Investigator
City Of Hope National Medical Center
From Fallopian Tube to Ovarian Cancer: Understanding the Evaluation and Management of Serous Tubal Intraepithelial Carcinoma Lesions
Opinion Statement Ovarian cancer, particularly high-grade serous carcinoma (HGSC), remains a leading cause of mortality in gynecologic oncology. Emerging research identifies serous tubal intraepithelial carcinoma (STIC) as a precursor lesion in many HGSC cases, highlighting its role in ovarian cancer pathogenesis and prevention. Management of STIC is challenging, as there is only limited data available to guide clinical decision-making. For average-risk women, opportunistic salpingectomy is increasingly being adopted during routine procedures such as hysterectomy or cesarean section. This intervention has demonstrated significant potential in reducing ovarian cancer incidence while maintaining safety and feasibility. For high-risk individuals, particularly BRCA mutation carriers, risk-reducing salpingo-oophorectomy (RRSO) remains the gold standard. RRSO significantly lowers ovarian cancer risk, though alternative approaches like salpingectomy alone or radical fimbriectomy are under investigation to preserve ovarian function in younger patients. To improve STIC detection, SEE-FIM pathology protocol is recommended when patients are undergoing risk-reducing surgery to prevent ovarian cancer, but challenges such as diagnostic variability and limited data persist. When STIC is detected incidentally, management varies based on risk factors and lesion characteristics. Genetic counseling and testing are essential when STIC is identified, as hereditary predisposition may guide further management. Surgical management is advised for cases of STIC with microinvasive carcinoma, but routine use of surgical management for STIC is not clearly defined in the literature. Bilateral oophorectomy is generally recommended when STIC is identified, and adnexal structures have not yet been removed. Chemotherapy is not recommended for treatment of STIC. Surveillance is suggested when STIC has been diagnosed, but there are no set guidelines as to the frequency and type of monitoring. Future directions include refining molecular profiling to predict progression and conducting randomized studies to establish evidence-based guidelines. Multidisciplinary collaboration is essential to optimize prevention and treatment, ultimately reducing HGSC incidence and improving patient outcomes.
Therapeutic Potential of Baicalein in Endometrial Cancer: Suppression of mTOR Signaling and Synergy with Metformin
Baicalein, a natural flavonoid derived from traditional medicinal herbs, has demonstrated anticancer activity in various malignancies, but its role in endometrial cancer remains largely unexplored. In this study, we investigated the therapeutic potential of baicalein, alone and in combination with metformin, in human endometrial cancer cells. Given that the mTOR signaling pathway is frequently dysregulated in endometrial cancer due to PTEN loss, we examined how baicalein affects this pathway. Our results demonstrated that baicalein significantly inhibited cell proliferation in a dose-dependent manner, which was associated with increased DDIT4 expression, activation of AMPK, and decreased phosphorylation of mTOR downstream targets S6K1 and S6. In vivo, baicalein treatment led to a reduction in tumor volume in HEC-1A xenograft female nude mice without affecting body weight. While metformin also reduced cell viability, baicalein achieved comparable effects at lower concentrations. The combination of baicalein and metformin produced a synergistic anti-tumor effect and more effectively inhibited the AMPK/PI3K/mTOR signaling pathway than either agent alone. These findings suggest that baicalein may represent a promising, non-toxic therapeutic option for endometrial cancer, particularly when used in combination with metformin. Further investigation is warranted to assess the clinical relevance of this strategy.
Specific targeting of ovarian tumor-associated macrophages by large, anionic nanoparticles
Significance Tumor-associated macrophages (TAMs) are abundant in tumor microenvironments and are predominantly immunosuppressive. The ratio between immunosuppressive M2 TAMs and proinflammatory M1 TAMs correlates with worse outcomes for many cancers, including ovarian cancer. TAMs are potential targets for immunotherapy, and here we show that, when relatively large (>100-nm) anionic nanoparticles are administered intraperitoneally (i.p.), they selectively accumulate in TAMs with high efficiency (>60% of injected dose). The composition of particles that achieve this targeting appears to be quite flexible. Thus, based on our results, many formulations can now be tested for targeted immunotherapy of ovarian cancer and other cancers of the i.p. cavity.
A Phase III Study of Pafolacianine Injection (OTL38) for Intraoperative Imaging of Folate Receptor–Positive Ovarian Cancer (Study 006)
PURPOSE The adjunctive use of intraoperative molecular imaging (IMI) is gaining acceptance as a potential means to improve outcomes for surgical resection of targetable tumors. This confirmatory study examined the use of pafolacianine for real-time detection of folate receptor–positive ovarian cancer. METHODS This phase III, open-label, 11-center study included subjects with known or suspected ovarian cancer, scheduled to undergo cytoreductive surgery. The objectives were to confirm safety and efficacy of pafolacianine (0.025 mg/kg IV), given ≥ 1 hour before intraoperative near-infrared imaging to detect macroscopic lesions not detected by palpation and normal white light. RESULTS From March 2018 through April 2020, 150 patients received a single infusion of pafolacianine (safety analysis set); 109 patients with folate receptor–positive ovarian cancer comprised the full analysis set for efficacy. In 33.0% of patients (95% CI, 24.3 to 42.7; P < .001), pafolacianine with near-infrared imaging identified additional cancer on tissue not planned for resection and not detected by white light assessment and palpation, exceeding the prespecified threshold of 10%. Among patients who underwent interval debulking surgery, the rate was 39.7% (95% CI, 27.0 to 53.4; P < .001). The sensitivity to detect ovarian cancer was 83%, and the patient false-positive rate was 24.8%. Investigators reported achieving complete R0 resection in 62.4% (68 of 109) of patients. Drug-related adverse events were reported by 30% of patients (45 of 150) and most commonly included nausea, vomiting, and abdominal pain. No drug-related serious adverse events or deaths were reported. CONCLUSION This phase III study of pafolacianine met its primary efficacy end point, identifying additional cancers not otherwise identified or planned for resection. Pafolacianine may offer an important real-time adjunct to current surgical approaches for ovarian cancer.
Hyperthermic Intraperitoneal Chemotherapy–Induced Molecular Changes in Humans Validate Preclinical Data in Ovarian Cancer
PURPOSE Hyperthermic intraperitoneal chemotherapy (HIPEC) confers a survival benefit in epithelial ovarian cancer (EOC) and in preclinical models. However, the molecular changes induced by HIPEC have not been corroborated in humans. PATIENTS AND METHODS A feasibility trial evaluated clinical and safety outcomes of HIPEC with cisplatin during optimal cytoreductive surgery (CRS) in patients with EOC diagnosed with stage III, IV, or recurrent EOC. Pre- and post-HIPEC biopsies were comprehensively profiled with genomic and transcriptomic sequencing to identify mutational and RNAseq signatures correlating with response; the tumor microenvironment was profiled to identify potential immune biomarkers; and transcriptional signatures of tumors and normal samples before and after HIPEC were compared to investigate HIPEC-induced acute transcriptional changes. RESULTS Thirty-five patients had HIPEC at the time of optimal CRS; all patients had optimal CRS. The median progression-free survival (PFS) was 24.7 months for primary patients and 22.4 for recurrent patients. There were no grade 4 or 5 adverse events. Anemia was the most common grade 3 adverse event (43%). Hierarchical cluster analyses identified distinct transcriptomic signatures of good versus poor responders to HIPEC correlating with a PFS of 29.9 versus 7.3 months, respectively. Among good responders, significant HIPEC-induced molecular changes included immune pathway upregulation and DNA repair pathway downregulation. Within cancer islands, % programmed cell death protein 1 expression in CD8+ T cells significantly increased after HIPEC. An exceptional responder (PFS 58 months) demonstrated the highest programmed cell death protein 1 increase. Heat shock proteins comprised the top differentially upregulated genes in HIPEC-treated tumors. CONCLUSION Distinct transcriptomic signatures identify responders to HIPEC, and preclinical model findings are confirmed for the first time in a human cohort.
OTL38 for Intra-operative Imaging of Folate Receptor Positive Ovarian Cancer
This is a phase 3, randomized, multi-center, single dose, open label, pivotal study in patients diagnosed with, or with high clinical suspicion of, ovarian cancer scheduled to undergo primary surgical cytoreduction, interval debulking, or recurrent ovarian cancer surgery.
Surgery and Chemotherapy With or Without Chemotherapy After Surgery in Treating Patients With Ovarian, Fallopian Tube, Uterine, or Peritoneal Cancer
This phase I trial studies the side effects and how well surgery and heated chemotherapy with or without non-heated chemotherapy after surgery works in treating patients with ovarian, fallopian tube, uterine, or peritoneal cancer. Giving a dose of heated chemotherapy into the abdomen during surgery that is done to remove ovarian, fallopian tube, uterine, or peritoneal cancer may help lower the risk of the cancer coming back. Giving unheated chemotherapy drugs directly into the abdomen after surgery may kill more tumor cells.
