobiological models and the different etiological spectrum of HCC, applicability of these results to European cohorts and centers remains questionable. The aim of this prospective study was to assess safety and efficacy and to determine the optimal dose of CIRT with active raster scanning based on the local effect model (LEM) I.
METHODS
CIRT was performed every other day in four fractions with relative biological effectiveness (RBE)-weighted fraction doses of 8.1-10.5 Gy (total doses 32.4-42.0 Gy [RBE]). Dose escalation was performed in five dose levels with at least three patients each. The primary endpoint was acute toxicity after 4 weeks.
RESULTS
Twenty patients received CIRT (median age 74.7 years, n = 16 with liver cirrhosis, Child-Pugh scores [CP] A5 [n = 10], A6 [n = 4], B8 [n = 1], and B9 [n = 1]). Median follow up was 23 months. No dose-limiting toxicities and no toxicities exceeding grade II occurred, except one grade III gamma-glutamyltransferase elevation 12 months after CIRT, synchronous to out-of-field hepatic progression. During 12 months after CIRT, no CP elevation occurred. The highest dose level could be applied safely. No local recurrence developed during follow up. The objective response rate was 80%. Median overall survival was 30.8 months (1/2/3 years: 75%/64%/22%). Median progression-free survival was 20.9 months (1/2/3 years: 59%/43%/43%). Intrahepatic progression outside of the CIRT target volume was the most frequent pattern of progression.
CONCLUSIONS
CIRT of HCC yields excellent local control without dose-limiting toxicity.
IMPACT AND IMPLICATIONS
To date, safety and efficacy of carbon ion radiotherapy for hepatocellular carcinoma have only been evaluated prospectively in Japanese and Chinese studies. The optimal dose and fractionation when using the local effect model for radiotherapy planning are unknown. The results are of particular interest for European and American particle therapy centers, but also of relevance for all specialists involved in the treatment and care of patients with hepatocellular carcinoma, as we present the first prospective data on carbon ion radiotherapy in hepatocellular carcinoma outside of Asia. The excellent local control should encourage further use of carbon ion radiotherapy for hepatocellular carcinoma and design of randomized controlled trials.
CLINICAL TRIALS REGISTRATION
The study is registered at ClinicalTrials.gov (NCT01167374).
PubMed: 38737600
DOI: 10.1016/j.jhepr.2024.101063