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Cancer Medicine Jun 2024Therapy-induced senescent cancer and stromal cells secrete cytokines and growth factors to promote tumor progression. Therefore, senescent cells may be novel targets for...
INTRODUCTION
Therapy-induced senescent cancer and stromal cells secrete cytokines and growth factors to promote tumor progression. Therefore, senescent cells may be novel targets for tumor treatment. Near-infrared photoimmunotherapy (NIR-PIT) is a highly tumor-selective therapy that employs conjugates of a molecular-targeting antibody and photoabsorber. Thus, NIR-PIT has the potential to be applied as a novel senolytic therapy. This study aims to investigate the efficacy of NIR-PIT treatment on senescent cancer and stromal cells.
METHODS
Two cancer cell lines (human lung adenocarcinoma A549 cells and human pancreatic cancer MIA PaCa-2 cells) and two normal cell lines (mouse fibroblast transfected with human epidermal growth factor receptor 2 [HER2] cells and human fibroblast WI38 cells) were used. The cytotoxicity of NIR-PIT was evaluated using anti-epidermal growth factor receptor (EGFR) antibody panitumumab and anti-HER2 antibody transtuzumab.
RESULTS
Cellular senescence was induced in A549 and MIA PaCa-2 cells by 10 Gy γ-irradiation. The up-regulation of cellular senescence markers and characteristic morphological changes in senescent cells, including enlargement, flattening, and multinucleation, were observed in cancer cells after 5 days of γ-irradiation. Then, NIR-PIT targeting EGFR was performed on these senescent cancer cells. The NIR-PIT induced morphological changes, including bleb formation, swelling, and the inflow of extracellular fluid, and induced a significant decrease in cellular viability. These results suggested that NIR-PIT may induce cytotoxicity using the same mechanism in senescent cancer cells. In addition, similar morphological changes were also induced in radiation-induced senescent 3T3-HER2 fibroblasts by NIR-PIT targeting human epidermal growth factor receptor 2.
CONCLUSION
NIR-PIT eliminates both senescent cancer and stromal cells in vitro suggesting it may be a novel strategy for tumor treatment.
Topics: Humans; Cellular Senescence; Animals; Mice; Immunotherapy; Stromal Cells; Phototherapy; ErbB Receptors; Cell Line, Tumor; Infrared Rays; Receptor, ErbB-2; Lung Neoplasms; Trastuzumab; Panitumumab; A549 Cells; Gamma Rays
PubMed: 38888415
DOI: 10.1002/cam4.7381 -
Gan To Kagaku Ryoho. Cancer &... May 2024Metastatic colorectal cancer with KRAS wild type is treated using a range of drug regimens, including fluorouracil, irinotecan, and Leucovorin(FOLFIRI)plus...
OBJECTIVE
Metastatic colorectal cancer with KRAS wild type is treated using a range of drug regimens, including fluorouracil, irinotecan, and Leucovorin(FOLFIRI)plus bevacizumab(Bmab), cetuximab(Cmab), or panitumumab(Pmab). The present study aimed to identify the optimal regimen using a decision analysis method, in combination with clinical and economic evidence.
METHOD
A simple Markov model with a monthly cycle time was constructed. Probabilistic variables for input into the model were derived from randomized controlled trials. Direct costs for the drugs, laboratory analyses, and medical staff were calculated and used in the model.
RESULTS
The expected survival times and costs of FOLFIRI alone and combination therapies were 20.9 months and 2,299,198 yen for FOLFIRI, 29.9 months and 8,929,888 yen for Bmab, 27.8 months and 11,811,849 yen for Cmab, and 22.6 months and 8,795,622 yen for Pmab. The incremental cost-effectiveness ratios to FOLFIRI were 736,743 yen/month for Bmab, 1,378,645 yen/month for Cmab, and 3,821,426 yen/month for Pmab.
CONCLUSIONS
These findings suggested that these regimens were not sufficiently cost-effective, although they have excellent therapeutic efficacy. From the economic point of view, these combination regimens were inferior to FOLFIRI alone.
Topics: Leucovorin; Humans; Antineoplastic Combined Chemotherapy Protocols; Cost-Benefit Analysis; Colorectal Neoplasms; Fluorouracil; Camptothecin; Neoplasm Metastasis; Clinical Decision-Making; Cost-Effectiveness Analysis
PubMed: 38881065
DOI: No ID Found -
Medicine International 2024The present systematic review evaluated the effectiveness of anti-EGFR therapy in combination with radiotherapy (RT) or with chemoradiation compared with the existing...
The present systematic review evaluated the effectiveness of anti-EGFR therapy in combination with radiotherapy (RT) or with chemoradiation compared with the existing standard of care for the treatment of locally advanced head and neck squamous cell carcinoma (LAHNSCC). The PubMed, SCOPUS, EMBASE and COCHRANE databases were searched and 12 phase III randomized controlled trials were included. The effectiveness of the anti-EGFR monoclonal antibody cetuximab was evaluated in nine trials. Nimotuzumab (one trial), zalutumumab (one trial) and panitumumab (one trial) were the monoclonal antibodies evaluated in the remaining three trials. One study tested the effectiveness of adding cetuximab to radical RT and found that patients with LAHNSCC exhibited improvement in locoregional control (LRC), overall survival (OS) and progression-free survival (PFS) compared with those of patients treated with RT alone. A total of three studies tested the effectiveness of adding an anti-EGFR agent to chemoradiation. Of these, a single institution study in which patients received cisplatin at 30 mg/m weekly, instead of the standard doses of 100 mg/m every 3 weeks or 40 mg/m every week, reported significant improvement in PFS with the addition of nimotuzumab to chemoradiotherapy without an improvement in overall survival. However, the other two studies indicated that, when added to standard chemoradiation, the anti-EGFR monoclonal antibodies cetuximab or zalutumumab did not improve survival outcomes. Two phase III trials evaluated RT plus an anti-EGFR agent compared with chemoradiation alone. Of these, one study reported inferior outcomes with cetuximab-RT in terms of OS and LRC, whereas the other study with panitumumab plus RT failed to prove the non-inferiority. Two trials evaluated induction chemotherapy followed by cetuximab-RT compared with chemoradiotherapy and reported no benefits in terms of OS or PFS. Furthermore, one study evaluated induction chemotherapy followed by cetuximab-RT compared with induction chemotherapy followed by chemoradiotherapy and found no improvement in OS or PFS. Finally, three phase III trials tested the effectiveness of cetuximab plus RT in the treatment of human papillomavirus-positive oropharyngeal carcinoma, and found it to be inferior compared with cisplatin-RT in terms of OS, PFS and failure-free survival. Based on the aforementioned findings, it is difficult to conclude that anti-EGFR therapy in any form has an advantage over conventional chemoradiation in the treatment of LAHNSCC.
PubMed: 38873325
DOI: 10.3892/mi.2024.165 -
Journal of Cosmetic Dermatology May 2024Innovative treatments for non-melanoma skin cancers (NMSCs) are required to enhance patient outcomes. (Review)
Review
BACKGROUND
Innovative treatments for non-melanoma skin cancers (NMSCs) are required to enhance patient outcomes.
AIMS
This review examines the effectiveness and safety of receptor tyrosine kinase inhibitors (RTKIs).
METHODS
A comprehensive review was conducted on the treatment potential of several RTKIs, namely cetuximab, erlotinib, gefitinib, panitumumab, and lapatinib.
RESULTS
The findings indicate that these targeted therapies hold great promise for the treatment of NMSCs. However, it is crucial to consider relapse rates and possible adverse effects. Further research is needed to improve treatment strategies, identify patient groups that would benefit the most, and assess the long-term efficacy and safety, despite the favorable results reported in previous studies. Furthermore, it is crucial to investigate the potential benefits of integrating RTKIs with immunotherapy and other treatment modalities to enhance the overall efficacy of therapy for individuals with NMSC.
CONCLUSIONS
Targeted therapies for NMSCs may be possible with the use of RTKIs. The majority of studies focused on utilizing epidermal growth factor receptor inhibitors as the primary class of RTKIs for the treatment of NMSC. Other RTKIs were only employed in experimental investigations. Research indicates that RTKIs could potentially serve as a suitable alternative for elderly patients who are unable to undergo chemotherapy and radiotherapy.
PubMed: 38812406
DOI: 10.1111/jocd.16355 -
Cureus Apr 2024Metastatic colorectal cancer (mCRC) presents significant clinical challenges due to its heterogeneous nature and variable treatment responses. The Gustave Roussy Immune...
INTRODUCTION
Metastatic colorectal cancer (mCRC) presents significant clinical challenges due to its heterogeneous nature and variable treatment responses. The Gustave Roussy Immune Score (GRIm-Score) has emerged as a potential biomarker for prognostication and prediction in mCRC, although its precise role remains under investigation.
METHODS
We conducted a retrospective study that included 173 patients diagnosed with mCRC. The patients were treated in the first line with 5-fluorouracil (5-FU)-based chemotherapy (CHT) and a molecular agent based on their eligibility. We assessed the overall survival (OS) time, progression-free survival (PFS) time, and the overall response rate (ORR), utilizing the GRIm-score measured at baseline (referred to as GRImT0) and the variance between GRImT0 and the GRIm score measured three months after treatment initiation (referred to as GRIm∆). We also performed a subgroup analysis based on the type of treatment received.
RESULTS
Our analysis revealed that the GRIm-Score holds promise as a prognostic marker in mCRC, with high scores correlating with poorer survival outcomes. However, in the subgroup analysis, this prognostic value remained relevant only for patients treated with CHT and anti-EGFR (epidermal growth factor receptor) agents, such as cetuximab and panitumumab. GRIm-Score exhibited no predictive value irrespective of the treatment received.
CONCLUSION
The GRIm-Score shows potential as a prognostic mCRC, although we believe that this potential is limited. Integration of the GRIm-Score into clinical practice should be done with caution and is not recommended at this time. However, further research is needed to fully elucidate its clinical utility and optimize its incorporation into routine clinical care.
PubMed: 38800241
DOI: 10.7759/cureus.58935 -
Targeted Oncology May 2024There are few third- and fourth-line therapeutic options for metastatic colorectal cancer (mCRC). In RAS/BRAF wild-type (wt) mCRC previously treated with anti-epidermal...
BACKGROUND
There are few third- and fourth-line therapeutic options for metastatic colorectal cancer (mCRC). In RAS/BRAF wild-type (wt) mCRC previously treated with anti-epidermal growth factor receptor (anti-EGFR) (first-line) and relapsed after a good response, retreatment with anti-EGFR (rechallenge) emerges as a therapeutic alternative.
OBJECTIVE
The aim was to show the activity and safety of anti-EGFR rechallenge in RAS/BRAF wt mCRC in real-world practice.
PATIENTS AND METHODS
A multicenter, retrospective, observational study (six hospitals of the Galician Group of Research in Digestive Tumors) was conducted. Adult patients with RAS/BRAF wt mCRC, evaluated by liquid biopsy, were included. They received anti-EGFR rechallenge (cetuximab, panitumumab) as monotherapy, or combined with chemotherapy, in third- or subsequent lines. Efficacy (overall response rate [ORR], disease control rate [DCR], overall survival [OS], and progression-free survival [PFS]) and safety (incidence of adverse events [AEs]) were assessed.
RESULTS
Thirty-one patients were analyzed. Rechallenge (median 6 cycles [range 1-27], mainly cetuximab [80.7%]), started at a median anti-EGFR-free time of 18.4 months (1.7-37.5 months) after two (38.7%) or more (61.3%) lines of treatment; 64.5% of patients received a full dose. Median OS and PFS were 9.8 months (95% confidence interval [CI] 8.2-11.4) and 2.6 months (95% CI 1.7-3.4), respectively. ORR was 10%, and DCR was 30%. The most common AEs were diarrhea (35.5%), anemia (29%), emesis (6.4%), and neutropenia (6.4%); < 5% grade ≥ 3; 48.4% of patients reported anti-EGFR-related skin toxicity (grade > 1). Hypomagnesemia required supplements in 29% of patients. Dose delays (≥ 3 days) and reduction (≥ 20%) were reported in 11 (35.5%) and seven patients (22.6%), respectively.
CONCLUSIONS
In RAS/BRAF wt mCRC patients, an anti-EGFR rechallenge provides a feasible therapeutic option with clinical benefit (survival) and a manageable safety profile.
PubMed: 38780742
DOI: 10.1007/s11523-024-01062-z -
Surgical Case Reports May 2024Colorectal cancer (CRC) often metastasizes to the liver, lungs, lymph nodes, and peritoneum but rarely to the bladder, small intestine, and skin. We here report the rare...
BACKGROUND
Colorectal cancer (CRC) often metastasizes to the liver, lungs, lymph nodes, and peritoneum but rarely to the bladder, small intestine, and skin. We here report the rare metastasis of anal cancer in the left bladder wall, followed by metastases to the small intestine and skin, after abdominoperineal resection and left lateral lymph node dissection with chemotherapy in a patient with clinician Stage IVa disease.
CASE PRESENTATION
A 66-year-old man presented with 1-month history of bloody stool and anal pain and diagnosed with clinical Stage IVa anal cancer with lymph node and liver metastases (cT3, N3 [#263L], M1a [H1]). Systemic chemotherapy led to clinical complete response (CR) for the liver metastasis and clinical near-CR for the primary tumor. Robot-assisted laparoscopic perineal rectal resection and left-sided lymph node dissection were performed. Computed tomography during 18-month postoperative follow-up identified a mass in the left bladder wall, which was biopsied with transurethral resection, was confirmed as recurrent anal cancer by histopathologic evaluation. After two cycles of systemic chemotherapy, partial resection of the small intestine was performed due to bowel obstruction not responding to conservative therapy. The histopathologic evaluation revealed lymphogenous invasion of the muscularis mucosa and subserosa of all sections. Ten months after the first surgery for bowel obstruction and two months before another surgery for obstruction of the small intestine, skin nodules extending from the lower abdomen to the thighs were observed. The histopathologic evaluation of the skin biopsy specimen collected at the time of surgery for small bowel obstructions led to the diagnosis of skin metastasis of anal cancer. Although panitumumab was administered after surgery, the patient died seven months after the diagnosis of skin metastasis.
CONCLUSIONS
This case illustrates the rare presentation of clinical Stage IVa anal cancer metastasizing to the bladder wall, small intestine, and skin several years after CR to chemotherapy.
PubMed: 38714637
DOI: 10.1186/s40792-024-01913-x -
Frontiers in Pharmacology 2024Emergence of acquired resistance limits the efficacy of the anti-EGFR therapies cetuximab and panitumumab in metastatic colorectal cancer. In the last decade,... (Review)
Review
Emergence of acquired resistance limits the efficacy of the anti-EGFR therapies cetuximab and panitumumab in metastatic colorectal cancer. In the last decade, preclinical and clinical cohort studies have uncovered genomic alterations that confer a selective advantage to tumor cells under EGFR blockade, mainly downstream re-activation of RAS-MEK signaling and mutations in the extracellular domain of EGFR (EGFR-ECD). Liquid biopsies (genotyping of ctDNA) have been established as an excellent tool to easily monitor the dynamics of genomic alterations resistance in the blood of patients and to select patients for rechallenge with anti-EGFR therapies. Accordingly, several clinical trials have shown clinical benefit of rechallenge with anti-EGFR therapy in genomically-selected patients using ctDNA. However, alternative mechanisms underpinning resistance beyond genomics -mainly related to the tumor microenvironment-have been unveiled, specifically relevant in patients receiving chemotherapy-based multi-drug treatment in first line. This review explores the complexity of the multifaceted mechanisms that mediate secondary resistance to anti-EGFR therapies and potential therapeutic strategies to circumvent acquired resistance.
PubMed: 38711991
DOI: 10.3389/fphar.2024.1398419 -
EJNMMI Radiopharmacy and Chemistry May 2024Radiation nanomedicines are nanoparticles labeled with radionuclides that emit α- or β-particles or Auger electrons for cancer treatment. We describe here our... (Review)
Review
BACKGROUND
Radiation nanomedicines are nanoparticles labeled with radionuclides that emit α- or β-particles or Auger electrons for cancer treatment. We describe here our 15 years scientific journey studying locally-administered radiation nanomedicines for cancer treatment. We further present a view of the radiation nanomedicine landscape by reviewing research reported by other groups.
MAIN BODY
Gold nanoparticles were studied initially for radiosensitization of breast cancer to X-radiation therapy. These nanoparticles were labeled with In to assess their biodistribution after intratumoural vs. intravenous injection. Intravenous injection was limited by high liver and spleen uptake and low tumour uptake, while intratumoural injection provided high tumour uptake but low normal tissue uptake. Further, [In]In-labeled gold nanoparticles modified with trastuzumab and injected iintratumourally exhibited strong tumour growth inhibition in mice with subcutaneous HER2-positive human breast cancer xenografts. In subsequent studies, strong tumour growth inhibition in mice was achieved without normal tissue toxicity in mice with human breast cancer xenografts injected intratumourally with gold nanoparticles labeled with β-particle emitting Lu and modified with panitumumab or trastuzumab to specifically bind EGFR or HER2, respectively. A nanoparticle depot (nanodepot) was designed to incorporate and deliver radiolabeled gold nanoparticles to tumours using brachytherapy needle insertion techniques. Treatment of mice with s.c. 4T1 murine mammary carcinoma tumours with a nanodepot incorporating [Y]Y-labeled gold nanoparticles inserted into one tumour arrested tumour growth and caused an abscopal growth-inhibitory effect on a distant second tumour. Convection-enhanced delivery of [Lu]Lu-AuNPs to orthotopic human glioblastoma multiforme (GBM) tumours in mice arrested tumour growth without normal tissue toxicity. Other groups have explored radiation nanomedicines for cancer treatment in preclinical animal tumour xenograft models using gold nanoparticles, liposomes, block copolymer micelles, dendrimers, carbon nanotubes, cellulose nanocrystals or iron oxide nanoparticles. These nanoparticles were labeled with radionuclides emitting Auger electrons (In, Tc, I, Pd, Pt, Pt), β-particles (Lu, Re, Re, Y, Au, I) or α-particles (Ac, Bi, Pb, At, Ra). These studies employed intravenous or intratumoural injection or convection enhanced delivery. Local administration of these radiation nanomedicines was most effective and minimized normal tissue toxicity.
CONCLUSIONS
Radiation nanomedicines have shown great promise for treating cancer in preclinical studies. Local intratumoural administration avoids sequestration by the liver and spleen and is most effective for treating tumours, while minimizing normal tissue toxicity.
PubMed: 38703297
DOI: 10.1186/s41181-024-00266-y -
Annales de Dermatologie Et de... Jun 2024
Topics: Aged; Female; Humans; Antineoplastic Agents, Immunological; Collagen Diseases; Drug Eruptions; Panitumumab
PubMed: 38678770
DOI: 10.1016/j.annder.2024.103271