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ESMO Open Jun 2024Paclitaxel resistance limits durability of response in patients with initial clinical benefit. Overexpression of spleen tyrosine kinase (SYK) has been proposed as a...
BACKGROUND
Paclitaxel resistance limits durability of response in patients with initial clinical benefit. Overexpression of spleen tyrosine kinase (SYK) has been proposed as a possible resistance mechanism. This phase I trial evaluated the safety and preliminary activity of the SYK inhibitor TAK-659 combined with paclitaxel in patients with advanced taxane-refractory solid tumors.
PATIENTS AND METHODS
Patients with advanced solid tumors and prior progression on taxane-based therapy received intravenous infusion of paclitaxel on days 1, 8, and 15 plus oral TAK-659 daily in 28-day cycles. The dose-escalation phase included six cohorts treated at different dose levels; the dose-expansion phase included patients with ovarian cancer treated at the highest dose level. Toxicity was graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Efficacy was evaluated using Response Evaluation Criteria in Solid Tumors version 1.1.
RESULTS
Our study included 49 patients. Maximum tolerated dose was not reached, but higher rates of adverse events were observed at higher dose levels. There were no treatment-related deaths. The most common treatment-related adverse events of any grade were increased aspartate aminotransferase (n = 31; 63%), increased alanine aminotransferase (n = 26; 53%), decreased neutrophil count (n = 26; 53%), and decreased white blood cell count (n = 26; 53%). Most adverse events were either grade 1 or 2. In the 44 patients with evaluable disease, 12 (27%) had stable disease as the best overall response, including three patients with prolonged stable disease, and 4 patients (9%) achieved a partial response.
CONCLUSIONS
The combination of paclitaxel and TAK-659 showed preliminary activity possibly overcoming resistance to taxane-based therapy as well as a tolerable safety profile in patients with advanced solid tumors.
Topics: Humans; Paclitaxel; Female; Middle Aged; Aged; Neoplasms; Male; Adult; Antineoplastic Combined Chemotherapy Protocols; Drug Resistance, Neoplasm; Taxoids; Maximum Tolerated Dose; Syk Kinase
PubMed: 38914452
DOI: 10.1016/j.esmoop.2024.103486 -
Fitoterapia Jun 2024Hemp (Cannabis sativa L.), an annual dioecious plant, has shown extensive application in the fields of fibers, food, oil, medicine, etc. Currently, most attention has...
Hemp (Cannabis sativa L.), an annual dioecious plant, has shown extensive application in the fields of fibers, food, oil, medicine, etc. Currently, most attention has been paid to the therapeutic properties of phytocannabinoids. However, the pharmaceutical research on essential oil from hemp is still lacking. In this study, hemp essential oil (HEO) was extracted from hemp flowers and leaves, and the components were analyzed by GC-MS. Quatitative analysis of three main compounds β-caryophyllene, β-caryophyllene oxide, α -humulene were determined by GC-FID. The anti-tumor and anti-neuropathic pain effects of HEO were evaluated. In the paclitaxel induced neuropathic mice model, HEO reduced the serum level of inflammatory cytokines TNF-α to achieve the analgesic effect, which was tested by evaluating mechanical and thermal hyperalgesia. Further investigation with cannabinoid receptor 2 (CB2 R) antagonist AM630 revealed the mechanism of reversing mechanical hyperalgesia may be related to CB2 R. In Lewis lung cancer grafted mice model, the tumor growth was significantly inhibited, the levels of tumor inflammatory cytokines TNF-α and IL-6 were downregulated, immune organ index was modified and immune-related CD4+, CD8+ T lymphocytes level, CD4+/CD8+ ratio were increased when administered with HEO. These results reveal that HEO plays a role not only in tumor chemotherapy induced peripheral neuropathy treatment, but also in anti-tumor treatment which offers key information for new strategies in cancer treatment and provides reference for the medicinal development of hemp.
PubMed: 38914272
DOI: 10.1016/j.fitote.2024.106092 -
Clinical Nuclear Medicine Jun 2024This study aimed to investigate the value of 68Ga-fibroblast activation protein inhibitor (FAPI) PET/MR semiquantitative parameters in the prediction of tumor response...
PURPOSE
This study aimed to investigate the value of 68Ga-fibroblast activation protein inhibitor (FAPI) PET/MR semiquantitative parameters in the prediction of tumor response and resectability after neoadjuvant therapy in patients with pancreatic cancer.
PATIENTS AND METHODS
This study was performed retrospectively in patients with borderline resectable or locally advanced pancreatic cancer who underwent 68Ga-FAPI PET/MRI from June 2020 to June 2022. The SUVmax, SUVmean, SUVpeak, uptake tumor volume (UTV), and total lesion FAP expression (TLF) of the primary tumor were recorded. The target-to-background ratios (TBRs) of the primary tumor to normal tissue muscle (TBRmuscle) and blood (TBRblood) were also calculated. In addition, the minimum apparent diffusion coefficient value of the tumor was measured. After 3-4 cycles of gemcitabine + nab-paclitaxel chemotherapy, patients were divided into responders and nonresponders groups according to RECIST criteria (v.1.1). They were also divided into resectable and unresectable groups according to the surgical outcome. The variables were compared separately between groups.
RESULTS
A total of 18 patients who met the criteria were included in this study. The UTV and TLF were significantly higher in nonresponders than in responders (P < 0.05). The SUVmax, SUVmean, and TBRmuscle were significantly higher in unresectable patients than in resectable ones (P < 0.05). Receiver operating characteristic curve analysis identified UTV (area under the curve [AUC] = 0.840, P = 0.015) and TLF (AUC = 0.877, P = 0.007) as significant predictors for the response to gemcitabine + nab-paclitaxel chemotherapy, with cutoff values of 25.05 and 167.38, respectively. In addition, SUVmax (AUC = 0.838, P = 0.016), SUVmean (AUC = 0.812, P = 0.026), and TBRmuscle (AUC = 0.787, P = 0.041) were significant predictors of the resectability post-NCT, with cutoff values of 14.0, 6.0, and 13.9, respectively. According to logistic regression analysis, TLF was found to be significantly associated with tumor response (P = 0.032) and was an independent predictor of tumor response (P = 0.032). In addition, apparent diffusion coefficient value was an independent predictor of tumor resectability (P = 0.043).
CONCLUSIONS
This pilot study demonstrates the value of 68Ga-FAPI PET/MR for the prediction of tumor response and resectability after neoadjuvant therapy. It may aid in individualized patient management by guiding the treatment regimens.
PubMed: 38914015
DOI: 10.1097/RLU.0000000000005300 -
The Oncologist Jun 2024To describe reasons for deviations from planned chemotherapy treatments in women with nonmetastatic breast cancer that contribute to less-than-planned receipt of...
BACKGROUND
To describe reasons for deviations from planned chemotherapy treatments in women with nonmetastatic breast cancer that contribute to less-than-planned receipt of chemotherapy.
METHODS
Electronic medical records for patients receiving chemotherapy were reviewed for adverse events and treatment modifications. Log-binomial regression models were used to estimate relative risks (RRs) with 95% CIs to examine associations between chemotherapy modifications, patient characteristics, and treatment modalities.
RESULTS
Delays in chemotherapy initiation (7%) were for surgical complications (58%), personal reasons (16%), and other (26%; port malfunction, infections, and obtaining extra imaging). Delays during chemotherapy (38%) were for infections (20%), neutropenia (13%), and personal reasons (13%). Dose reductions (38%) were for neuropathy (36%), unknown causes (9%), anemia (9%), and neutropenia (8%). Early treatment discontinuations (23%) were for neuropathy (29%). Patients receiving paclitaxel/nab-paclitaxel (RR 2.05; 95% CI, 1.47-2.87) and an anthracycline (RR 1.89; 95% CI, 1.39-2.57) reported more dose delays during chemotherapy. Black race (RR 1.46; 95% CI, 1.07-2.00), stage 3 (RR 1.79; 95% CI, 1.09-2.93), and paclitaxel/nab-paclitaxel receipt (RR 1.39; 95% CI, 1.02-1.90) increased the likelihood of dose reduction. Both Black race (RR 2.06; 95% CI, 1.35-3.15) and receipt of paclitaxel/nab-paclitaxel (RR 1.93; 95% CI, 1.19-3.13) increased the likelihood of early discontinuation. Patients receiving anthracyclines had higher rates of hospitalizations during chemotherapy (RR: 1.79; 95% CI, 1.11-2.89).
CONCLUSION
Toxicities are the most common reason for treatment modifications and need close monitoring in high-risk groups for timely intervention. Dose reductions and early treatment discontinuations occurred more for Black patients and need further study.
PubMed: 38913986
DOI: 10.1093/oncolo/oyae150 -
Journal of the National Cancer Institute Jun 2024In KEYNOTE-522 (NCT03036488), neoadjuvant pembrolizumab+chemotherapy then adjuvant pembrolizumab significantly improved pathological complete response and event-free...
BACKGROUND
In KEYNOTE-522 (NCT03036488), neoadjuvant pembrolizumab+chemotherapy then adjuvant pembrolizumab significantly improved pathological complete response and event-free survival vs neoadjuvant chemotherapy in early-stage triple-negative breast cancer (TNBC). We report patient-reported outcomes (PROs) from KEYNOTE-522.
METHODS
Patients were randomized 2:1 to neoadjuvant pembrolizumab 200 mg or placebo every 3 weeks, plus 4 cycles of paclitaxel+carboplatin then 4 cycles of doxorubicin (or epirubicin)+cyclophosphamide. After surgery, patients received adjuvant pembrolizumab or placebo for up to 9 cycles. EORTC QLQ-30 and QLQ-BR23 were prespecified secondary objectives. Between-group differences in least squares (LS) mean change from baseline (day 1/cycle 1 in both neoadjuvant and adjuvant phases) to the prespecified latest time point with ≥60%/80% completion/compliance were assessed using a longitudinal model (no alpha error assigned).
RESULTS
Week 21 (neoadjuvant phase) and week 24 (adjuvant phase) were the latest time points at which completion/compliance rates were ≥60%/80%. In the neoadjuvant phase, between-group differences (pembrolizumab+chemotherapy [N = 762] vs placebo+chemotherapy [N = 383]) in LS mean change from baseline to week 21 in QLQ-C30 GHS/QoL, emotional functioning, and physical functioning were -1.04 (95% CI, -3.46 to 1.38), -0.69 (95% CI, -3.13 to 1.75), and -2.85 (95% CI, -5.11 to - 0.60), respectively. In the adjuvant phase, between-group differences (pembrolizumab [N = 539] vs placebo [N = 308]) in LS mean change from baseline to week 24 were -0.41 (95% CI, -2.60 to 1.77), -0.60 (95% CI, -2.99 to 1.79), and -1.57 (95% CI, -3.36 to 0.21).
CONCLUSIONS
No substantial differences in PRO assessments were observed between neoadjuvant pembrolizumab+chemotherapy followed by adjuvant pembrolizumab vs neoadjuvant placebo+chemotherapy in early-stage TNBC.
TRIAL REGISTRATION
ClinicalTrials.gov, NCT03036488.
PubMed: 38913881
DOI: 10.1093/jnci/djae129 -
Methods in Molecular Biology (Clifton,... 2024Polyploid giant cancer cells (PGCCs) play a fundamental role in tumor initiation, dormancy, drug resistance, and metastasis, although the detailed biology of PGCCs...
Polyploid giant cancer cells (PGCCs) play a fundamental role in tumor initiation, dormancy, drug resistance, and metastasis, although the detailed biology of PGCCs remains poorly understood. The lack of literature on establishing a reproducible in vitro system for generating PGCCs is the leading technological obstacle to studying the biology of PGCCs. Here we provide a detailed protocol for generating stable PGCCs from Hey cancer cells and studying the PGCCs' embryonic stemness. This protocol includes (1) generating PGCCs of high purity in 2D culture by exposing Hey cells to paclitaxel, monitoring the cell cycle and amitotic budding of daughter cells from PGCCs, and collecting and studying the daughter cells; (2) inducing PGCCs to form spheroids expressing embryonic stemness markers and observing the spheroids' cleavage and blastocyst-like structure; and (3) inducing redifferentiation of PGCCs into different lineages of differentiated cells.
Topics: Humans; Polyploidy; Ovarian Neoplasms; Female; Cell Line, Tumor; Cell Differentiation; Giant Cells; Cell Culture Techniques; Neoplastic Stem Cells; Spheroids, Cellular; Paclitaxel; Cell Cycle
PubMed: 38913316
DOI: 10.1007/978-1-0716-3946-7_16 -
International Journal of Clinical... Jun 2024Advanced recurrent endometrial cancer (EC) has a poor prognosis and new treatment options are needed. In 2013, EC was classified by genomic analysis into four groups:... (Review)
Review
Advanced recurrent endometrial cancer (EC) has a poor prognosis and new treatment options are needed. In 2013, EC was classified by genomic analysis into four groups: the POLE ultra-mutated group, the MSI-high hypermutated group (MSI-H), the copy number low group, and the copy number high group. The prognosis differs based on the classification, which should enable the individualization of treatment. The MSI-H and POLE types can induce PD-L1 expression in cancer cells. Among the gynecological cancers, EC exhibits the highest levels of PD-1 and PD-L1 expression and has the highest proportion of MSI-H. Thus, an immune checkpoint inhibitor (ICI) is expected to be effective. The first ICI to show efficacy in recurrent EC was the anti-PD1 antibody pembrolizumab, which exhibited efficacy in MSI-H EC. The combination of pembrolizumab and the multi-kinase inhibitor lenvatinib significantly prolongs OS/PFS compared with single-agent chemotherapy in previously treated recurrent EC, regardless of MSI status. ICIs are now moving from second-line and beyond to first-line treatment regimens. The efficacy of paclitaxel plus carboplatin (TC) and ICI combinations compared with TC have been demonstrated, including an ongoing Phase III trial comparing chemotherapy with the combination of pembrolizumab and lenvatinib. Although ICIs are becoming the mainstay of EC, they cause systemic inflammatory side effects known as irAEs. The incidence of irAEs is higher for combination therapy with CT or lenvatinib compared with ICI therapy alone. Even though they are rarely fatal, irAEs should be addressed promptly.
PubMed: 38913219
DOI: 10.1007/s10147-024-02568-2 -
Cancer Chemotherapy and Pharmacology Jun 2024Different regimens of low-dose chemotherapy (LDC) are currently being actively developed and introduced into clinical practice. Along with its obvious advantages...
Immunoregulatory cyclophilin a improves low-dose chemotherapy with a modulation of the immune tumor microenvironment in experimental models of melanoma B16 and lymphoma EL4 in vivo.
PURPOSE
Different regimens of low-dose chemotherapy (LDC) are currently being actively developed and introduced into clinical practice. Along with its obvious advantages compared to conventional chemotherapy (low toxicity, prevention of drug resistance), LDC could also stimulate anti-tumor immune responses in a patient by activating effectors of innate and adaptive immunity and diminishing tumor-associated immunosuppression. As non-myeloablative, LDC could be successfully combined with different anti-cancer immunotherapeutic strategies, including immunoregulatory cytokines. Secreted cyclophilin A (CypA) is of particular interest in this respect. Previously, we showed that recombinant human CypA (rhCypA) had pleiotropic immunostimulatory activity and anti-tumor effects. Thus, rhCypA could be potentially proposed as a perspective component of combined therapy with LDC.
METHODS
In this work, we evaluated the anti-tumor effects of rhCypA combined with low doses of cyclophosphamide, doxorubicin, dacarbazine, and paclitaxel in the experimental mouse tumor models of melanoma B16 and lymphoma EL4 in vivo.
RESULTS
Synergic and potentiating effects of rhCypA combined with LDC were shown in these studies. Furthermore, as a monotherapeutic agent and a component of combined chemoimmunotherapy, rhCypA was shown to modulate the immune tumor microenvironment by enhancing tumor infiltration with macrophages, NK cells, and T cells. It was also found that rhCypA stimulated both systemic and local anti-tumor immune responses.
CONCLUSION
RhCypA could be potentially proposed as a perspective component of the combined cancer chemoimmunotherapy.
PubMed: 38913118
DOI: 10.1007/s00280-024-04691-3 -
Biomaterials Science Jun 2024Breast cancer is the most common malignancy accounting for 12.5% of all newly diagnosed cancer cases across the globe. Breast cancer cells are known to metastasize to...
Breast cancer is the most common malignancy accounting for 12.5% of all newly diagnosed cancer cases across the globe. Breast cancer cells are known to metastasize to distant organs (, brain), wherein they can exhibit a dormant phenotype for extended time periods. These dormant cancer cells exhibit reduced proliferation and therapeutic resistance. However, the mechanisms by which dormant cancer cells exhibit resistance to therapy, in the context of brain metastatic breast cancer (BMBC), is not well understood. Herein, we utilized hyaluronic acid (HA) hydrogels with varying stiffnesses to study drug responsiveness in dormant proliferative BMBC cells. It was found that cells cultured on soft HA hydrogels (∼0.4 kPa) that showed a non-proliferative (dormant) phenotype exhibited resistance to Paclitaxel or Lapatinib. In contrast, cells cultured on stiff HA hydrogels (∼4.5 kPa) that showed a proliferative phenotype exhibited responsiveness to Paclitaxel or Lapatinib. Moreover, dormancy-associated resistance was found to be due to upregulation of the serum/glucocorticoid regulated kinase 1 (SGK1) gene which was mediated, in part, by the p38 signaling pathway. Accordingly, SGK1 inhibition resulted in a dormant-to-proliferative switch and response to therapy. Overall, our study demonstrates that matrix stiffness influences dormancy-associated therapy response mediated, in part, the p38/SGK1 axis.
PubMed: 38912649
DOI: 10.1039/d4bm00342j -
Journal of Inflammation Research 2024Dermatomyositis (DM) represents a group of inflammatory myopathies, with TIF1-γ positive DM strongly associated with malignancies. Spontaneous muscular hematoma in DM...
BACKGROUND
Dermatomyositis (DM) represents a group of inflammatory myopathies, with TIF1-γ positive DM strongly associated with malignancies. Spontaneous muscular hematoma in DM patients is exceedingly rare and often prognosticates a severe clinical outcome, especially in the context of concurrent malignancy.
CASE PRESENTATION
We describe a novel survival case of a patient with TIF1-γ positive DM and an underlying ovarian tumor who developed a spontaneous muscular hematoma. Despite the traditionally poor prognosis of these conditions, the patient survived through a comprehensive treatment regimen. This included targeted chemotherapy for ovarian cancer (Carboplatin and Paclitaxel), alongside corticosteroids, immunoglobulins, and immunosuppressants for DM, as well as component blood transfusions, coagulation correction therapy to control hematoma, and integrated management: nutritional support, lung function exercise, volume management.
RESULTS
The integrated treatment strategy stabilized the patient's condition and resolved the hematoma, a significant achievement given the usual high mortality rate of such complications.
CONCLUSION
This case underscores the importance of a multidisciplinary approach in the early diagnosis and treatment of TIF1-γ positive DM with complex comorbidities, including spontaneous muscular hematoma and ovarian cancer. It highlights the potential for favorable outcomes with aggressive and coordinated treatment strategies.
PubMed: 38911988
DOI: 10.2147/JIR.S469401