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Acta Medica Okayama Apr 2024Chronic graft-versus-host disease (GVHD) is a major cause of late death and morbidity following allogeneic hematopoietic cell transplantation (HCT), but its pathogenesis...
Chronic graft-versus-host disease (GVHD) is a major cause of late death and morbidity following allogeneic hematopoietic cell transplantation (HCT), but its pathogenesis remains unclear. Recently, haplo-identical HCT with post-transplant cyclophosphamide (Haplo-HCT with PTCY) was found to achieve a low incidence rate of acute GVHD and chronic GVHD. However, while the pathogenesis of acute GVHD following Haplo-HCT with PTCY has been well investigated, that of chronic GVHD remains to be elucidated, especially in HLA-matched HCT with PTCY. Based on its safety profile, PTCY is currently applied for the human leucocyte antigen (HLA)-matched HCT setting. Here, we investigated the mechanisms of chronic GVHD following HLA-matched HCT with PTCY using a well-defined mouse chronic GVHD model. PTCY attenuated clinical and pathological chronic GVHD by suppressing effector T-cells and preserving regulatory T-cells compared with a control group. Additionally, we demonstrated that cyclosporine A (CsA) did not show any additional positive effects on attenuation of GVHD in PTCY-treated recipients. These results suggest that monotherapy with PTCY without CsA could be a promising strategy for the prevention of chronic GVHD following HLA-matched HCT.
Topics: Graft vs Host Disease; Animals; Cyclophosphamide; Hematopoietic Stem Cell Transplantation; Mice; Chronic Disease; Immunosuppressive Agents; Calcineurin Inhibitors; Female; Mice, Inbred BALB C; Mice, Inbred C57BL; Cyclosporine; Disease Models, Animal
PubMed: 38688830
DOI: 10.18926/AMO/66915 -
Journal of Cancer Research and... Apr 2024The complex strategy of hypo-fractionated radiotherapy (HFRT) in combination with an immune checkpoint inhibitor (ICI) can stimulate a potential systemic antitumor...
PURPOSE
The complex strategy of hypo-fractionated radiotherapy (HFRT) in combination with an immune checkpoint inhibitor (ICI) can stimulate a potential systemic antitumor response; however, the abscopal effect is always precluded by the tumor microenvironment, which may limit sufficient T-cell infiltration of distant nonirradiated tumors for certain kinds of inhibitory factors, such as regulatory T-cells (Tregs). Additionally, low-dose cyclophosphamide (LD-CYC) can specifically kill regulatory Tregs and strongly synergize antigen-specific immune responses, which could promote an abscopal effect.
MATERIALS AND METHODS
We explored whether a triple regimen consisting of HFRT, ICI, and LD-CYC could achieve a better systemic antitumor response in bilateral mouse tumor models.
RESULT
Our data demonstrate that LD-CYC combined with HFRT and antiprogrammed cell death ligand 1 (PDL-1) therapy could enhance the abscopal effect than only HFRT/antiPDL-1 or HFRT alone. Surprisingly, repeat CYC doses cannot further restrain tumor proliferation but can prolong murine overall survival, as revealed by the major pathologic responses. These results are associated with increased CD8 + effector T-cell infiltration, although LD-CYC did not upregulate PDL-1 expression in the tumor.
CONCLUSIONS
Compared with traditional strategies, for the first time, we demonstrated that a triple treatment strategy remarkably increased the number of radiation-induced tumor-infiltrating CD8 + T-cells, effectively decreasing infiltrating Tregs, and promoting an abscopal effect. Thus, we describe a novel and effective therapeutic approach by combining multiple strategies to target several tumor-mediated immune inhibitory mechanisms.
Topics: Animals; Cyclophosphamide; Mice; Immune Checkpoint Inhibitors; Tumor Microenvironment; T-Lymphocytes, Regulatory; Female; Combined Modality Therapy; Disease Models, Animal; Melanoma, Experimental; Radiation, Ionizing; B7-H1 Antigen; Antineoplastic Agents, Alkylating; Mice, Inbred C57BL; Humans; Cell Line, Tumor
PubMed: 38687945
DOI: 10.4103/jcrt.jcrt_616_23 -
Journal of Medical Economics 2024There are multiple recently approved treatments and a lack of clear standard-of-care therapies for relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). While...
AIMS
There are multiple recently approved treatments and a lack of clear standard-of-care therapies for relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). While total cost of care (TCC) by the number of lines of therapy (LoTs) has been evaluated, more recent cost estimates using real-world data are needed. This analysis assessed real-world TCC of R/R DLBCL therapies by LoT using the IQVIA PharMetrics Plus database (1 January 2015-31 December 2021), in US patients aged ≥18 years treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or an R-CHOP-like regimen as first-line therapy.
METHODS
Treatment costs and resources in the R/R setting were assessed by LoT. A sensitivity analysis identified any potential confounding of the results caused by the impact of the COVID-19 pandemic on healthcare utilization and costs. Overall, 310 patients receiving a second- or later-line treatment were included; baseline characteristics were similar across LoTs. Inpatient costs represented the highest percentage of total costs, followed by outpatient and pharmacy costs.
RESULTS
Mean TCC per-patient-per-month generally increased by LoT ($40,604, $48,630, and $59,499 for second-, third- and fourth-line treatments, respectively). Costs were highest for fourth-line treatment for all healthcare resource utilization categories. Sensitivity analysis findings were consistent with the overall analysis, indicating results were not confounded by the COVID-19 pandemic.
LIMITATIONS
There was potential misclassification of LoT; claims data were processed through an algorithm, possibly introducing errors. A low number of patients met the inclusion criteria. Patients who switched insurance plans, had insurance terminated, or whose enrollment period met the end of data availability may have had truncated follow-up, potentially resulting in underestimated costs.
CONCLUSION
Total healthcare costs increased with each additional LoT in the R/R DLBCL setting. Further improvements of first-line treatments that reduce the need for subsequent LoTs would potentially lessen the economic burden of DLBCL.
Topics: Humans; Lymphoma, Large B-Cell, Diffuse; Male; Female; Middle Aged; Doxorubicin; Antineoplastic Combined Chemotherapy Protocols; Vincristine; Cyclophosphamide; Aged; Prednisone; Rituximab; Adult; Health Expenditures; United States; Insurance Claim Review; Health Resources
PubMed: 38686393
DOI: 10.1080/13696998.2024.2349472 -
Archives of Iranian Medicine Apr 2024Neoadjuvant chemotherapy (NCT) has become an increasingly popular approach in management of breast cancer (BC). This study was conducted to evaluate the pathologic...
BACKGROUND
Neoadjuvant chemotherapy (NCT) has become an increasingly popular approach in management of breast cancer (BC). This study was conducted to evaluate the pathologic response and 36-month recurrence and survival rates of patients with human epidermal growth factor receptor 2 (HER2)-negative BC treated with different NCT regimens.
METHODS
A total of 163 female patients with HER2-negative BC who received NCT during 2017-2020 were identified from the Clinical Breast Cancer Registry of Iran and entered the study. The prescribed NCT regimens included 4 cycles of doxorubicin plus cyclophosphamide, 4 cycles of doxorubicin plus cyclophosphamide followed by 4 cycles of paclitaxel, 4 cycles of doxorubicin plus cyclophosphamide followed by 4 cycles of docetaxel or 6 cycles of doxorubicin plus cyclophosphamide plus docetaxel (TAC).
RESULTS
Thirty-two patients (19.6%) experienced pathologic complete response (pCR). TAC regimen, triple negative-BC and ki67>10% were significantly associated with increased pCR. The recurrence, overall survival (OS) and disease-free survival (DFS) rate at 36 months for all patients were 16.6%, 84.7% and 79.8%, respectively. Type of neoadjuvant regimen as well as age, hormone receptor status, Ki67, grade, clinical stage, type of surgery and pathologic response to chemotherapy did not significantly influence the survival and recurrence; however, TAC results in improved recurrence, OS and DFS rates.
CONCLUSION
This study provides further evidence that NCT is a viable treatment option for patients with HER2-negative BC. The TAC regimen resulted in a significantly higher pCR rate compared to other regimens, but did not result in a significant improvement in recurrence, OS and DFS and rates.
Topics: Humans; Female; Iran; Middle Aged; Neoadjuvant Therapy; Adult; Receptor, ErbB-2; Breast Neoplasms; Antineoplastic Combined Chemotherapy Protocols; Registries; Cyclophosphamide; Doxorubicin; Docetaxel; Aged; Neoplasm Recurrence, Local; Disease-Free Survival; Paclitaxel; Chemotherapy, Adjuvant
PubMed: 38685847
DOI: 10.34172/aim.2024.30 -
The Veterinary Quarterly Dec 2024In the present study, we investigated the potential immunomodulatory effects of heat-killed (hLR) and live PSC102 (LR; formerly PSC102) in RAW264.7 macrophage cells...
In the present study, we investigated the potential immunomodulatory effects of heat-killed (hLR) and live PSC102 (LR; formerly PSC102) in RAW264.7 macrophage cells and Sprague-Dawley rats. RAW264.7 murine macrophage cells were stimulated with hLR and LR for 24 h. Cyclophosphamide (CTX)-induced immunosuppressed Sprague-Dawley rats were orally administered with three doses of hLR (L-Low, M-Medium, and H-High) and LR for 3 weeks. The phagocytic capacity, production of nitric oxide (NO), and expression of cytokines in RAW264.7 cells were measured, and the different parameters of immunity in rats were determined. hLR and LR treatments promoted phagocytic activity and induced the production of NO and the expression of iNOS, TNF-α, IL-1β, IL-6, and Cox-2 in macrophage cells. In the experiment, hLR and LR treatments significantly increased the immune organ indices, alleviated the spleen injury, and ameliorated the number of white blood cells, granulocytes, lymphocytes, and mid-range absolute counts in immunosuppressive rats. hLR and LR increased neutrophil migration and phagocytosis, splenocyte proliferation, and T lymphocyte subsets (CD4, CD8, CD45RA, and CD28). The levels of immune factors (IL-2, IL-4, IL-6, IL-10, IL-12A, TNF-α, and IFN-γ) in the hLR and LR groups were upregulated compared with those in the CTX-treatment group. hLR and LR treatments could also modulate the gut microbiota composition, thereby increasing the relative abundance of Bacteroidetes and Firmicutes but decreasing the level of Proteobacteria. hLR and LR protected against CTX-induced adverse reactions by modulating the immune response and gut microbiota composition. Therefore, they could be used as potential immunomodulatory agents.
Topics: Animals; Cyclophosphamide; Rats; Mice; Rats, Sprague-Dawley; RAW 264.7 Cells; Gastrointestinal Microbiome; Limosilactobacillus reuteri; Probiotics; Male; Cytokines; Phagocytosis; Nitric Oxide; Immunosuppressive Agents
PubMed: 38682319
DOI: 10.1080/01652176.2024.2344765 -
Asian Pacific Journal of Cancer... Apr 2024Tumor hypoxia induces the production of Hypoxia-Inducible Factor (HIF)-1 alpha, which interacts with NF-kB, leading to cancer proliferation and metastasis. This study... (Randomized Controlled Trial)
Randomized Controlled Trial
The Impact of Tumor Hypoxia Modulation on sIL-2R Levels in Newly Diagnosed Diffuse Large B Cell Lymphoma (DLBCL) Patients Undergoing Chemotherapy: A Randomized Clinical Trial.
OBJECTIVE
Tumor hypoxia induces the production of Hypoxia-Inducible Factor (HIF)-1 alpha, which interacts with NF-kB, leading to cancer proliferation and metastasis. This study investigated the effect of tumor hypoxia modulation using carbogen (95% O2 and 5% CO2) and nicotinamide on reducing soluble interleukin-2 receptor (sIL-2R) levels in newly diagnosed DLBCL patients with tissue overexpression of HIF-1α ≥10%.
MATERIAL AND METHODS
A prospective randomized controlled clinical trial was conducted at Dr. Kariadi Hospital in Semarang, Indonesia, from 2021 to 2022. Newly diagnosed DLBCL patients with tissue HIF-1α ≥10% were randomized into an intervention group (nicotinamide 2,000 mg + carbogen 10 liters/min during R-CHOP) and a control group (R-CHOP alone) for one cycle. sIL-2R levels were measured in the blood before and after intervention.
RESULTS
The intervention group showed a significant reduction in sIL-2R levels after chemotherapy (p=0.026), with 85% of samples exhibiting a decrease. In contrast, only 45% of samples in the control group demonstrated a decrease in sIL-2R levels (p=0.184). The median sIL-2R level decreased from 139.50 pg/mL to 70.50 pg/mL in the intervention group, while the control group exhibited an increase from 182.50 pg/mL to 250.00 pg/mL following one cycle of chemotherapy.
CONCLUSION
Tumor hypoxia modulation led to a significant decrease in serum sIL-2R levels, potentially through improvements in the crosstalk between hypoxia and inflammation pathways.
Topics: Humans; Lymphoma, Large B-Cell, Diffuse; Male; Female; Antineoplastic Combined Chemotherapy Protocols; Middle Aged; Tumor Hypoxia; Prospective Studies; Receptors, Interleukin-2; Vincristine; Doxorubicin; Cyclophosphamide; Adult; Prednisone; Prognosis; Rituximab; Follow-Up Studies; Aged; Indonesia; Hypoxia-Inducible Factor 1, alpha Subunit; Biomarkers, Tumor
PubMed: 38679992
DOI: 10.31557/APJCP.2024.25.4.1315 -
Stem Cell Research & Therapy Apr 2024Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for leukemia and a range of non-malignant disorders. The success of the therapy is...
BACKGROUND
Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for leukemia and a range of non-malignant disorders. The success of the therapy is hampered by occurrence of acute graft-versus-host disease (aGvHD); an inflammatory response damaging recipient organs, with gut, liver, and skin being the most susceptible. Intestinal GvHD injury is often a life-threatening complication in patients unresponsive to steroid treatment. Allogeneic mesenchymal stromal/stem cell (MSC) infusions are a promising potential treatment for steroid-resistant aGvHD. Data from our institution and others demonstrate rescue of approximately 40-50% of aGvHD patients with MSCs in Phase I, II studies and minor side effects. Although promising, better understanding of MSC mode of action and patient response to MSC-based therapy is essential to improve this lifesaving treatment.
METHODS
Single cell human small intestine organoids were embedded in Matrigel, grown for 5 days and treated with busulfan for 48 h. Organoids damaged by treatment with busulfan or control organoids were co-cultured with 5000, 10,000, and 50,000 MSCs for 24 h, 48 h or 7 days and the analyses such as surface area determination, proliferation and apoptosis assessment, RNA sequencing and proteomics were performed.
RESULTS
Here, we developed a 3D co-culture model of human small intestinal organoids and MSCs, which allows to study the regenerative effects of MSCs on intestinal epithelium in a more physiologically relevant setting than existing in vitro systems. Using this model we mimicked chemotherapy-mediated damage of the intestinal epithelium. The treatment with busulfan, the chemotherapeutic commonly used as conditioning regiment before the HSCT, affected pathways regulating epithelial to mesenchymal transition, proliferation, and apoptosis in small intestinal organoids, as shown by transcriptomic and proteomic analysis. The co-culture of busulfan-treated intestinal organoids with MSCs reversed the effects of busulfan on the transcriptome and proteome of intestinal epithelium, which we also confirmed by functional evaluation of proliferation and apoptosis.
CONCLUSIONS
Collectively, we demonstrate that our in vitro co-culture system is a new valuable tool to facilitate the investigation of the molecular mechanisms behind the therapeutic effects of MSCs on damaged intestinal epithelium. This could benefit further optimization of the use of MSCs in HSCT patients.
Topics: Humans; Mesenchymal Stem Cells; Intestinal Mucosa; Regeneration; Organoids; Coculture Techniques; Graft vs Host Disease; Mesenchymal Stem Cell Transplantation; Busulfan; Cell Proliferation; Apoptosis
PubMed: 38679715
DOI: 10.1186/s13287-024-03738-9 -
Phytomedicine : International Journal... Jul 2024Premature ovarian insufficiency (POI) is a tricky puzzle in the field of female reproductive medicine. Bushen Huoxue recipe (BHR), a traditional Chinese medicine...
BACKGROUND
Premature ovarian insufficiency (POI) is a tricky puzzle in the field of female reproductive medicine. Bushen Huoxue recipe (BHR), a traditional Chinese medicine compound based on the combination of kidney-tonifying and blood-activating functions, has shown excellent efficacy in improving female irregular menstruation, POI, and infertility. However, the potential mechanism of BHR in POI treatment has not yet been elucidated. Bone marrow mesenchymal stem cells (BMSCs), a type of pluripotent stem cells, have received increasing attention for their significant role in improving ovarian function and restoring fertility in women with POI.
PURPOSE
This study aimed to evaluate the therapeutic effect of BHR in POI mice and explore its potential mechanism.
METHODS
A POI mouse model was established with a single intraperitoneal injection of 120 mg/kg cyclophosphamide (CTX). Distilled water, BHR, or dehydroepiandrosterone was administered via gavage for 28 consecutive days. The effect of BHR on ovarian function in POI mice was evaluated by assessing the estrous cycle, ovarian morphology, follicular development, hormone levels, and angiogenesis. The proportion of BMSCs in bone marrow, peripheral blood, and ovary was analyzed via flow cytometry, and the level of molecules mediating migration and homing in ovary was measured. Cell viability assays, scratch healing assays and transwell migration assays were performed to explore the effect of BHR on BMSCs proliferation and migration in vitro, and its potential mechanism was explored.
RESULTS
BHR significantly ameliorated estrous cycle disorders, hormone disorders, ovarian morphology, ovarian microvascular formation, and ovarian reserve in POI mice. Meanwhile, the number of BMSCs number in the bone marrow, peripheral blood, and ovary was apparently increased. Of note, BHR increased the level of hepatocyte growth factor (HGF)/cellular mesenchymal epithelial transition factor (cMET) and stromal cell-derived factor-1(SDF-1)/CXC chemokine receptor 4 (CXCR4) in the ovaries of POI mice. Moreover, BHR treatment promoted BMSCs proliferation and migration in vitro, with a significant increase in the level of proliferating cell nuclear antigen, cMET, and CXCR4.
CONCLUSIONS
BHR effectively restored ovarian reserve, ovarian function, and ovarian angiogenesis in CTX-induced POI mice. In addition, BHR promoted BMSCs proliferation, migration, and homing to the ovary, which was mediated by the SDF-1/CXCR4 and HGF/cMET signaling axis. Finally, the amelioration of ovarian reserve and ovarian function in CTX-induced POI mice by BHR may be related to its promotion of endogenous BMSCs proliferation and homing.
Topics: Animals; Female; Drugs, Chinese Herbal; Primary Ovarian Insufficiency; Mesenchymal Stem Cells; Ovary; Cell Proliferation; Mice; Disease Models, Animal; Cyclophosphamide; Estrous Cycle; Cell Movement
PubMed: 38678952
DOI: 10.1016/j.phymed.2024.155630 -
Medicine Apr 2024Primary central nervous system lymphoma (PCNSL) is a rare, highly malignant form of non-Hodgkin lymphoma categorized under the diffuse large B-cell type. It accounts for...
RATIONALE
Primary central nervous system lymphoma (PCNSL) is a rare, highly malignant form of non-Hodgkin lymphoma categorized under the diffuse large B-cell type. It accounts for merely 1% of all non-Hodgkin lymphoma cases and comprises approximately 3% of all brain tumors. The involvement of the cerebellum is observed in only 9% of these cases. Recently, we came across an unusual instance: a young man presenting with multiple lesions located specifically within the cerebellum.
PATIENT CONCERNS
A 26-year-old male was admitted to the hospital due to severe headaches. He has a medical history of sporadic headaches, accompanied by dizziness, nausea, and vomiting persisting for a month. Over the last 10 days, his headaches have intensified, coupled with decreased vision and protrusion of the eyeballs. Magnetic resonance imaging (MRI) revealed abnormal signals in both cerebellar hemispheres.
DIAGNOSES, INTERVENTIONS, AND OUTCOMES
Diagnostic procedures included cerebellar biopsy, posterior fossa decompression, and lateral ventricle drainage. Histopathological examination identified diffuse large B-cell lymphoma (DLBCL) with high proliferative activity. To minimize neurotoxicity, chemotherapy involved intrathecal methotrexate (MTX) injections combined with the CHOP program. The patient has shown good tolerance to the treatment so far.
LESSONS
While the definitive optimal treatment approach remains elusive, current chemotherapy centered on high-dose MTX stands as the standard induction therapy. Integrating surgery with radiotherapy and chemotherapy significantly extends patient survival.
Topics: Humans; Male; Adult; Lymphoma, Large B-Cell, Diffuse; Antineoplastic Combined Chemotherapy Protocols; Cerebellar Neoplasms; Cyclophosphamide; Vincristine; Doxorubicin; Methotrexate; Prednisone; Combined Modality Therapy; Magnetic Resonance Imaging; Cerebellum
PubMed: 38669361
DOI: 10.1097/MD.0000000000037923 -
Journal of Cancer Research and Clinical... Apr 2024Morinda citrifolia fruit juice (noni) is an herbal remedy documented to have antioxidant properties. It has been suggested that prevention of carcinogen-DNA adduct...
BACKGROUND AND AIM
Morinda citrifolia fruit juice (noni) is an herbal remedy documented to have antioxidant properties. It has been suggested that prevention of carcinogen-DNA adduct formation and the antioxidant activity of NJ may contribute to the cancer preventive effect. In the present study, the antitumor activity of noni was investigated in the presence of cyclophosphamide (CYL) in vitro and in vivo.
METHODS
In vitro breast cancer cells (MDA-MB-468) were used to measure the percentage of inhibition and the IC. The in vivo antitumor activity of noni was studied by monitoring the mean survival time (MST), percentage increase in life span (%ILS), viable and non-viable cell count, tumor volume, body weight, and hematological and serum biochemical parameters in mice. Treatment with noni and CYL exhibited dose- and time-dependent cytotoxicity toward breast cancer cells.
RESULTS
Individual treatment of noni and CYL exhibited dose- and time-dependent cytotoxicity on breast cancer cell lines, while in combination therapy of noni and CYL, noni enhances cytotoxic effect of CYL at 48 h than that at 24 h. Similar result was found in in vivo studies, the results of which revealed that alone treatment of CYL and noni suppressed tumor growth. However, combination treatment with CYL and noni presented better tumor inhibition than that of alone treatment of CYL and noni. On the contrary, CYL alone drastically attenuated hematological parameters, i.e., RBC, WBC, and Hb compared to normal and control groups, and this change was reversed and normalized by noni when given as combination therapy with CYL. Moreover, the levels of serum biochemical markers, i.e., AST, ALP, and ALT, were significantly increased in the control and CYL-treated groups than those in the normal group. In the combination treatment of noni and CYL, the above biochemical marker levels significantly decreased compared to CYL alone-treated group.
CONCLUSIONS
The present study suggested that CYL treatment can cause serious myelotoxicity and hepatic injury in cancer patients. In conclusion, the combined use of noni with CYL potentially enhances the antitumor activity of CYL and suppresses myelotoxicity and hepatotoxicity induced by CYL in tumor-bearing mice.
Topics: Animals; Cyclophosphamide; Mice; Humans; Female; Morinda; Breast Neoplasms; Cell Line, Tumor; Fruit and Vegetable Juices; Xenograft Model Antitumor Assays; Drug Synergism; Plant Extracts; Antineoplastic Combined Chemotherapy Protocols; Antineoplastic Agents, Alkylating; Mice, Inbred BALB C; Chemical and Drug Induced Liver Injury
PubMed: 38662247
DOI: 10.1007/s00432-024-05734-1