Fertility-sparing management of stage IIIC serous borderline ovarian tumor: A case report of a 20-year follow-up.

Multimodal treatment, including assisted reproductive technology, is necessary in young patients with advanced borderline ovarian tumors. However, the details of long-term follow-up cases have not been reported. In this report, a 19-year-old patient presented with a stage IIIC serous borderline tumor. The patient underwent five fertility-sparing surgeries. The tumor did not respond to any of the three lines of chemotherapy administered. Serological and radiological responses were observed following hormonal treatment with leuprorelin, followed by a fourth surgery. Before the planned fifth surgery for complete resection of both adnexa, cryopreservation of the fertilized eggs was performed. At age 36, when the disease-free interval exceeded the previous one, we proposed embryo transfer; however, she declined fertility treatment. The patient had developed rheumatoid arthritis and childbirth not a priority. The patient had lived without any evidence of disease for 7 years following the last surgery and 20 years after the initial visit.

Medroxyprogesterone as the Initial Systemic Treatment of Recurrent Endometrial Cancer: A Single Institutional Study.

BACKGROUND/AIM: Hormonal treatment is the preferred initial systemic therapy for patients with advanced or recurrent G1 or G2 endometrial cancer (EC) in terms of efficacy, toxicity, and economy. Few reports are available on the topic and we, therefore, conducted a retrospective study. PATIENTS AND METHODS: Patients with EC who received high-dose medroxyprogesterone (MPA) at our Hospital between January 2010 and December 2022 were reviewed. Patients who were treated for fertility preservation or had a history of systemic chemotherapy other than adjuvant therapy were excluded. RESULTS: Sixteen patients who were eligible for study inclusion had recurrent G1 or G2 EC. Their median age was 65 years (range=51-82 years), median body mass index was 22.6 kg/m2 (range=15.3-43.2 kg/m2), and all patients had an ECOG Performance Status of 0. All patients received 200 mg/day of MPA, and eight patients concomitantly received 100 mg/day of aspirin. None of the patients experienced severe adverse events. One patient had grade 2 deep vein thrombosis. Two patients discontinued MPA treatment because of adverse events. The response rate was 44% [95% confidence interval (CI)=20-68%] and median progression-free survival (PFS) was 6.9 months (95% CI=7.5-26 months). Four of 16 patients had PFS longer than 12 months, all of whom had positive tissue estrogen receptor (ER) and progesterone receptor (PR), and PFS at 2 years was 35% (95% CI=10.2-59.8%). CONCLUSION: Hormone therapy is effective long-term in ER- and PR-positive EC and can be recommended as initial systemic therapy. Toxicity is mild and manageable.

Primordial follicles remaining in young cancer survivors who received chemotherapy.

AIM: Ovarian tissue cryopreservation (OTC) is performed for fertility preservation in cancer patients undergoing chemotherapy. Although anti-Müllerian hormone is used as a marker for ovarian reserve, serum levels do not always correlate with the number of follicles. Additionally, the follicle development stage most affected by chemotherapy is unclear. We examined the association between serum anti-Müllerian hormone levels and the number of remaining primordial follicles after chemotherapy, as well as which follicle stage is most affected by chemotherapy before ovarian cryopreservation. METHODS: Thirty-three patients who underwent OTC were divided into the chemotherapy (n = 22) and non-chemotherapy (n = 11) groups; their ovarian tissues underwent histological examination. Pathological ovarian damage induced by chemotherapy was assessed. Ovarian volumes were estimated from weights. We compared the number of follicles at each developmental stage as a percentage of primordial follicles between the groups. The relationship between serum anti-Müllerian hormone level and primordial follicle density was analyzed. RESULTS: The chemotherapy group had a significantly lower serum anti-Müllerian hormone level, ovarian volume, and density of developing follicles than the non-chemotherapy group. Serum anti-Müllerian hormone levels correlated with primordial follicle density only in the non-chemotherapy group. The chemotherapy group had significantly lower numbers of primary and secondary follicles. CONCLUSIONS: Chemotherapy induces ovarian damage and follicle loss. However, serum anti-Müllerian hormone level does not always reflect the number of primordial follicles after chemotherapy, and chemotherapy more significantly affects primary and secondary follicles than primordial follicles. Many primordial follicles remain in the ovary after chemotherapy, supporting OTC for fertility preservation.

Construction of a Bicyclo[2.2.2]octene Skeleton via a Visible-Light-Mediated Radical Cascade Reaction of Amino Acid Derivatives with N-(2-Phenyl)benzoyl Groups.

Bridged polycyclic ring systems constitute the core structures of numerous natural products and biologically active molecules. We found that simple biphenyl substrates derived from amino acids participate in a radical cascade reaction under visible light irradiation in the presence of [Ir{dF(CF3)ppy}2(dtbpy)]PF6 to enable the direct construction of bicyclo[2.2.2]octene structures. Isotopic labeling experiments suggested that intramolecular hydrogen atom transfer is involved in the cascade processes.

Comprehensive Genomic Profiling Detects Hereditary Cancers and Confers Survival Advantage in Patients With Gynaecological Cancers.

BACKGROUND/AIM: The clinical benefits of comprehensive genomic profiling (CGP) of tumours in patients with gynaecological cancers remain unknown. We investigated the utility of CGP in assessing patient survival and its efficacy in detecting hereditary cancers in gynaecological patients. PATIENTS AND METHODS: We retrospectively analysed the medical records of 104 gynaecological patients who underwent CGP between August 2018 and December 2022. The detection of actionable and accessible genomic alterations and administration of targeted therapy, as recommended by the molecular tumour board (MTB), were assessed. The overall survival (after second-line treatment in cervical and endometrial carcinomas and after platinum-resistant recurrence in ovarian carcinoma) was compared between patients with or without administration of MTB-recommended genotype-matched therapy. Germline findings were assessed using a variant allele frequency-tumour content graph. RESULTS: Among 104 patients, actionable and accessible genomic alterations were observed in 53 patients. Matched therapy was applied in 21 patients, comprising administration of repurposing itraconazole (n=7), immune checkpoint inhibitors (n=7), poly (ADP-ribose) polymerase inhibitors (n=5), and others (n=2). The median overall survival of patients receiving and not receiving matched therapy were 19.3 months and 11.2 months, respectively (p=0.036, hazard ratio=0.48). Among 12 patients with hereditary cancers, 11 patients were previously undiagnosed. Seven patients had hereditary breast and ovarian cancer, and five had other cancer. CONCLUSION: The implementation of CGP testing prolonged overall survival in gynaecological cancer as well as provided an opportunity for genetic counselling for newly-diagnosed patients with hereditary cancers and their families.

Itraconazole Modulates Phospholipid Levels in Tumor-associated Macrophages.

BACKGROUND/AIM: Itraconazole, an antifungal drug, repolarizes pro-tumorigenic M2 tumor-associated macrophages to anti-tumorigenic M1-like phenotypes, thereby inhibiting the proliferation of cancer cells; however, the underlying mechanism remains unclear. Therefore, we investigated the effect of itraconazole on membrane-associated lipids in tumor-associated macrophages (TAM). MATERIALS AND METHODS: M1 and M2 macrophages were derived from the human monocyte leukemia cell line (THP-1) and cultured with or without 10 µM itraconazole. Cells were homogenized and subjected to liquid chromatography/mass spectrometry (LC/MS) analysis to estimate the glycerophospholipid levels in the cells. RESULTS: Lipidomic analysis results, displayed on a volcano plot, revealed that itraconazole-induced altered phospholipid composition, with more pronounced changes in M2 macrophages than in M1. Notably, itraconazole significantly increased intracellular phosphatidylinositol and lysophosphatidylcholine levels in M2 macrophages. CONCLUSION: Itraconazole modulates the lipid metabolism of TAMs, which could have implications for the development of novel cancer therapies.

Itraconazole Repolarizes Tumor-associated Macrophages and Suppresses Cervical Cancer Cell Growth.

BACKGROUND/AIM: Itraconazole (ITZ), an antifungal agent, has been reported to have anti-tumor effects in patients with multiple cancer types. We investigated the involvement of tumor-associated macrophages (TAMs) in its tumor-agnostic mechanism. MATERIALS AND METHODS: M1 and M2 macrophages were established from human monocyte leukemia cell line (THP-1) and their phenotypes were determined morphologically. Cell membrane antigens and secreted proteins were evaluated by western blots and enzyme-linked immunosorbent assay, respectively. The proteomic profiling of cells was done by liquid chromatography with tandem mass spectrometry and analyzed. Viability of cervical cancer cells (CaSki) was evaluated after addition of the supernatant of M2 macrophages and during co-culture with M2 macrophages, with or without 10-5 M ITZ. RESULTS: Co-culture of M1 macrophages inhibited the proliferation of CaSki cells (p=0.012), while that of M2 macrophages promoted their proliferation (p<0.0001). After treatment of M2 macrophages with ITZ for 24 h, they changed into M1-like shape with decreased expression of cluster of differentiation 163 (CD163) and chemokine ligand 18 (CCL18). The M1-like shape was maintained for 7 weeks of ITZ treatment and reverted to original after ITZ removal. Proteomic analysis of ITZ treated-M2 macrophages also demonstrated M1-like signature including the elevated levels of tumor necrosis factor (TNF)-related proteins. After treatment with ITZ, both the supernatant of the M2 macrophages and the co-culture with M2 macrophages significantly inhibited the proliferation of CaSki cells (each, p<0.0001). CONCLUSION: ITZ repolarized M2 macrophages to M1 type and suppressed cervical cancer cell growth demonstrating TAM-mediated anti-cancer activity of ITZ.

Structure-Activity Relationships of Styrylquinoline and Styrylquinoxaline Derivatives as α-Synuclein Imaging Probes.

Synucleinopathies are characterized by the deposition of α-synuclein (α-syn) aggregates before the onset of clinical symptoms. Therefore, in vivo imaging of α-syn may contribute to early diagnosis of these diseases and has attracted much attention in recent years. However, no clinically useful probes have been reported. In the present study, 16 quinoline/quinoxaline derivatives with different styryl and fluorine groups were evaluated in order to develop α-syn imaging probes. Among them, SQ3, which is a quinoline analogue with a p-(dimethylamino)styryl group and fluoroethoxy group at the 2- and 7- positions of the skeleton, displayed moderate selectivity for α-syn aggregates over ß-amyloid (Aß) aggregates (K i = 230 nM), while maintaining high binding affinity for α-syn aggregates (K i = 39.3 nM). In a biodistribution study, [18F]SQ3 exhibited high uptake (2.08% ID/g at 2 min after intravenous injection) into a normal mouse brain. Taken together, we demonstrate that [18F]SQ3 has basic properties as a lead compound for the development of a useful α-syn imaging probe.

Total Synthesis of Zephycarinatines via Photocatalytic Reductive Radical ipso-Cyclization.

We report herein a nonbiomimetic strategy for the total synthesis of the plicamine-type alkaloids zephycarinatines C and D. The key feature of the synthesis is a stereoselective reductive radical ipso-cyclization using visible-light-mediated photoredox catalysis. This cyclization enabled the construction of a 6,6-spirocyclic core structure through the addition of a carbon-centered radical onto the aromatic ring. Biological evaluation of zephycarinatines and their derivatives revealed that the synthetic derivative with a keto group displays moderate inhibitory activity against LPS-induced NO production. This approach could offer future opportunities to expand the chemical diversity of plicamine-type alkaloids as well as providing useful intermediates for their syntheses.

[Fabrication of annealing equipment for optically stimulated luminescence (OSL) dosimeter].

The optically stimulated luminescence (OSL) dosimeter is a useful detector for measuring absorbed doses of X-rays. A small-type OSL dosimeter, "nanoDot", has recently been developed by Landauer, Inc., who also manufacture "microStar" reading equipment. However, additional annealing equipment is needed if the nanoDot OSL dosimeter is used repeatedly. The aim of this study was to fabricate suitable annealing equipment using commonly available products. Our device positions four fluorescent light tubes in a close configuration. The heat from the fluorescent light tubes is dissipated using fans. Experiments using diagnostic X-ray equipment were carried out to evaluate the capability of our annealing equipment. The results indicated that our equipment can fully anneal the nanoDot OSL dosimeter with annealing times of approximately 20 hours.

[Measurement of response function of CdTe detector using diagnostic X-ray equipment and evaluation of Monte Carlo simulation code].

An X-ray spectrum measured with CdTe detector has to be corrected with response function, because the spectrum is composed of full energy peaks (FEP) and escape peaks (EP). Recently, various simulation codes were developed, and using them the response functions can be calculated easily. The aim of this study is to propose a new method for measuring the response function and to compare it with the calculated value by the Monte Carlo simulation code. In this study, characteristic X-rays were used for measuring the response function. These X-rays were produced by the irradiation of diagnostic X-rays with metallic atoms. In the measured spectrum, there was a background contamination, which was caused by the Compton scattering of the irradiated X-ray in the sample material. Therefore, we thought of a new experimental methodology to reduce this background. The experimentally derived spectrum was analyzed and then the ratios of EP divided by FEP (EP/FEP) were calculated to compare the simulated values. In this article, we showed the property of the measured response functions and the analysis accuracy of the EP/FEP, and we indicated that the values calculated by Monte Carlo simulation code could be evaluated by using our method.