During the COVID-19 pandemic recommendations were made to adapt cancer care. This population-based study aimed to investigate possible differences between the treatment of patients with metastatic ...cancer before and during the pandemic by comparing the initial treatments in five COVID-19 periods (weeks 1-12 2020: pre-COVID-19, weeks 12-20 2020: 1st peak, weeks 21-41 2020: recovery, weeks 42-53 2020: 2nd peak, weeks 1-20 2021: prolonged 2nd peak) with reference data from 2017 to 2019. The proportion of patients receiving different treatment modalities (chemotherapy, hormonal therapy, immunotherapy or targeted therapy, radiotherapy primary tumor, resection primary tumor, resection metastases) within 6 weeks of diagnosis and the time between diagnosis and first treatment were compared by period. In total, 74,208 patients were included. Overall, patients were more likely to receive treatments in the COVID-19 periods than in previous years. This mainly holds for hormone therapy, immunotherapy or targeted therapy and resection of metastases. Lower odds were observed for resection of the primary tumor during the recovery period (OR 0.87; 95% CI 0.77-0.99) and for radiotherapy on the primary tumor during the prolonged 2nd peak (OR 0.84; 95% CI 0.72-0.98). The time from diagnosis to the start of first treatment was shorter, mainly during the 1st peak (average 5 days, p < .001). These findings show that during the first 1.5 years of the COVID-19 pandemic, there were only minor changes in the initial treatment of metastatic cancer. Remarkably, time from diagnosis to first treatment was shorter. Overall, the results suggest continuity of care for patients with metastatic cancer during the pandemic.
Deregulated Notch signaling due to mutation or overexpression of ligands and/or receptors is implicated in various human malignancies. γ-Secretase inhibitors inhibit Notch signaling by preventing ...cleavage of transmembrane domain of Notch protein. LY3039478 is a novel, potent Notch inhibitor decreases Notch signaling and its downstream biologic effects. In this first-in-human study, we report the safety, pharmacokinetic (PK) profile, pharmacodynamic effects, and antitumor activity of LY3039478 in patients with advanced or metastatic cancer.
This phase I, open-label, multicenter, nonrandomized, and dose-escalation phase study determined and confirmed the recommended phase II dose of LY3039478 (oral dose: 2.5–100mg, thrice weekly (TIW) on a 28-day cycle). The primary objectives are to determine (part A) and confirm (part B) a recommended phase II dose that may be safely administered to patients with advanced or metastatic cancer, and secondary objectives include evaluation of safety, tolerability, PK parameters, and preliminary antitumor activity of LY3039478.
A total of 110 patients were treated with LY3039478 monotherapy between 31 October 2012 and 15 July 2016. Dose-limiting toxicities were thrombocytopenia, colitis, and nausea. Most adverse events were gastrointestinal. The recommended phase II dose was 50mg TIW, because of its better tolerability compared with 75mg. The PKs of LY3039478 appeared dose proportional. Pharmacodynamic data indicate an ∼80% inhibition of plasma Aβ, and >50% inhibition of Notch-regulated genes hairy and enhancer of split-1, cyclin D1, and Notch-regulated ankyrin repeat at 45–100-mg dose. Clinical activity (tumor necrosis, metabolic response, or tumor shrinkage) was observed in patients with breast cancer, leiomyosarcoma, and adenoid cystic carcinoma.
Potent inhibition of Notch signaling by LY3039478 was well tolerated at doses associated with target engagement, and demonstrated evidence of clinical activity in heavily pretreated patients. Further investigation with LY3039478 as monotherapy and in combination with targeted agent or chemotherapy is ongoing.
NCT01695005.
Primary tumor metastasis remains to be a tough obstacle for clinical breast cancer treatment. Since evidences have shown that mitochondria play a crucial role in tumor metastasis, we designed a ...mitochondrial targeted drug delivery system (P-D-R8MTS) based on N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers to simultaneously inhibit breast cancer progression and metastasis. A novel mitochondrial targeted hybrid peptide R8MTS, which consists of a cell penetrating peptide octaarginine (R8) and a mitochondrial targeting sequence ALD5MTS, was used as targeting ligand and attached to doxorubicin (DOX) as model drug (DOX-R8MTS). After entering into the tumor cells, DOX-R8MTS was pH-responsibly released from HPMA copolymer backbone in acidic lysosome and efficiently targeted to mitochondria, resulting in enhanced reactive oxygen species (ROS) generation and apoptosis initiation. By destroying mitochondria, P-D-R8MTS not only inhibited cell proliferation but also suppressed migration and invasion of breast cancer 4T1 and MDA-MB-231 cells in vitro. Moreover, P-D-R8MTS exhibited superior inhibition of tumor growth and showed no apparent lung metastatic nodules on 4T1-bearing mice in vivo, which was partially via down-regulation of typical proteins associated with tumor metastasis and invasion: matrix metalloproteinases-2 (MMP-2), vascular endothelial growth factor (VEGF) and transforming growth factor-β (TGF-β). Collectively, our work provided a prospectively potential strategy for metastatic cancer treatment through mitochondrial targeted drug delivery.
A novel mitochondrial targeted hybrid peptide modified copolymer with doxorubicin was developed. This pH-sensitive copolymer exhibited efficient mitochondrial accumulation and anti-metastasis efficacy against metastatic breast cancer via down-regulation of metastasis-associated proteins (MMP-2, VEGF and TGF-β). Display omitted
•A mitochondrial targeted HPMA copolymer (P-D-R8MTS) was designed for anti-metastasis.•P-D-R8MTS delivered DOX to mitochondria via MTS mediated active targeting.•R8 introduction remarkably increased cellular uptake and lysosome escape of P-D-R8MTS.•P-D-R8MTS exhibited superior tumor growth suppression by destroying mitochondria.•P-D-R8MTS effectively inhibited metastasis via down-regulation of MMP2, VEGF and TGF-β.
Malignant pleural effusions are common in advanced malignancy and associated with overall poor survival. The presence of sarcopenia (decreased muscle mass) is associated with poor outcomes in ...numerous disease states, however, its relationship to malignant pleural disease has not been defined. We sought to understand if there was an association between decreased survival and decreased muscle mass in patients with malignant pleural effusion.
Patients with malignant pleural disease undergoing indwelling tunneled pleural catheter placement were retrospectively reviewed. Computed tomography was reviewed and cross-sectional area of pectoralis and paraspinous muscle areas were calculated. Overall survival and associations with muscle mass were calculated.
A total of 309 patients were available for analysis, with a median age of 67 years and the majority female (58%). The median survival was 129 days from initial pleural drainage to death. Regression analysis and Kaplan-Meier survival analysis did not reveal an association with survival and muscle mass for the entire population. However, Kaplan-Meier survival analysis of the lung cancer subgroup revealed the presence of decreased muscle mass and decreased survival time.
The presence of decreased muscle mass within a lung cancer population that has malignant pleural effusions are associated with decreased survival. However, the presence of decreased muscle mass within a heterogenous population of malignant pleural disease was not associated with decreased overall survival time. Further study of the role that sarcopenia may play in malignant pleural disease is warranted.
•Decreased pectoral and paraspinous muscle mass in lung cancer is associated with decreased overall survival.•Pectoral and paraspinous muscle mass in a heterogenous solid tumor population is not associated with overall survival.•Malignant pleural effusion is associated with poor overall survival, however survival times remain difficult to predict.
Previous studies suggested that obesity pro-inflammatory state could improve immune checkpoint inhibitors (ICI) clinical efficacy. This is a retrospective, multicenter, and observational study that ...included patients treated in a private Brazilian Oncology Group. Primary outcomes were the association of body mass index (BMI) category with overall survival (OS) and progression free survival (PFS). Secondary outcomes were association between BMI and objective response rate (ORR). In the total cohort, 448 patients were classified as a normal weight (43%), overweight (36%), obese (17%) and underweight (4%). The patients were predominantly male gender (62%), with stage IV lung cancer (57%) and melanoma (19%). The obese group (BMI ≥ 30 kg/m
2
) had a not statistically significant longer median OS than the non-obese group (BMI < 30 kg/m
2
) - 21.8 months (95% CI NR - NR) versus 14.9 months (95% CI 8.3 - 21.5); HR = 0.82, (95% CI 0.57 - 1.18, P = 0.28). Obese patients treated with anti-CTLA4 did not reach the mOS, while the non-obese group had a mOS of 23.1 months (P = 0.04). PFS did not differ between subgroups. Obese patients had also lower ORR, but without reaching statistical significance. In conclusion, this study did not report an improved OS among high BMI patients treated with ICI.
Several recent phase 2 and 3 trials have evaluated the efficacy and toxicity of checkpoint inhibitor (CPI) therapy for urothelial carcinoma (UC) in the metastatic, localized muscle-invasive UC ...(MIUC), upper tract UC, and non-muscle-invasive bladder cancer (NMIBC) disease state.
To assess the outcomes and toxicity of CPIs across the treatment landscape of UC and contextualize their application to current real-world treatment.
We queried PubMed, Web of Science, and EMBASE databases and conference abstracts to identify prospective trials examining CPIs in UC. The primary endpoints included overall survival, recurrence-free survival, and toxicity (when available). A secondary analysis included biomarker evaluation of response.
We identified 21 trials, 12 phase 2 and nine phase 3 trials, in which a CPI was used for metastatic UC (seven), MIUC (nine), and NMIBC (five). For first-line (1L) metastatic UC, concurrent chemotherapy with CPIs failed to show superiority. Improved overall and progression-free survival for switch maintenance avelumab (after achieving stable disease or response with induction systemic chemotherapy) has established the current standard of care for 1L metastatic UC. A single-agent CPI is a consideration for patients unable to tolerate chemotherapy. CPIs in the perioperative setting are limited to only the adjuvant treatment with nivolumab after radical surgery for MIUC in patients at a higher risk of recurrence based on pathologic stage. Only pembrolizumab is approved by the Food and Drug Administration for carcinoma in situ unresponsive to bacillus Calmette-Guérin (BCG) in patients who are not fit for or who refuse radical cystectomy. Trials investigating CPIs in combination with multiple immune regulators, antibody drug conjugates, targeted therapies, antiangiogenic agents, chemotherapy, and radiotherapy are enrolling patients and may shape the future treatment of patients with UC.
CPIs have an established role across multiple states of UC, with broadened applications likely to occur in the future. Several combinations are being evaluated, while the development of predictive biomarkers and their validation may help identify patients who are most likely to respond.
Our findings highlight the broad activity of checkpoint inhibitors in urothelial carcinoma, noting the need for further investigation for the best application of combinations and patient selection to patient care.
Brain metastasis is a frequent complication of cancer and may be mediated, at least in part, by the internalization of cancer-cell-derived exosomes into brain capillary endothelial cells. Clarifying ...the mechanism(s) of this internalization is of interest because it could help us to develop ways to block brain metastasis, as well as affording a potential new route for drug delivery into the brain. Therefore, the purpose of the present study was to address this issue by identifying the receptors involved in the internalization of exosomes derived from a brain-metastatic cancer cell line (SK-Mel-28) into human blood–brain barrier endothelial cells (hCMEC/D3 cells). The combination of sulfo-SBED-based cross-linking and comprehensive proteomics yielded 20 proteins as exosome receptor candidates in hCMEC/D3 cells. The uptake of PKH67-labeled exosomes by hCMEC/D3 cells measured at 37 °C was significantly reduced by 95.6% at 4 °C and by 15.3% in the presence of 1 mM RGD peptide, an integrin ligand. Therefore, we focused on the identified RGD receptors, integrin α5 and integrin αV, and CD46, which is reported to act as an adenovirus receptor, together with integrin αV. A mixture of neutralizing antibodies against integrin α5 and integrin αV significantly decreased the exosome uptake by 11.8%, while application of CD46 siRNA reduced it by 39.0%. Immunohistochemical analysis confirmed the presence of CD46 in human brain capillary endothelial cells. These results suggest that CD46 is a major receptor for the uptake of SK-Mel-28-derived exosomes by human blood–brain barrier endothelial cells (hCMEC/D3 cells).
A low-cost microfluidic microarray capable of lysing cells and quantifying proteins released after lysis was designed and 3D-printed. The array lyses cells on-chip in lysis buffer augmented with a 2s ...pulse of a sonic cell disruptor. Detection of desmoglein 3 (DSG3), a metastatic biomarker for head and neck squamous cell carcinoma (HNSCC), along with two accompanying HNSCC biomarkers from a single cell lysate of oral cancer cell cultures was demonstrated. A lysis chamber and reagent compartments deliver sample and reagents into detection chambers decorated with capture antibodies immobilized onto inner walls coated with a highly swollen 3D chitosan hydrogel film. Sandwich immunoassays are achieved when captured analytes labeled with biotinylated secondary antibodies, which then capture streptavidin-poly horse radish peroxidase (Poly-HRP). Subsequent delivery of super-bright femto-luminol with H2O2 generates chemiluminescence captured with a CCD camera. DSG3 is membrane-bound protein in HNSCC cells of invaded lymph nodes, vascular endothelial growth factor-A (VEGF-A), vascular endothelial growth factor-C (VEGF-C) were positive controls overexpressed into the HNSCC culture medium. Beta-tubulin (β-Tub) was used as a loading control to estimate the number of cells in analyzed samples. Limits of detection (LOD) were 0.10 fg/mL for DSG3, and 0.20 fg/mL for VEGF-A, VEGF-C and β-Tub. Three orders of magnitude semilogarithmic dynamic ranges were achieved. VEGF-A showed high in-cell expression, but VEGF-C had low levels inside cells. The very low LODs enabled quantifying these proteins released from single cells. Strong correlation between results from on-chip cell lysis, conventional off-line lysis and ELISA confirmed accuracy.
Display omitted
•This is the first automated 3D-printed microfluidic immunoarray capable of lysing byusing a 50 KHz cell disruptor and quantifying released biomarker proteins bound to cells.•Advantages over other single cell approaches are low cost, speed, accuracy andsensitivity.•Unprecedented sub-fg/mL limits of detection are achieved by combining cylindricaldetection chambers filled with capture antibodies on a highly swollen 3D chitosanhydrogel, streptavidin polyhorseradish peroxidase (Poly-HRP) labels and ultrabrightfemto-luminol reagent to generate chemiluminescence.•Proteins residing within single cells were quantitatively measured.
Checkpoint inhibitor-induced uveitis: a case series Conrady, Christopher D.; Larochelle, Marissa; Pecen, Paula ...
Graefe's archive for clinical and experimental ophthalmology,
01/2018, Letnik:
256, Številka:
1
Journal Article
Recenzirano
Purpose
Checkpoint inhibitors are now a common treatment modality for metastatic cancer. In this manuscript, we describe the clinical features and management of autoimmune non-infectious uveitis ...induced by this class of drugs.
Methods
Seven patients undergoing checkpoint inhibitor treatment for metastatic cancer from uveitis practices at three tertiary referral centers.
Results
All seven patients developed various severities of ocular inflammatory disease while taking checkpoint inhibitors for metastatic disease.
Conclusions
Checkpoint inhibitors may induce autoimmune uveitis. Ocular complaints should prompt an early evaluation by an ophthalmologist.
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