-
The New England Journal of Medicine Dec 2023Mirvetuximab soravtansine-gynx (MIRV), a first-in-class antibody-drug conjugate targeting folate receptor α (FRα), is approved for the treatment of platinum-resistant... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
Mirvetuximab soravtansine-gynx (MIRV), a first-in-class antibody-drug conjugate targeting folate receptor α (FRα), is approved for the treatment of platinum-resistant ovarian cancer in the United States.
METHODS
We conducted a phase 3, global, confirmatory, open-label, randomized, controlled trial to compare the efficacy and safety of MIRV with the investigator's choice of chemotherapy in the treatment of platinum-resistant, high-grade serous ovarian cancer. Participants who had previously received one to three lines of therapy and had high FRα tumor expression (≥75% of cells with ≥2+ staining intensity) were randomly assigned in a 1:1 ratio to receive MIRV (6 mg per kilogram of adjusted ideal body weight every 3 weeks) or chemotherapy (paclitaxel, pegylated liposomal doxorubicin, or topotecan). The primary end point was investigator-assessed progression-free survival; key secondary analytic end points included objective response, overall survival, and participant-reported outcomes.
RESULTS
A total of 453 participants underwent randomization; 227 were assigned to the MIRV group and 226 to the chemotherapy group. The median progression-free survival was 5.62 months (95% confidence interval [CI], 4.34 to 5.95) with MIRV and 3.98 months (95% CI, 2.86 to 4.47) with chemotherapy (P<0.001). An objective response occurred in 42.3% of the participants in the MIRV group and in 15.9% of those in the chemotherapy group (odds ratio, 3.81; 95% CI, 2.44 to 5.94; P<0.001). Overall survival was significantly longer with MIRV than with chemotherapy (median, 16.46 months vs. 12.75 months; hazard ratio for death, 0.67; 95% CI, 0.50 to 0.89; P = 0.005). During the treatment period, fewer adverse events of grade 3 or higher occurred with MIRV than with chemotherapy (41.7% vs. 54.1%), as did serious adverse events of any grade (23.9% vs. 32.9%) and events leading to discontinuation (9.2% vs. 15.9%).
CONCLUSIONS
Among participants with platinum-resistant, FRα-positive ovarian cancer, treatment with MIRV showed a significant benefit over chemotherapy with respect to progression-free and overall survival and objective response. (Funded by ImmunoGen; MIRASOL ClinicalTrials.gov number, NCT04209855.).
Topics: Female; Humans; Antibodies, Monoclonal, Humanized; Carcinoma, Ovarian Epithelial; Immunoconjugates; Maytansine; Ovarian Neoplasms; Folate Receptor 1; Drug Resistance, Neoplasm; Platinum Compounds
PubMed: 38055253
DOI: 10.1056/NEJMoa2309169 -
Langmuir : the ACS Journal of Surfaces... Dec 2023Lipids, and cationic lipids in particular are of interest as delivery vectors for hydrophobic drugs such as the cancer therapeutic paclitaxel, and the structures of...
Lipids, and cationic lipids in particular are of interest as delivery vectors for hydrophobic drugs such as the cancer therapeutic paclitaxel, and the structures of lipid assemblies affect their efficacy. We investigated the effect of incorporating the multivalent cationic lipid MVL5 (+5) and poly(ethylene glycol)-lipids (PEG-lipids), alone and in combination, on the structure of fluid-phase lipid assemblies of the charge-neutral lipid 1,2-dioleoyl--glycero-phosphocholine (DOPC). This allowed us to elucidate lipid-assembly structure correlations in sonicated formulations with high charge density, which are not accessible with univalent lipids such as the well-studied DOTAP (+1). Cryogenic transmission electron microscopy (cryo-TEM) allowed us to determine the structure of the lipid assemblies, revealing diverse combinations of vesicles and disc-shaped, worm-like, and spherical micelles. Remarkably, MVL5 forms an essentially pure phase of disc micelles at 50 mol % MVL5. At a higher (75 mol %) content of MVL5, short- and intermediate-length worm-like micellar rods were observed, and in ternary mixtures with PEG-lipid, longer and highly flexible worm-like micelles formed. Independent of their length, the worm-like micelles coexisted with spherical micelles. In stark contrast, DOTAP forms mixtures of vesicles, disc micelles, and spherical micelles at all studied compositions, even when combined with PEG-lipids. The observed similarities and differences in the effects of charge (multivalent versus univalent) and high curvature (multivalent charge versus PEG-lipid) on the assembly structure provide insights into parameters that control the size of fluid lipid nanodiscs, relevant for future applications.
Topics: Micelles; Phosphatidylcholines; Fatty Acids, Monounsaturated; Microscopy, Electron, Transmission; Liposomes
PubMed: 38051205
DOI: 10.1021/acs.langmuir.3c02664 -
Journal of Controlled Release :... Jan 2024As one of the most challenging cancers, glioma still lacks efficient therapeutic treatment in clinics. The dilemmas of nanodrug-based therapies for glioma are due not...
As one of the most challenging cancers, glioma still lacks efficient therapeutic treatment in clinics. The dilemmas of nanodrug-based therapies for glioma are due not only the limited permeability of the blood-brain barrier (BBB) but also the deficiency of targeting tumor lesions. Thus, spatiotemporally sequential delivery of therapeutics from BBB-crossing to glioma accumulation is considered a strategy to obtain better outcomes. Here, we developed a biomimetic chemotherapy nanodrug composed of the hybrid membrane envelope of U87 cell membranes and RAW264.7 cell membranes, and the core of paclitaxel (PTX)-loaded liposome (PTX@C-MMCL). In the research, PTX@C-MMCL showed superior ability to cross the BBB via RAW264.7 cell membranes and accurate targeting to the brain tumor lesions relying on the homotypic targeting capacity of U87 cell membranes. Furthermore, PTX@C-MMCL can maintain a prolonged circulation in vivo. Importantly, PTX@C-MMCL effectively inhibited the development of glioma. Conclusively, our biomimetic nanodrug holds great potential for brain tumor targeting therapy.
Topics: Humans; Liposomes; Biomimetics; Cell Line, Tumor; Glioma; Brain Neoplasms; Paclitaxel; Drug Delivery Systems; Blood-Brain Barrier
PubMed: 38030082
DOI: 10.1016/j.jconrel.2023.11.046 -
Journal of Gynecologic Oncology Jan 2024Epithelial ovarian cancer is the leading cause of death among gynecological malignancies. Platinum resistance remains a dilemma and bottleneck in treatment, and salvage... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Epithelial ovarian cancer is the leading cause of death among gynecological malignancies. Platinum resistance remains a dilemma and bottleneck in treatment, and salvage chemotherapy has limited effectiveness. Recently, the role of secondary cytoreductive surgery (SCS) in patients with platinum-resistant recurrent ovarian cancer (ROC) has caused attention especially in patients with oligometastases. However, there is neither high-quality evidence-based evidence nor standardized criteria for selecting SCS for patients with platinum-resistant ROC until now.
METHODS
This multicenter, randomized, controlled clinical trial is to evaluate the value of SCS and to clarify reliable criteria of utilizing SCS in women with ROC, which is led by Gynecologic Oncology Group, Women's Hospital, Zhejiang University School of Medicine. Recruitment has started on January 1st, 2023, and is scheduled to end in December 2026. One hundred and forty participants with platinum-resistant ROC who meet the "RSCS criteria" will be randomized assigned at a ratio of 1:1 to either the experimental arm or the standard arm. Patients in the experimental arm will receive SCS followed by non-platinum single agent chemotherapy (paclitaxel, gemcitabine or liposomal adriamycin) for at least 4 cycles while patients in the standard arm will be provided with only non-platinum single agent chemotherapy. The primary outcome is progression-free survival. The secondary outcomes are overall survival, adverse events and health-related cancer-specific quality of life.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT05633199.
Topics: Female; Humans; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Ovarian Epithelial; Cytoreduction Surgical Procedures; Neoplasm Recurrence, Local; Ovarian Neoplasms; Paclitaxel; Platinum; Quality of Life
PubMed: 37945326
DOI: 10.3802/jgo.2024.35.e22 -
Synthesis and Characterization of Paclitaxel-Loaded PEGylated Liposomes by the Microfluidics Method.Molecular Pharmaceutics Dec 2023For cancer therapy, paclitaxel (PX) possesses several limitations, including limited solubility and untargeted effects. Loading PX into nanoliposomes to enhance PX...
For cancer therapy, paclitaxel (PX) possesses several limitations, including limited solubility and untargeted effects. Loading PX into nanoliposomes to enhance PX solubility and target their delivery as a drug delivery system has the potential to overcome these limitations. Over the other conventional method to prepare liposomes, a microfluidic system is used to formulate PX-loaded PEGylated liposomes. The impact of changing the flow rate ratio (FRR) between the aqueous and lipid phases on the particle size and polydispersity index (PDI) is investigated. Moreover, the effect of changing the polyethylene glycol (PEG) lipid ratio on the particle size, PDI, stability, encapsulation efficiency % (EE %), and release profile is studied. The physicochemical characteristics of the obtained formulation were analyzed by dynamic light scattering, FTIR spectroscopy, and AFM. This work aims to use microfluidic technology to produce PEGylated PX-loaded liposomes with a diameter of <200 nm, low PDI < 0.25 high homogeneity, and viable 28 day stability. The results show a significant impact of FRR and PEG lipid ratio on the empty liposomes' physicochemical characteristics. Among the prepared formulations, two formulations produce size-controlled, low PDI, and stable liposomes, which make them preferable for PX encapsulation. The average EE % was >90% for both formulations, and the variation in the PEG lipid ratio affected the EE % slightly; a high packing for PX was reported at different drug concentrations. A variation in the release profiles was notified for the different PEG lipid ratios.
Topics: Paclitaxel; Liposomes; Microfluidics; Polyethylene Glycols; Lipids; Particle Size
PubMed: 37931072
DOI: 10.1021/acs.molpharmaceut.3c00596 -
BioRxiv : the Preprint Server For... Oct 2023Paclitaxel (PTX) is a hydrophobic small-molecule cancer drug that loads into the membrane (tail) region of lipid carriers such as liposomes and micelles. The development...
Paclitaxel (PTX) is a hydrophobic small-molecule cancer drug that loads into the membrane (tail) region of lipid carriers such as liposomes and micelles. The development of improved lipid-based carriers of PTX is an important objective to generate chemotherapeutics with fewer side effects. The lipids 1,2-dioleoyl--glycero-3-phosphoethanolamine (DOPE) and glyceryl monooleate (GMO) show propensity for fusion with other lipid membranes, which has led to their use in lipid vectors of nucleic acids. We hypothesized that DOPE and GMO could enhance PTX delivery to cells through a similar membrane fusion mechanism. As an important measure of drug carrier performance, we evaluated PTX solubility in cationic liposomes containing GMO or DOPE. Solubility was determined by time-dependent kinetic phase diagrams generated from direct observations of PTX crystal formation using differential-interference-contrast optical microscopy. Remarkably, PTX was much less soluble in these liposomes than in control cationic liposomes containing univalent cationic lipid 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) and 1,2-dioleoyl--glycero-3-phosphatidylcholine (DOPC), which are not fusogenic. In particular, PTX was not substantially soluble in GMO-based cationic liposomes. The fusogenicity of DOPE and GMO is related to the negative spontaneous curvature of membranes containing these lipids, which drives formation of nonlamellar self-assembled phases (inverted hexagonal or gyroid cubic). We used synchrotron small-angle x-ray scattering to determine whether PTX solubility is governed by lipid membrane structure (condensed with DNA in pellet form) or by local intermolecular interactions. The results suggest that local intermolecular interactions are of greater importance and that the negative spontaneous curvature-inducing lipids DOPE and GMO are not suitable components of lipid carriers for PTX delivery regardless of carrier structure.
PubMed: 37905081
DOI: 10.1101/2023.10.18.563006 -
BMC Women's Health Oct 2023Ovarian remnant syndrome (ORS) is a rare complication that occurs after oophorectomy, characterized by residual ovarian tissue causing pelvic pain, masses, and various...
BACKGROUND
Ovarian remnant syndrome (ORS) is a rare complication that occurs after oophorectomy, characterized by residual ovarian tissue causing pelvic pain, masses, and various symptoms. The clinical manifestations of ORS are nonspecific, and its diagnosis relies on histological examination. Since ORS typically represents a benign ovarian lesion, there have been few reported cases of malignant transformation. In this report, we presented a unique case of ovarian clear cell carcinoma (OCCC) arising from an ovarian remnant following salpingo-oophorectomy.
CASE PRESENTATION
Our patient was a 47-year-old female initially diagnosed with uterine myoma. She had previously undergone cesarean section and unilateral salpingo-oophorectomy. Transvaginal ultrasound and computed tomography (CT) scans revealed a soft tissue mass adjacent to the right lateral wall of the myometrium. The patient opted for transabdominal hysterectomy, left adnexal resection, laparoscopic omentectomy, appendectomy, and pelvic and abdominal lymphadenectomy. The final pathology results confirmed the diagnosis of OCCC, consistent with ORS. The patient subsequently received six cycles of intravenous chemotherapy using the carboplatin/paclitaxel (TC) regimen (paclitaxel liposomes 175 mg/m², carboplatin AUC 5). After 3 years of follow-up, the patient's condition remained normal.
CONCLUSION
ORS can significantly impact patients' quality of life and pose challenges for clinicians. Complete excision of ovarian tissue during the initial surgery is crucial in preventing ORS recurrence and potential malignant transformation of ovarian remnants.
Topics: Humans; Pregnancy; Female; Middle Aged; Ovarian Neoplasms; Carboplatin; Cesarean Section; Quality of Life; Paclitaxel; Carcinoma
PubMed: 37891576
DOI: 10.1186/s12905-023-02695-4 -
Heliyon Oct 2023Advanced non-small cell lung cancer (NSCLC) is often complicated by leptomeningeal metastases (LMs), especially in patients carrying EGFR mutations. EGFR tyrosine kinase...
Afatinib overcoming resistance to icotinib and osimertinib in NSCLC with leptomeningeal metastasis in patients with acquired EGFR L858R/T790M or L858R/S768I mutations: Two case reports.
BACKGROUND
Advanced non-small cell lung cancer (NSCLC) is often complicated by leptomeningeal metastases (LMs), especially in patients carrying EGFR mutations. EGFR tyrosine kinase inhibitors (TKIs) are the first-line drug for patients with specific gene mutations, such as EGFR exon 19 deletion or exon 21 L858R mutation. However, after long-term TKI use, patients eventually develop drug resistance and acquire new mutations. Acquiring the EGFR T790 M mutation during TKI treatment is a marker for first/second generation TKI resistance. Osimertinib (a third-generation TKI) could overcome this resistance, especially for patients who have already developed NSCLC-LM. Treating NSCLC patients with osimertinib resistance is challenging. Our aim was to investigate whether afatinib is effective in NSCLC-LM patient who showed resistance to osimertinib. Herein, we report two patients with resistance to first- and third-generation TKIs who benefited from second-generation TKI.
CASE SUMMARY
Case one: A 43-year-old man was diagnosed with stage 3A NSCLC with EGFR exon 19 deletion. He underwent surgery and received 4 rounds of chemotherapy (oxaliplatin combined with liposomal paclitaxel), after which the disease was controlled by icotinib (a first-generation TKI) for 4 years. Then, he showed poor drug response and bone metastasis. A liquid biopsy was carried out, and the EGFR L858R/T790 M compound mutation was found. The patient was given osimertinib (a third-generation TKI). The patient was in a stable condition for 2 years and then he developed bilateral peripheral facial palsy. Brain MRI showed enhancement in the left temporal lobe and meninges, and cerebrospinal fluid (CSF) cytology detected tumour cells in the CSF. NSCLC-LM was diagnosed. His performance status (PS) score was 3-4. Liquid biopsy and next-generation sequencing were performed again. Different gene mutations and copy number alterations were found this time, including EGFR L858R, but without the EGFR T790 M mutation. His disease was controlled with intrathecal methotrexate and oral afatinib (a second generation TKI). The patient has shown clinical remission (PS score: 1-2) until now, which is longer than 10 months.
CASE TWO
A 50-year-old man was diagnosed with NSCLC in May 2020. He underwent one round of chemotherapy before thoracoscopic partial lobectomy of the right upper lung. Histological study of the lung tissue showed lung adenocarcinoma with the EGFR L858R mutation. Then, the disease was controlled with icotinib. One year later, he was diagnosed with NSCLC-LM. Liquid biopsy and sequencing showed an EGFR L858R/S768I compound mutation. The patient was treated with osimertinib. His condition was stable for 5 months before his central nervous system (CNS) symptoms were exacerbated. Liquid biopsy and sequencing were carried out again, and his gene mutation profile had not changed much. Then, the patient was given afatinib, and his condition has remained stable for 11 months.
CONCLUSION
Afatinib might be suitable for NSCLC-LM patients with EGFR compound mutations who show resistance to icotinib and osimertinib, since it might help overcome first- and third-generation TKI resistance.
PubMed: 37860534
DOI: 10.1016/j.heliyon.2023.e20690 -
Journal of Medical Case Reports Oct 2023An estimated 119,300 new cases of cervical cancer occur annually in China, accounting for 372,00 deaths. Cutaneous metastasis from cervical cancer is a rare event, with... (Review)
Review
BACKGROUND
An estimated 119,300 new cases of cervical cancer occur annually in China, accounting for 372,00 deaths. Cutaneous metastasis from cervical cancer is a rare event, with an incidence of 0.1-1.3% and typically a preterminal occurrence. Scalp metastasis from cervical cancer is exceptionally anecdotal, with only a dozen examples well documented.
CASE PRESENTATION
The patient is a 33-year-old Chinese woman who was diagnosed with International Federation of Gynecology and Obstetrics stage IVB cervical cancer in November 2021. From December 2021 to April 2022, the patient was enrolled in the clinical trial of sintilimab combined with chemotherapy and radiotherapy for treatment of stage IV cervical cancer and underwent six cycles of immunotherapy and chemotherapy (sintilimab plus paclitaxel liposome and cisplatin). Treatment was well tolerated and led to a partial response. The masses adjacent to the spine and iliac bone was largely reduced. Thus, radiotherapy of the metastatic residues was carried out and followed by radiotherapy to the primary tumor at the cervix uteri. However, by the time of the radiotherapy completion in October 2022, the patient noticed painless nodules at the left scapular region and the right hypochondrium. The following month, more nodules occurred on the scalp and trunk, including the left axilla, anterior abdomen, and left back, along with a lesion invading the sternum that caused acute bone pain. The cutaneous masses were white, discrete with a rubbery consistency, and fixed to the skin. Several nodules increased in size and eventually ulcerated. Fine‑needle aspiration cytology of the left back swellings revealed metastatic squamous cell carcinoma, P16 positive. No visceral or brain metastasis was observed at this point.
CONCLUSIONS
Cervical cancer metastases to the scalp are extremely uncommon. When a scalp metastasis is present, it might be the only symptomatic sign of disease progression or widespread metastatic lesions. So far, there is no clear guideline regarding skin metastases treatment. Such skin lesions warrant a thorough radiologic and pathologic workup to form a comprehensive management plan.
Topics: Female; Humans; Adult; Uterine Cervical Neoplasms; Scalp; Skin Neoplasms; Carcinoma, Squamous Cell; Cisplatin
PubMed: 37853494
DOI: 10.1186/s13256-023-04171-x -
Frontiers in Oncology 2023Immune checkpoint inhibitors (ICIs) have been widely applicated in clinical therapy in recent years. Skin-related adverse reaction is one of the most common adverse...
Immune checkpoint inhibitors (ICIs) have been widely applicated in clinical therapy in recent years. Skin-related adverse reaction is one of the most common adverse events for ICIs. Stevens-Johnson syndrome (SJS) is one of the serious cutaneous reactions threatening the life. Here, we reported a case of 76-year-old male patient with poorly differentiated metastatic lung adenocarcinoma, after 9 weeks exposure of sintilimab (3 doses) combined with paclitaxel liposome after concurrent chemotherapy/radiotherapy, experienced Stevens-Johnson syndrome involving limbs, trunk, lip and the oral mucosa. Biopsy of the skin tissue showed infiltration of CD4 and CD8 positive T lymphocytes. We also found PD-L1 expression in the glands and the basal layer of the skin. This finding is distinct from the previously reported expression of PD-L1 on the surface of epidermal keratinocytes in patients with SJS due to immunotherapy.
PubMed: 37781182
DOI: 10.3389/fonc.2023.912168