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Human Reproduction Update Jun 2024Chemotherapy-associated ovarian damage (CAOD) is one of the most feared short- and long-term side effects of anticancer treatment in premenopausal women. Accumulating...
BACKGROUND
Chemotherapy-associated ovarian damage (CAOD) is one of the most feared short- and long-term side effects of anticancer treatment in premenopausal women. Accumulating detailed data show that different chemotherapy regimens can lead to disturbance of ovarian hormone levels, reduced or lost fertility, and an increased risk of early menopause. Previous studies have often focused on the direct effects of chemotherapeutic drugs on ovarian follicles, such as direct DNA damage-mediated apoptotic death and primordial follicle burnout. Emerging evidence has revealed an imbalance in the ovarian microenvironment during chemotherapy. The ovarian microenvironment provides nutritional support and transportation of signals that stimulate the growth and development of follicles, ovulation, and corpus luteum formation. The close interaction between the ovarian microenvironment and follicles can determine ovarian function. Therefore, designing novel and precise strategies to manipulate the ovarian microenvironment may be a new strategy to protect ovarian function during chemotherapy.
OBJECTIVE AND RATIONALE
This review details the changes that occur in the ovarian microenvironment during chemotherapy and emphasizes the importance of developing new therapeutics that protect ovarian function by targeting the ovarian microenvironment during chemotherapy.
SEARCH METHODS
A comprehensive review of the literature was performed by searching PubMed up to April 2024. Search terms included 'ovarian microenvironment' (ovarian extracellular matrix, ovarian stromal cells, ovarian interstitial, ovarian blood vessels, ovarian lymphatic vessels, ovarian macrophages, ovarian lymphocytes, ovarian immune cytokines, ovarian oxidative stress, ovarian reactive oxygen species, ovarian senescence cells, ovarian senescence-associated secretory phenotypes, ovarian oogonial stem cells, ovarian stem cells), terms related to ovarian function (reproductive health, fertility, infertility, fecundity, ovarian reserve, ovarian function, menopause, decreased ovarian reserve, premature ovarian insufficiency/failure), and terms related to chemotherapy (cyclophosphamide, lfosfamide, chlormethine, chlorambucil, busulfan, melphalan, procarbazine, cisplatin, doxorubicin, carboplatin, taxane, paclitaxel, docetaxel, 5-fluorouraci, vincristine, methotrexate, dactinomycin, bleomycin, mercaptopurine).
OUTCOMES
The ovarian microenvironment shows great changes during chemotherapy, inducing extracellular matrix deposition and stromal fibrosis, angiogenesis disorders, immune microenvironment disturbance, oxidative stress imbalances, ovarian stem cell exhaustion, and cell senescence, thereby lowering the quantity and quality of ovarian follicles. Several methods targeting the ovarian microenvironment have been adopted to prevent and treat CAOD, such as stem cell therapy and the use of free radical scavengers, senolytherapies, immunomodulators, and proangiogenic factors.
WIDER IMPLICATIONS
Ovarian function is determined by its 'seeds' (follicles) and 'soil' (ovarian microenvironment). The ovarian microenvironment has been reported to play a vital role in CAOD and targeting the ovarian microenvironment may present potential therapeutic approaches for CAOD. However, the relation between the ovarian microenvironment, its regulatory networks, and CAOD needs to be further studied. A better understanding of these issues could be helpful in explaining the pathogenesis of CAOD and creating innovative strategies for counteracting the effects exerted on ovarian function. Our aim is that this narrative review of CAOD will stimulate more research in this important field.
REGISTRATION NUMBER
Not applicable.
PubMed: 38942605
DOI: 10.1093/humupd/dmae020 -
Clinical Drug Investigation Jun 2024Trastuzumab targets human epidermal growth factor receptor 2 (HER2) receptors and is indicated for treating HER2-positive metastatic breast cancer. BP02, a recombinant...
BACKGROUND AND OBJECTIVE
Trastuzumab targets human epidermal growth factor receptor 2 (HER2) receptors and is indicated for treating HER2-positive metastatic breast cancer. BP02, a recombinant IgG1 kappa humanized monoclonal antibody, is being developed as a trastuzumab biosimilar. The objective of this study was to evaluate the equivalence of BP02 with reference trastuzumab (RT: Herceptin-EU) in patients with HER2-positive metastatic breast cancer.
METHODS
This double-blinded, 1:1 randomized, parallel-group, active-controlled, phase III equivalence trial recruited women aged 18-75 years with histologically/cytologically confirmed HER2- positive, locally recurrent or metastatic breast cancer with systemic metastasis, from 59 sites in India. Patients were randomly allocated 1:1 stratified by estrogen receptor/progesterone receptor status to receive BP02/RT (8-mg/kg loading dose on day 1-cycle 1, 6 mg/kg on day 1-cycles 2-8, of each 3-week cycle) combined with docetaxel (75 mg/m on day 1-cycles 1-8) [induction phase]. Participants with complete or partial response, or stable disease at the end of the induction phase continued the study drug until disease progression/treatment discontinuation [maintenance phase]. The primary efficacy endpoint was the objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
RESULTS
Between 23 September, 2020 and 16 September, 2022, 690 patients were recruited (n = 345 each to BP02/RT). At the end of the induction phase (intent-to-treat population), a similar proportion of patients achieved an objective response rate with BP02 (n = 231 [67.0%], 95% confidence interval [CI] 62.0, 71.9) and RT (n = 238 [69.0%], 95% CI 64.1, 73.9). The 95% CI of risk difference (-2.03, 95% CI -9.15, 5.09) and 90% CI of risk ratio (0.97, 90% CI 0.89, 1.06) were within equivalence margins of ± 13% and (0.80, 1.25), respectively. Treatment-emergent adverse events leading to treatment withdrawal were reported in 2.9% and 3.2% patients with BP02 and RT, respectively.
CONCLUSIONS
BP02 showed an equivalent efficacy and similar safety profile to RT at the end of 24 weeks.
CLINICAL TRIAL REGISTRATION
CTRI Number: CTRI/2020/04/024456.
PubMed: 38937403
DOI: 10.1007/s40261-024-01374-y -
Gynecologic Oncology Jun 2024Chemotherapy-induced alopecia (CIA) is a common and emotionally-taxing side effect of chemotherapy, including taxane agents used frequently in treatment of gynecologic... (Review)
Review
BACKGROUND
Chemotherapy-induced alopecia (CIA) is a common and emotionally-taxing side effect of chemotherapy, including taxane agents used frequently in treatment of gynecologic cancers. Scalp hypothermia, also known as "cold caps", is a possible method to prevent severe CIA, studied primarily in the breast cancer population.
OBJECTIVES
To compile existing data on scalp hypothermia in cancer patients receiving taxane chemotherapy in order to investigate its application to the gynecologic cancer population.
SEARCH STRATEGY
MEDLINE, Embase, CINAHL, ClinicalTrials.gov, and Cochrane were searched through January 31, 2023.
SELECTION CRITERIA
Full-text manuscripts reporting on the results of scalp hypothermia in patients receiving taxane-based chemotherapy.
DATA COLLECTION AND ANALYSIS
Binomial proportions were summed, and random-effects meta-analyses performed.
MAIN RESULTS
From 1424 records, we included 31 studies, representing 14 different countries. Only 5 studies included gynecologic cancer patients. We extracted the outcome of the proportion of patients with <50% hair loss. Among 2179 included patients, 60.7% were reported to have <50% hair loss (meta-analysis: 60.6%, 95% confidence interval [CI] 54.9-66.1%). Among the 28 studies reporting only on taxane-based chemotherapy, the rate of <50% hair loss was 60.0% (meta-analysis: 60.9%, (95% CI: 54.9-66.7%). In comparative studies, hair loss was significantly less in patients who received scalp hypothermia versus those who did not (49.3% versus 0% with <50% hair loss; OR 40.3, 95% CI: 10.5-154.8). Scalp cooling achieved <50% hair loss in patients receiving paclitaxel (67.7%; meta-analysis 69.9%, 95% CI 64.1-75.4%) and docetaxel (57.1%; meta-analysis 60.5%, 95% CI 50.0-71.6%). Meta-analysis on patient satisfaction in regard to scalp cooling found a satisfaction rate of 78.9% (95% CI 69.1-87.4%).
CONCLUSION
Scalp hypothermia may be an effective method to reduce some cases of CIA due to taxane chemotherapy, especially paclitaxel. More trials need to be done to determine the precise effects of scalp hypothermia in gynecologic cancer patients.
PubMed: 38936283
DOI: 10.1016/j.ygyno.2024.06.012 -
Journal of the Science of Food and... Jun 2024Betel nut chewing is a significant risk factor for oral cancer due to arecoline, its primary active component. Resveratrol, a non-flavonoid polyphenol, possesses...
BACKGROUND
Betel nut chewing is a significant risk factor for oral cancer due to arecoline, its primary active component. Resveratrol, a non-flavonoid polyphenol, possesses anti-cancer properties. It has been shown to inhibit arecoline-induced oral malignant cells in preliminary experiments but the underlying mechanism remains unclear. This research therefore aimed to explore the potential therapeutic targets of resveratrol in treating arecoline-induced oral cancer.
METHODS
Data mining identified common targets and hub targets of resveratrol in arecoline-induced oral cancer. Gene set variation analysis (GSVA) was used to score and validate the expression and clinical significance of these hub targets in head and neck cancer (HNC) tissues. Molecular docking analysis was conducted on the hub targets. The effect of resveratrol intervention on hub targets was verified by experiments.
RESULTS
Sixty-one common targets and 15 hub targets were identified. Hub targets were highly expressed in HNC and were associated with unfavorable prognoses. They played a role in HNC metastasis, epithelial-mesenchymal transition, and invasion. Their expression also affected immune cell infiltration and correlated negatively with sensitivity to chemotherapeutic agents such as bleomycin and docetaxel. Experiments demonstrated that resveratrol down-regulated the expression of the hub targets, inhibited their proliferation and invasion, and induced apoptosis.
CONCLUSION
Resveratrol inhibits the arecoline-induced malignant phenotype of oral epithelial cells by regulating the expression of some target genes, suggesting that resveratrol may be used not only as an adjuvant treatment for oral cancer, but also as an adjuvant for oral cancer prevention due to its low toxicity and high efficacy. © 2024 Society of Chemical Industry.
PubMed: 38934557
DOI: 10.1002/jsfa.13664 -
Pharmaceutics May 2024This research underscores the potential of combining nanotechnology with conventional therapies in cancer treatment, particularly for challenging cases like pancreatic...
This research underscores the potential of combining nanotechnology with conventional therapies in cancer treatment, particularly for challenging cases like pancreatic cancer. We aimed to enhance pancreatic cancer treatment by investigating the synergistic effects of gold nanoparticles (GNPs) and docetaxel (DTX) as potential radiosensitizers in radiotherapy (RT) both in vitro and in vivo, utilizing a MIA PaCa-2 monoculture spheroid model and NRG mice subcutaneously implanted with MIA PaCa-2 cells, respectively. Spheroids were treated with GNPs (7.5 μg/mL), DTX (100 nM), and 2 Gy of RT using a 6 MV linear accelerator. In parallel, mice received treatments of GNPs (2 mg/kg), DTX (6 mg/kg), and 5 Gy of RT (6 MV linear accelerator). In vitro results showed that though RT and DTX reduced spheroid size and increased DNA DSBs, the triple combination of DTX/RT/GNPs led to a significant 48% ( = 0.05) decrease in spheroid size and a 45% ( = 0.05) increase in DNA DSBs. In vivo results showed a 20% ( = 0.05) reduction in tumor growth 20 days post-treatment with (GNPs/RT/DTX) and an increase in mice median survival. The triple combination exhibited a synergistic effect, enhancing anticancer efficacy beyond individual treatments, and thus could be employed to improve radiotherapy and potentially reduce adverse effects.
PubMed: 38931837
DOI: 10.3390/pharmaceutics16060713 -
Cancers Jun 2024Due to limited effective therapeutics for uterine leiomyosarcoma (uLMS), the impact of the gamma secretase inhibitor (GSI) MK-0752 with common chemotherapeutics was...
Due to limited effective therapeutics for uterine leiomyosarcoma (uLMS), the impact of the gamma secretase inhibitor (GSI) MK-0752 with common chemotherapeutics was explored in uLMS. MTT assays were performed on two human uLMS cell lines, SK-UT-1B and SK-LMS-1, using MK-0752, docetaxel, doxorubicin, and gemcitabine, individually and in combination, to determine cell viability after treatment. Synergistic combinations were used in transwell invasion assays, cell cycle flow cytometry, proliferation assays, and RNA sequencing. In SK-UT-1B, MK-0752 was synergistic with doxorubicin and gemcitabine plus docetaxel. In SK-LMS-1, MK-0752 was synergistic with all individual agents and with the combination of gemcitabine plus docetaxel. MK-0752, gemcitabine, and docetaxel decreased invasion in SK-UT-1B 2.1-fold* and in SK-LMS-1 1.7-fold*. In SK-LMS-1, invasion decreased 1.2-fold* after treatment with MK-0752 and docetaxel and 2.2-fold* after treatment with MK-0752 and doxorubicin. Cell cycle analysis demonstrated increases in the apoptotic sub-G1 population with MK-0752 alone in SK-UT-1B (1.4-fold*) and SK-LMS-1 (2.7-fold**), along with increases with all combinations in both cell lines. The combination treatments had limited effects on proliferation, while MK-0752 alone decreased proliferation in SK-LMS-1 (0.63-fold**). Both MK-0752 alone and in combination altered gene expression and KEGG pathways. In conclusion, the combinations of MK-0752 with either doxorubicin, docetaxel, or gemcitabine plus docetaxel are potential novel therapeutic approaches for uLMS. (* < 0.05, ** < 0.01).
PubMed: 38927890
DOI: 10.3390/cancers16122184 -
Journal of the American Geriatrics... Jun 2024The landscape of systemic therapies for metastatic hormone-sensitive (mHSPC) and castration resistant prostate cancer (mCRPC) extensively improved within the last...
BACKGROUND
The landscape of systemic therapies for metastatic hormone-sensitive (mHSPC) and castration resistant prostate cancer (mCRPC) extensively improved within the last decades resulting in a significantly prolonged overall survival. However, subgroup analyses of phase III trials suggest potentially different overall survival outcomes for older adults.
METHODS
We relied on our institutional metastatic prostate cancer database to identify mHSPC and subsequently mCRPC patients. Older adults were stratified according to age groups 70-74 versus ≥75-79 versus ≥80 years at metastatic occurrence. Subsequently, uni- and multivariable time to mCRPC and overall survival analyses were performed.
RESULTS
Of 494 older adults, 217 (44%) were 70-74 versus 180 (36%) 75-79 versus 97 (20%) ≥80 years old. Rates of local prostate cancer treatment differed significantly between all three groups (p < 0.01). Regarding mHSPC treatment, androgen receptor signaling inhibitors (ARSI) were administered in 30-39% of patients and docetaxel with 9% in age group 70-74 years and 6% and 3% in age groups 75-79 years and ≥80 years. Regarding mCRPC treatment, significant differences between treatment proportions were observed (p < 0.01). Most common treatment was ARSI for all three groups. Conversely, chemotherapy was more frequently administered in patients aged 70-74 (16%), relative to 4% and 3% in 75-79 year and ≥80 year aged patients. In univariable and multivariable time to mCRPC analyses, overall survival in mHSPC and OS in mCRPC analyses, no significant differences between all three age groups were observed (all p ≥ 0.3).
CONCLUSIONS
Treatment patterns differ significantly between older adults with metastatic prostate cancer. However, these differences may not result in differences of overall life expectancy.
PubMed: 38922830
DOI: 10.1111/jgs.19045 -
Shock (Augusta, Ga.) Jun 2024Sepsis is a life-threatening disease due to a dysregulated host response to infection, with an unknown regulatory mechanism for prognostic necroptosis-related genes...
Sepsis is a life-threatening disease due to a dysregulated host response to infection, with an unknown regulatory mechanism for prognostic necroptosis-related genes (NRGs). Using GEO datasets GSE65682 and GSE134347, we identified six NRG biomarkers (ATRX, TSC1, CD40, BACH2, BCL2, and LEF1) with survival and diagnostic significance through Kaplan-Meier (KM) and Receiver Operating Characteristic (ROC) analyses. Afterwards, the ingenuity pathway analysis (IPA) highlighted enrichment in hepatic fibrosis pathways and BEX2 protein. Moreover, we examined their regulatory targets and functional links with necroptotic signaling molecules via miRDB, TargetScan, Network analyst, and GeneMANIA. The molecular regulatory network displayed that hsa-miR-5195-3p and hsa-miR-145-5p regulated ATRX, BACH2, and CD40, while YY1 showed strong connectivity, concurrently controlling LEF1, ATRX, BCL2, BACH2, and CD40. CD40 exhibited similar expression patterns to RIPK3 and MLKL, and LEF1 was functionally associated with MLKL. Additionally, DrugBank analysis identified Paclitaxel, Docetaxel, and Rasagiline as potential BCL2-targeting sepsis treatments. Finally, Real-Time Quantitative PCR confirmed ATRX, TSC1, and LEF1 down-regulation in sepsis samples, contrasting CD40's increased expression in CTL samples. In conclusion, ATRX, TSC1, CD40, BACH2, BCL2, and LEF1 may be critical regulatory targets of necroptosis in sepsis, providing a basis for further necroptosis-related studies in sepsis.
PubMed: 38920136
DOI: 10.1097/SHK.0000000000002414 -
Frontiers in Oncology 2024Larynx organ preservation (LOP) in locoregional-advanced laryngeal and hypopharyngeal squamous cell carcinoma (LA-LHSCC) being only R0-resectable (clear margins > 5 mm)...
INTRODUCTION
Larynx organ preservation (LOP) in locoregional-advanced laryngeal and hypopharyngeal squamous cell carcinoma (LA-LHSCC) being only R0-resectable (clear margins > 5 mm) by total laryngectomy (TL) is desirable. Based on tumor-specific survival (TSS) and overall survival (OS) data from the RTOG 91-11 trial and meta-analyses of randomized clinical trials (RCTs), cisplatin-based concurrent radiochemotherapy (CRT) is discussed being superior to cisplatin-based induction chemotherapy followed by radiotherapy (IC+RT) and TL followed by postoperative RT (TL+PORT) or radiochemotherapy (TL+PORCT). Outside of RCTs, T4 LHSCC treated with TL+PORCT demonstrated improved OS and TSS compared to CRT alone; comparisons with docetaxel plus cisplatin (TP)-based IC+RT are unpublished. Head-to-head comparisons in RCTs of these four alternatives are missing.
MATERIALS AND METHODS
We utilized monocentric registry data to compare the outcome in the LOP trial DeLOS-II (NCT00508664) and propensity score (PS)-matched LHSCC patients. DeLOS-II utilized endoscopic tumor staging after one cycle of TP-based IC for selecting TL+R(C)T for non-responders versus IC+RT for responders. Main risk factors for survival (localization hypopharynx, T4, N+, tobacco smoking >30 pack years, alcohol consumption >60 g/day, age, sex) were used to calculate the individual PS for each DeLOS-II patient and 330 LHSCC patients suitable for DeLOS-II according to eligibility criteria in Leipzig by CRT (78), TL+PORT (148), and TL+PORCT (104). We performed PS matching with caliper width 0.2.
RESULTS
The 52 DeLOS-II patients (whole intent-to-treat cohort) and three PS-matched cohorts (52 LHSCC patients each) had equal distribution regarding risk factors including Charlson comorbidity score (CS; all > 0.05) but differed in outcome. During 12,498.6 months of follow-up, 162 deaths (36/41/43/42 in DeLOS-II/TL+PORCT/TL+PORT/CRT, = 0.356) occurred; DeLOS-II patients had superior OS and TSS. Compared to DeLOS-II, the HR (95% CI) observed in TL+PORCT, TL+PORT, and CRT for OS and TSS were 1.49 (0.92-2.43), 1.49 (1.15-3.18), and 1.81 (1.11-2.96) for OS; and 2.07 (0.944-4.58), 3.02 (1.32-6.89), and 3.40 (1.58-7.31) for TSS.
CONCLUSION
In addition potential LOP, LA-LHSCC suitable for LOP according the DeLOS-II protocol may achieve improved survival.
PubMed: 38919522
DOI: 10.3389/fonc.2024.1394691 -
Asian Pacific Journal of Cancer... Jun 2024There have been several reports on rechallenge with docetaxel, cabazitaxel, abiraterone acetate, or ethinylestradiol for metastatic castration-resistant prostate cancer...
OBJECTIVE
There have been several reports on rechallenge with docetaxel, cabazitaxel, abiraterone acetate, or ethinylestradiol for metastatic castration-resistant prostate cancer (mCRPC). However, the efficacy of enzalutamide rechallenge for mCRPC has not been evaluated.
METHODS
We retrospectively reviewed 63 consecutive patients who received enzalutamide for mCRPC at our institution between 2014 and 2022. Eight of these patients underwent rechallenge with enzalutamide after disease progression on prior enzalutamide and other therapy and were the focus of this study. The prostate-specific antigen (PSA) response (PSA decrease >50%), PSA progression-free survival, treatment duration, overall survival (OS) after CRPC, and treatment-related adverse events were evaluated.
RESULTS
PSA decline to enzalutamide rechallenge was observed in 6 patients (75%), of which 2 patients had a PSA response. The median treatment duration was 4 months (range 1-12) and median PSA progression-free survival was 3 months (range 1-7). Median OS after CRPC was 41 months. OS after CRPC was not increased in patients with a PSA response. No toxicities were worse than grade ≥3.
CONCLUSION
Enzalutamide rechallenge achieved a PSA response in a quarter of our patients with mCRPC after disease progression on prior enzalutamide. However, no improvement of OS was identified in these patients.
Topics: Humans; Male; Prostatic Neoplasms, Castration-Resistant; Phenylthiohydantoin; Nitriles; Benzamides; Retrospective Studies; Aged; Middle Aged; Prostate-Specific Antigen; Follow-Up Studies; Survival Rate; Prognosis; Aged, 80 and over; Antineoplastic Agents
PubMed: 38918645
DOI: 10.31557/APJCP.2024.25.6.1863