Optimizing Timing of Intraperitoneal Chemotherapy to Enhance Intravenous Carboplatin Concentration.

Despite advances in systemic chemotherapy, patients with gastric cancer (GC) and peritoneal metastases (PMs) continue to have poor prognoses. Intraperitoneal (IP) administration of Paclitaxel (PTX) combined with systemic chemotherapy shows promise in treating PMs from GC. However, methods of drug administration need to be optimized to maximize efficacy. In this study, we utilized a mouse model with PMs derived from a human GC cell line, administering PTX either IP or intravenously (IV), and Carboplatin (CBDCA) IV 0, 1, and 4 days after PTX administration. The PMs were resected 30 min later, and concentrations of PTX and CBDCA in resected tumors were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Results indicated that PTX concentrations were higher with IP administration than with IV administration, with significant differences observed on days 0 and 1. CBDCA concentrations 4 days post-IP PTX administration were higher than with simultaneous IV PTX administration. These findings suggest that IP PTX administration enhances CBDCA concentration in peritoneal tumors. Therefore, sequential IV administration of anti-cancer drugs appears more effective than simultaneous administration with IP PTX, a strategy that may improve prognoses for patients with PMs.

The role of non-genomic actions of progesterone and its membrane receptor agonist in ovarian cancer cell death.

BACKGROUND: Progesterone therapy is a relatively inexpensive treatment option for endometrial and breast cancers, with few side effects. Two signaling pathways usually mediate the physiological effects of progesterone, namely genomic and non-genomic actions. Genomic action occurs slowly via the nuclear progesterone receptor (PR), whereas the membrane progesterone receptor (mPR) induces rapid non-genomic action. AIMS: We investigated the effects of progesterone and various PR agonists on ovarian cancer cells. METHODS AND RESULTS: PR expression of six serous ovarian cancer cell lines was examined by western blotting, and mPR expression was examined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). PR-negative and mPR-positive ovarian cancer cells were exposed to progesterone and seven types of PR agonists (medroxyprogesterone acetate [MPA], dehydroepiandrosterone, dienogest, levonorgestrel, drospirenone, pregnenolone, and allopregnanolone) at 10-400 µM, and viable cell counts after exposure for 30 min were measured using the water-soluble tetrazolium (WST-1) assay. Ovarian cancer cell lines were exposed to 100 µM progesterone, and the expression of BAX, a pro-apoptotic protein, after 1-5 min was examined by western blotting. Western blotting detected no PR expression in the six serous ovarian cancer cell lines. In contrast, RT-qPCR detected mPR expression in all six serous ovarian cancer cell lines. Progesterone and MPA-induced cell death in all tested ovarian cancer cell lines in a concentration-dependent manner, whereas no effect was observed for other PR agonists. Western blotting revealed that pro-apoptotic protein BAX expression occurred 1 min after exposure to progesterone, suggesting that the cytocidal effects are mediated by rapid non-genomic action. CONCLUSION: Progesterone and MPA exhibited a rapid cytocidal effect on PR-negative ovarian cancer cells through non-genomic action. Progesterone and MPA could be novel adjuvant therapies for ovarian cancer.

Increase in creatinine levels associated with niraparib maintenance therapy in ovarian cancer.

AIM: In Japan, Niraparib maintenance therapy for primary and recurrent ovarian cancer was approved in September 2020 and is expected to improve the prognosis of ovarian cancer. However, the safety of niraparib maintenance therapy in Japanese patients has not been fully evaluated. METHODS: Patients with ovarian cancer (including fallopian tube and peritoneal cancer) treated with niraparib at Jichi Medical University Hospital from September 2020 to August 2022 were enrolled in this study. Patient background, starting dose, rates of interruption, reduction, or discontinuation, adverse events (AEs) during treatment, and estimated glomerular filtration rate (eGFR) trends were retrospectively analyzed. RESULTS: Twenty-nine patients received niraparib maintenance therapy during the study period, including 21 with primary cancer and 8 patients with recurrent cancer. Seventeen patients (58.6%) required dose interruptions and 16 patients (55.2%) required dose reductions. Only two patients (6.9%) discontinued treatment due to fatigue and nausea. The most frequent AE was creatinine increases in 18 patients (62.1%, all grades). Although eGFR levels decreased significantly after niraparib therapy compared to before niraparib therapy (59.3 vs. 50.3 mL/min/1.73 m2 , p < 0.001), the levels returned to pre-niraparib initiation levels after discontinuation of niraparib (64.6 vs. 64.6 mL/min/1.73 m2 , p = 0.96). Multivariate regression analysis showed that diabetes was independently associated with decreased eGFR (p = 0.013). CONCLUSIONS: Niraparib maintenance therapy frequently increased serum creatinine, but the change was reversible. Further studies are needed to determine the effects of niraparib on renal function in Japanese patients.

Late-Onset Ovarian Bleeding After Transvaginal Oocyte Retrieval in a Patient With Suspected Hereditary Hemorrhagic Telangiectasia.

Assisted reproductive technology (ART) requires transvaginal oocyte retrieval (TVOR), and ovarian bleeding after TVOR rarely occurs. We present a case of a 37-year-old woman (0-gravida) who was diagnosed with possible hemorrhagic telangiectasia (HHT) and had a history of three laparotomies for ovarian bleeding and an inclusion cyst adjacent to the right ovary after the third operation. HHT is a hereditary disease characterized by spontaneous hemorrhage of some organs, such as the nose, brain, lungs, gastrointestinal tract, and liver. She desired ART after fertility treatment and then had abdominal pain with ovarian swelling five days after TVOR. Moreover, both the right ovary and inclusion cyst were gradually swollen with hematoma. Finally, abdominal pain and the hemoglobin level deteriorated, necessitating an emergency surgery on the eighth day. We notify reproductive physicians that patients with HHT may readily develop ovarian bleeding with or without inclusion cysts after TVOR, although inclusion cysts may also be associated with late-onset bleeding.

Ovarian vein thrombosis after bilateral adnexectomy in a symptomatic patient with concomitant pulmonary embolism: A case report.

OBJECTIVE: Ovarian vein thrombosis (OVT) after adnexectomy is usually asymptomatic, and pulmonary embolism (PE) has not been reported following this type of OVT. We present the case of a patient with symptomatic OVT after bilateral adnexectomy who experienced PE. CASE REPORT: A 52-year-old woman underwent total laparoscopic hysterectomy and bilateral adnexectomy for early stage endometrial cancer. On the 12th postoperative day, she presented with a fever of 38.7 °C. Computed tomography (CT) revealed bilateral OVT. Anticoagulant and antibacterial therapy was initiated; after five days, the fever subsided. On the 19th postoperative day, CT revealed a decrement in OVT; however, PE was observed. By the 60th postoperative day, PE disappeared. No deep vein thromboses were detected at any time. CONCLUSION: This case highlights that OVT, even after adnexectomy, can cause symptoms and PE can occur after this type of OVT. Anticoagulation therapy may be considered in such cases.

Activated neutrophils inhibit chemotactic migration of activated T lymphocytes to CXCL11 by multiple mechanisms.

Accumulation of T lymphocytes and neutrophils shows inversed association with the prognosis of cancer patients, suggesting infiltration of neutrophils and T cells might be differently regulated in tumor tissue. In this study, we stimulated neutrophils with PMA or LPS to produce neutrophil extracellular traps (NETs) and examined the effects on chemotactic migration of activated T cells to a representative T cell chemokine, CXCL11. Migration of the activated T cells was totally abrogated by PMA-stimulated neutrophils placed either in upper or lower chamber, which was mostly canceled by pretreatment with Catalase. Although LPS-stimulated neutrophils also inhibited T cell migration, depletion of NETs by ultracentrifugation or degradation of NETs with DNAse I restored T cell migration. Western blots showed that LPS-stimulated neutrophils thoroughly degraded CXCL11 with NETs dependent manner. Activated neutrophils inhibit T cell chemotaxis via multiple mechanisms including the release of H2O2 and chemokine degradation by NETs, which may suppress adaptive immunity.

Neutrophil extracellular traps (NETs) reduce the diffusion of doxorubicin which may attenuate its ability to induce apoptosis of ovarian cancer cells.

Purpose: Although neutrophil extracellular traps (NETs) are present in various tumors, their roles in tumor biology have not been clarified yet. In this study, we examined how NETs affect the pharmacokinetics and effects of doxorubicin (DOX). Methods: NETs were generated by neutrophils stimulated with phorbol 12-myristate 13-acetate (PMA) or lipopolysaccharide (LPS). DOX was added to NETs and their distribution was observed under fluorescein microscopy, and the diffusion of DOX through 3 µM pores from lower to upper chambers was evaluated with a fluorescence-based assay. Ovarian cancer cells, KOC-2S and SKOV3, were embedded in collagen gel droplets and cultured in 3D way and their apoptosis was examined with flow cytometry. Results: DOX was mostly co-localized with NETs. The transfer of DOX to upper chambers increased over time, which was significantly decreased by the presence of neutrophils stimulated with PMA or LPS in the lower chamber. DOX outside of the gel increased the rates of annexin V (+) apoptotic cells, which were significantly reduced by the addition of LPS-stimulated neutrophils in media both in KOC-2S and SKOV3. The reduced diffusion and apoptosis were mostly restored by the destruction of the NETs structure with 1000 u/ml DNAse I. Conclusion: NETs efficiently trap and inhibit the diffusion of DOX which may attenuate its ability to induce apoptosis of ovarian cancer cells. Degradation of NETs with DNAse I may augment the response of ovarian cancer to DOX.

Durable response after the discontinuation of pembrolizumab treatment due to an adverse event in a patient with advanced endometrial cancer: A case report.

The persistence of antitumor effects has been reported after the completion of treatment with immune checkpoint inhibitors (ICIs) for various types of carcinoma, such as malignant melanoma, exhibiting a durable response. A durable response has also been noted after the discontinuation of treatment at an early stage due to adverse events, including in renal pelvic cancer, pancreatic cancer and intrahepatic cholangiocarcinoma; however, to the best of our knowledge, a similar case report has not yet been published in the malignant gynecological tumor field. The present study described a patient with refractory advanced endometrial cancer in whom the administration of pembrolizumab was discontinued after the completion of the 7th course due to renal dysfunction; however, persistent tumor-reducing effects and decreases in the levels of tumor markers were noted for more than 18 months after the cessation of treatment. Pembrolizumab may be continuously administered to some patients for a long period, whereas a durable response is achieved by others even after its discontinuation at an early stage; therefore, difficulties are associated with selecting an appropriate duration of administration. Further studies are required to search for biomarkers that facilitate high-accuracy effect predictions, and to establish an optimal administration period in consideration of specific adverse reactions to ICIs and cost-effectiveness.

Response to and toxicity of weekly paclitaxel and carboplatin in patients with stage IIIC-IV ovarian cancer and poor general condition.

It has remained elusive whether standard chemotherapy regimens are safe for patients with ovarian cancer and poor general condition. The purpose of the present study was to assess the response to and toxicity of weekly paclitaxel and carboplatin (W-PC) in patients with ovarian cancer and poor general condition. The subjects were patients with ovarian cancer who received W-PC at Jichi Medical University Hospital (Shimotsuke, Japan) between January 2008 and December 2016. Patients who were ≥80 years old and/or had a performance status ≥3 and/or severe complications/underlying diseases were selected. Patients received paclitaxel (60 mg/m2) and carboplatin (area under the curve 2 mg/ml/min) on days 1, 8, and 15 of a 28-day cycle. Their medical records were retrospectively reviewed. A total of 31 patients were included in the study. Grade 3/4 neutropenia, anemia and thrombocytopenia developed in 18 (58%), 5 (16%) and 1 (3%) patients, respectively. Furthermore, three (10%) patients had a complete response (CR), 12 (39%) had a partial response (PR), 5 (16%) had stable disease and 11 (35%) had progressive disease. The overall response rate was 48% (15/31) and the disease control rate was 65% (20/31). The 5-year progression-free survival was 15% and the 5-year overall survival was 15%. A total of 9 patients survived for >40 months, one of whom survived without recurrence for 122 months. Performance status <3, a tumor response of CR or PR and >5 chemotherapy cycles were indicators of favorable prognosis. Only >5 chemotherapy cycles (vs. ≤5; P=0.002) was an independent good prognostic factor according to multivariate analysis. In conclusion, W-PC was tolerable and slightly effective in patients with ovarian cancer and poor general condition. W-PC may be one option for patients who are unable to receive standard chemotherapy regimens.

Prognostic significance of the number of removed lymph nodes according to FIGO stage in ovarian clear cell carcinoma.

A previous study by our group reported that removing a larger number of lymph nodes in patients with stage I ovarian clear cell carcinoma (OCCC) improved progression-free survival (PFS). The present study investigated whether clinical conditions, particularly the number of removed lymph nodes, are independent predictors of progression for stage II or higher OCCC and whether the significance of the number of removed lymph nodes differs according to FIGO stage for OCCC. A total of 113 patients with OCCC who had undergone surgery between January 1993 and December 2015 were retrospectively enrolled and the clinicopathological data were obtained from their medical records. Among patients with stage II or higher OCCC, PFS of those with no residual tumor or no lymph node metastasis was significantly better than that of those with residual tumor (P=0.023) or lymph node metastasis (P=0.035). Multivariate analysis revealed that no residual tumor was the only independent predictor for improved PFS of patients with stage II or higher. Regarding the number of removed lymph nodes, it did not significantly affect the PFS of patients with stage II or higher OCCC, whereas it improved the PFS of those with stage I, being an independent predictor of progression of stage I OCCC. In summary, although the number of removed lymph nodes was an independent predictor of progression for stage I OCCC, it was not for stage II or higher OCCC. The prognostic significance of the number of removed lymph nodes in OCCC may differ depending on the FIGO stage.

Knockout of vasohibin-2 reduces tubulin carboxypeptidase activity and increases paclitaxel sensitivity in ovarian cancer.

Vasohibin-1 (VASH1) is a VEGF-inducible endothelium-derived angiogenesis inhibitor, and vasohibin-2 (VASH2), its homolog, exhibits proangiogenic activity. VASH2 is expressed by various cancer cells and accelerates tumor angiogenesis and progression. VASH2 was recently shown to exhibit tubulin carboxypeptidase (TCP) activity related to microtubule functions. Paclitaxel (PTX), an effective chemotherapeutic agent that is widely used to treat ovarian cancer, inhibits microtubule depolymerization and may interact with VASH2. We herein established several VASH2 knockout ovarian cancer cell lines using the CRISPR/Cas9 genome editing system to examine the intracellular tubulin detyrosination status and PTX chemosensitivity. The knockout of VASH2 did not affect the proliferation or sphere-forming activity of ovarian cancer cells in vitro. A Western blot analysis of VASH2 knockout cells revealed the weak expression of detyrosinated tubulin and upregulated expression of cyclin B1. The knockout of VASH2 significantly increased chemosensitivity to PTX, but not to cisplatin in ovarian cancer cell lines. The knockout of VASH2 reduced TCP activity and increased cyclin B1 expression, resulting in increased PTX chemosensitivity in ovarian cancer cells. The inhibition of angiogenesis and regulation of microtubule activity may be achieved in ovarian cancer treatment strategies targeting VASH2.

Efficacy and toxicity of pegylated liposomal doxorubicin as therapy for recurrent ovarian cancer in relation to the number of previous chemotherapy regimens: Comparison with gemcitabine.

AIM: Pegylated liposomal doxorubicin (PLD) is one of the second-line chemotherapy regimens for platinum-resistant recurrent ovarian cancer, but in clinical practice, it is also used for third or subsequent lines of chemotherapy. There is no report on the efficacy and toxicity of PLD in relation to the number of previous chemotherapy regimens. The purpose of this study was to clarify these points and compare with the results of gemcitabine (GEM) therapy we reported previously. METHODS: We retrospectively reviewed the medical records of patients with platinum-resistant recurrent ovarian cancer who underwent two or more cycles of PLD therapy between July 2009 and March 2017 at our institution. We used our reported data of GEM for comparison analysis. RESULTS: Seventy-eight patients were enrolled in this study. The overall response rate was 19.2% and the disease control rate (DCR) was 53.8%. The DCR with 1, 2, 3, and 4 or more previous regimens was 53.8%, 48.6%, 63.6% and 66.7%, respectively. Grade 3/4 neutropenia and anemia developed in 59.0% and 12.8%, respectively. Grade 2 or higher hand -foot syndrome, stomatitis, and liver dysfunction developed in 25.6%, 25.6% and 2.6%, respectively. When the number of previous regimens was 3 or higher, the DCR of PLD was significantly higher than that of GEM (64.7% vs 30.8%, P = 0.037). CONCLUSION: The DCR did not decrease with a greater number of previous regimens. When the number of previous regimens was 3 or higher, PLD therapy had a superior DCR to GEM therapy. Toxicity was tolerable in PLD therapy.

Oestrogen receptor-ß CA repeat polymorphism is associated with incidence of colorectal cancer among females.

AIMS: Increasing evidence suggests an association between oestrogens and colorectal cancer. Oestrogen receptor beta, ER-ß, putatively plays a pathobiological role in colorectal cancer as colorectal epithelial cells frequently express ER-ß. The aim was to elucidate the association of the dinucleotide (CA) repeat polymorphism of the ER-ß gene (ESR2) with colorectal cancer. METHODS AND RESULTS: Deoxyribonucleic acids extracted from the renal cortex of 1488 Japanese autopsies with complete clinical/pathological data were studied. CA repeat polymorphism was determined by polymerase chain reaction using fluorescein-labelled primers. Patients were divided into three genotype groups according to the number of CA repeats of each allele (S < 22, L ≥ 22); SS (with two S alleles), SL (with one each S and L allele) and LL (with two L alleles). The presence/absence of colorectal cancers was determined by examining the clinical records and autopsy material. The incidence of colorectal cancer was significantly different according to the ESR2 CA repeat genotype only among females (SS, 37/202 = 18.3%; SL, 19/332 = 5.7%; LL, 5/155 = 3.2%, P < 0.0001). Immunohistochemically, cancers in females with the SS genotype, but not the SL genotype, frequently expressed the C-terminus portion of ER-ß1 (wild-type ER-ß). CONCLUSIONS: A role for ESR2 CA repeat polymorphism in the pathogenesis of colorectal cancer among females is suggested.

Inhibitory effect of selective serotonin reuptake inhibitors on the vesicular monoamine transporter 2.

The neuronal vesicular monoamine transporter (VMAT2) is the target molecule of action of some psychostimulants, such as methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA). The present study examined the effect of antidepressants, such as selective serotonin reuptake inhibitors (SSRIs), on VMAT2 activity by measuring adenosine triphosphate-dependent [(3)H]dopamine uptake into synaptic vesicles prepared from rat striatum. SSRIs, fluoxetine, paroxetine, and fluvoxamine, inhibited vesicular [(3)H]dopamine uptake in vitro. The rank order of potency was reserpine>>fluoxetine, paroxetine>fluvoxamine, methamphetamine>MDMA. Moreover, kinetic analysis revealed that inhibition by reserpine, a typical VMAT2 inhibitor, was uncompetitive, decreasing maximum velocity and affinity for dopamine. Inhibition by fluoxetine was noncompetitive, only decreasing maximum velocity for dopamine. These results suggest that fluoxetine inhibited the activity of VMAT2 by a mechanism different from that of reserpine and did not directly interact with the active site of VMAT2.