Prospective analysis of patient-reported outcomes and physician-reported outcomes with gynecologic cancer chemotherapy.

OBJECTIVE: Gynecologic cancer chemotherapy impacts the quality of life (QOL) of patients, with lasting adverse events that may require treatment adjustments or discontinuation. Consequently, real-time symptom monitoring before outpatient visits has resulted in improved QOL for patients and extended survival times. This study investigated whether there are differences between electronic patient-reported outcomes (e-PRO-CTCAE) and physician-assessed outcomes (NCI-CTCAE) evaluated in an outpatient setting in gynecologic cancer chemotherapy. METHODS: The study was conducted on 50 patients who received their first chemotherapy treatment at St. Marianna University Hospital Obstetrics and Gynecology from July 1, 2021 to December 31, 2022. PRO-CTCAE and NCI-CTCAE were evaluated at each instance of chemotherapy and 2 weeks after. The PRO-CTCAE was additionally collected weekly using e-PRO. RESULTS: The values for "Joint Pain," "Nausea," "Taste Disturbance," "Constipation," "Insomnia," "Fatigue," "Limb Edema," and "Concentration Impairment" were consistently higher in PRO-CTCAE than in NCI-CTCAE, indicating that physicians underestimated the severity of adverse events. In contrast, there was no significant difference in "Peripheral Neuropathy," demonstrating that physicians had a good understanding of this condition in patients. The weekly responses obtained from e-PRO revealed that symptom exacerbations peaked outside of clinic visits. CONCLUSIONS: This study demonstrated physicians tend to underestimate most adverse events. Moreover, the responses using e-PRO revealed peak symptom deterioration occurred outside of outpatient visits. This suggested that e-PRO and actions taken in response to them can improve patients' QOL.

Novel ultrasound assessment of placental pathological function using superb microvascular imaging.

Ultrasound Doppler method of Superb Microvascular Imaging (SMI) can significantly visualize low-velocity blood flow using a unique algorithm. We scanned placenta antenatally using SMI and compared those findings with histological findings after delivery in cases with placental abnormalities. In normal, SMI expresses stem villous vessels connecting to the tertiary villous vessels which are sharply diminished, and expresses intervillous blood flow as "scatter." Placental infarction was expressed as an anechoic area in SMI. Avascular villi was expressed as absent villous blood trees in a background scatter flow in SMI. In this report, we demonstrated typical SMI findings of the pathologic placenta as a pilot study.

Current state of fertility preservation for adolescent and young adult patients with gynecological cancer.

Although the incidence of the various gynecological cancers has been increasing in recent years, long-term survival is now possible for many patients thanks to advances in multimodality treatment. When treating gynecological cancer in adolescent and young adult (AYA) patients who desire future pregnancy, it is necessary to preserve the reproductive organs and their function to prevent loss of fertility. However, because treatment targets these organs, in the large majority of cases, patients must have these organs removed. In the subfield of oncofertility, treatment of the underlying disease takes priority, and the main principle is preventing delay in treatment. Close cooperation between obstetricians and gynecologists involved in reproductive medicine and oncologists involved in cancer treatment is necessary. In addition, it is important that clinicians work closely not only with other specialists but also with such medical professionals as nurses and counselors so that cancer patients of the AYA generation can be provided the support they need to fight their cancer with hope. Herein, we describe the current status of fertility-sparing therapy for AYA patients with gynecological cancer (cervical cancer, endometrial cancer, or ovarian cancer). In addition, we explain points to keep in mind during a patient's pregnancy after fertility preservation, the latest findings on assisted reproductive technology, and the challenges and prospects of fertility preservation therapy for patients with gynecologic cancer.

Primary malignant melanoma of uterine cervix treated with pembrolizumab as adjuvant immunotherapy.

This is the case report of primary malignant melanoma (MM) of uterine cervix treated by immune checkpoint inhibitor: the Pembrolizumab. Despite the merge of the novel drugs that has been strikingly improving prognosis of MM, we still struggle treatment of MM of uterine cervix that has aggressive characteristics with unknown etiology. We present our case to contribute its rarity of the disease case report, the primary MM of the uterine cervix that had poor response to pembrolizumab and had OS of 6 months. The treatment ineffectiveness is mainly considered for mucosal MM of low tumor mutation burden and its unusual type of pathology. Accumulation of retrospective studies exclusively on cervical melanoma needs to be proceeded to investigate on characteristics between poor and long survival to establish standardized treatment.

Surgical management of unilateral oophorectomy for ovarian tissue cryopreservation in high-risk children and adolescents with varied backgrounds.

PURPOSE: Fertility preservation (FP) for children is still challenging due to an information gap. In particular, there is little information about the surgical aspects of ovarian tissue cryopreservation (OTC) for children. In the present study, the appropriateness of preoperative management and the criteria of our cases were investigated with the aim of establishing a safe OTC procedure. METHODS: A total of 25 girls who underwent OTC from November 2015 through May 2020 were retrospectively analyzed with IRB approval. RESULTS: The median age of the patients was 13 (1-17) years. The medical indications were varied (e.g., leukemia, lymphoma, brain tumor), and included rare diseases. Seventeen cases (68%) underwent OTC during chemotherapy or radiotherapy, and 21 (84%) had comorbidities. All cases underwent ovarian tissue retrieval (OTR) with laparoscopy, and the median operating time was 64 (36-97) min, with little bleeding. Although two had complications, all patients started treatment on schedule. The median WBC and CRP increases a day after OTR were 0 (- 4400 to + 5200)/µl and 0.21 (- 0.2 to 0.87) mg/dl, respectively, with no complications. CONCLUSION: As long as the preoperative criteria are met, OTC could be possible even for children with a severe blood condition. In such cases, the degrees of the WBC and CRP elevations are useful to assess surgical infection.

Accuracy of predicting neonatal distress using a five-level classification of fetal heart rate monitoring.

AIM: To assess the accuracy of neonatal distress prediction using the five-level classification of fetal heart rate (FHR) and management protocol of the Japan Society of Obstetrics and Gynecology (JSOG). METHODS: A case-control study was conducted. Vertex singleton pregnant women who delivered after 37 weeks' gestation from 2013 to 2015 were enrolled. The participants were categorized into two groups; controls were levels 1-3 (n = 1184), whereas cases were levels 4-5 (n = 117) group. Neonatal distress was defined as Apgar score < 8 points at 5 min or umbilical cord artery pH < 7.1. RESULTS: There were 117 cases (9.0%). The frequency of the neonatal distress was observed in 1.3% controls and 6.8% cases (P < 0.01). Diagnostic accuracy of neonatal distress for cases showed a 6.8% positive-predictive value, 34.8% sensitivity, 91.5% specificity and 98.7% negative-predictive value. Among various obstetrical conditions, high sensitivity (100%) for prediction of neonatal distress was observed in women with chromosome abnormalities, placental abruption, umbilical cord abnormalities and excessive labor pain. Conversely, relatively low specificity (<50%) was observed in cases with oligohydramnios and excessive labor pain. CONCLUSION: The five-level classification scheme was efficient for neonatal distress prediction. However, depending on the obstetric condition, the FHR findings and neonatal condition might be independent.

Value of adjuvant chemotherapy and informed microscopic examination for occult gynecologic cancer detected upon risk-reducing salpingo-oophorectomy after chemotherapy for BRCA1/2-associated breast cancer: a case report.

BRCA1/2 mutation carriers are at high risk for type II ovarian, fallopian tube or peritoneal cancer. Although risk-reducing salpingo-oophorectomy plays an important role in the prevention of these BRCA1/2-associated gynecological cancers, occult ovarian, fallopian tube, or peritoneal cancer is discovered upon risk-reducing salpingo-oophorectomy in 1-4% of BRCA1/2 mutation carriers. Notably, around 30% of BRCA1/2 mutation carriers who undergo risk-reducing salpingo-oophorectomy have undergone adjuvant chemotherapy for breast cancer. We describe the discovery and treatment of occult cancer at the edge of the left fimbria in a BRCA1 mutation carrier who had, just a short time previously, undergone neoadjuvant paclitaxel plus carboplatin (TC) chemotherapy for triple-negative breast cancer. During subsequent risk-reducing salpingo-oophorectomy, a 5.5-mm nodule was observed at the edge of the left fimbria. Microscopic examination of the tumour tissue revealed high-grade serous carcinoma with degenerate tumour cells and fibrosis. Peritoneal fluid was negative for cancer cells. Two months later, hysterectomy, omentectomy and retroperitoneal lymphadenectomy were performed. The final diagnosis was stage FIGO IA fallopian tube cancer. Adjuvant chemotherapy (TC administered every 3 weeks) was applied, and there has been no evidence of recurrence for 5 years. In applying gynecologic surgery and adjuvant chemotherapy, we followed the general recommendation for stage IA fallopian tube cancer. There is no standard strategy for the treatment of occult fallopian tube cancer detected after chemotherapy for BRCA1-associated triple-negative breast cancer. According to our experience in this case, we believe the clinical value of staging laparotomy in cases of a small occult BRCA1/2-associated gynecological cancer should be further investigated.

Preliminary human application of optical coherence tomography for quantification and localization of primordial follicles aimed at effective ovarian tissue transplantation.

PURPOSE: The purpose of this study was to evaluate the possible clinical application of optical coherence tomography for assessing ovarian reserve in individual specimens of human ovarian tissue for fertility preservation. METHODS: Ovarian tissue examination by optical coherence tomography was performed before ovarian tissue cryopreservation. Three of the four subjects had hematological disease or cancer, and they faced a threat to their fertility due to impending chemotherapy. One patient underwent ovarian tissue extraction for in vitro activation of dormant follicles as fertility treatment. RESULTS: The current full-field optical coherence tomography technique can detect primordial follicles in non-fixed and non-embedded human ovarian tissue. These images are well correlated with histological evaluation and the ovarian reserve test, including follicle counts. CONCLUSION: It was demonstrated that optical coherence tomography could assess localization of primordial follicles and ovarian reserve in specimens of non-fixed human ovarian cortex, although optimization for examination of human ovarian tissue is needed for clinical application. Additionally, this technique holds the possibility of assessing the ovarian reserve of patients with unevaluable ovarian reserve. TRIAL REGISTRATION NUMBER: UMIN000023141.

Multicenter Clinicopathological Study of High-Grade Serous Carcinoma Presenting as Primary Peritoneal Carcinoma.

OBJECTIVE: We conducted a multicenter clinicopathological study to characterize patients with high-grade serous carcinoma presenting as primary peritoneal carcinoma (clinical PPC). METHODS: At 9 sites in Japan, patients with clinical PPC diagnosed according to Gynecologic Oncology Group criteria were enrolled retrospectively. The Gynecologic Oncology Group criteria allow for minor ovarian involvement by high-grade serous carcinoma. There was no systematic detailed histopathological review of the fallopian tubes to determine whether they were involved by serous carcinoma. RESULTS: There were 139 patients and 64% were aged 60 years or older. Median pretreatment serum CA-125 was 1653.5 IU/mL. Pretreatment performance status was poor in more than 50%, endometrial cytology was positive in 40.3%, and the preoperative clinical diagnosis was correct in 72.7%. Primary debulking surgery was performed in 36% of patients, whereas 64% underwent neoadjuvant chemotherapy (NAC) with interval debulking surgery (IDS). The main tumor sites were the upper abdomen (greater omentum), extrapelvic peritoneum, mesentery, and diaphragm. Lymph node metastasis was found in 46.8% of patients undergoing systematic retroperitoneal node dissection. The optimal surgery rate was 32.0% with primary debulking surgery versus 53.9% with NAC and IDS (P = 0.0139). The response rate was 82.0% with NAC and 80.6% with postoperative chemotherapy. Median progression-free survival was 19.0 months and median overall survival was 41.0 months. Multivariate analysis showed that prognostic factors for progression-free survival were NAC and residual tumor diameter after debulking surgery, whereas the only prognostic factor for overall survival was the residual tumor diameter. CONCLUSIONS: This study identified various characteristics of clinical PPC. Neoadjuvant chemotherapy with IDS is a reasonable treatment strategy, and complete debulking surgery is optimum.

Combination of irinotecan (CPT-11) and nedaplatin (NDP) for recurrent patients with uterine cervical cancer.

BACKGROUND: The clinical activity of combination of irinotecan (CPT-11) and nedaplatin (NDP) for recurrent patients with uterine cervical cancer was evaluated retrospectively. METHODS: Intravenous CPT-11 was given at 60 mg/m(2) (days 1, 8, 15), followed by NDP 80 mg/m(2) (day 1), every 4 weeks. RESULTS: According to the medical records, 29 cases have received this regimen since 2000. Median age was 57 years (range, 29-80), and performance status (PS) of the patients was 18 cases with PS 0, 10 cases with PS 1, and 1 case with PS 2, respectively. Clinical stage was as follows: 3 cases of stage Ib1, 2 cases of Ib2, 2 cases of IIa, 10 cases of IIb, 8 cases of IIIb, and 4 cases of IVb. There were 27 cases of squamous cell carcinoma and 2 cases of adenocarcinoma. Concerning hematological toxicity of grade 3 or more, neutropenia, leukopenia, and febrile neutropenia were observed in 79.3 %, 96.6 %, and 13.8 % of cases, respectively. For nonhematological toxicity, nausea, anorexia, joint pain, and confusion were observed in only 1 case, respectively, and as a result, in 7 cases chemotherapy was not completed. Among 26 cases with clinically evaluable lesions, there were 7 complete responses, 3 partial responses, 7 stable disease, and 9 progressive disease; the clinical response rate was 38.5 %. Median progression-free survival was 7 months (range, 0-38 months). CONCLUSION: The combination of CPT-11 and NDP seems to be active for patients with recurrent uterine cervical cancer.

Two cases of pregnancy involving conjoined twins, with details of management after opting for live birth.

Conjoined twinning is a unique complication of monochorionic pregnancy. This report describes the clinical findings in two cases of conjoined twins, and discusses their management. One case involved thoracopagus complicating a triplet pregnancy, and the other involved cephalothoracopagus, in which the outcome was intrauterine fetal death due to abruptio placentae after amniocentesis. Recent improvements in ultrasound imaging have facilitated the diagnosis of conjoined twins as early as the first trimester. Although many mothers opt to terminate pregnancy when conjoined twins are diagnosed, a few do not, as in the cases described. In such cases, pregnancy management, including accurate determination of the degree of organ fusion and psychological follow up, are important. On the basis of the two present cases, we present a systematic flow diagram for management of conjoined twin pregnancy from the time of diagnosis until delivery.

[Usefulness of clinical study of irinotecan and cisplatin for recurrent ovarian cancer].

So far, there is no recommended evidence-based chemotherapeutic regimen for recurrent or refractory ovarian carcinoma in the guideline. In our institute, combination chemotherapy of CPT-11 and CDDP (CPT-P) was administered for recurrent or refractory ovarian carcinoma patients previously treated with regimens including taxane. In fourteen cases treated with CPT-P, there were 2 cases of CR, 2 of PR, 3 of SD, and 7 of PD. Overall response rate was 28. 5%, and the median progression-free interval was 5.5 months. No severe side effect was observed except in one patient in whom chemotherapy was discontinued due to grade 4 neutropenia and grade 3 diarrhea. Thus CPT-P seemed to be effective and safe for the recurrent or refractory ovarian carcinoma previously treated with taxane-included regimen.

Concurrent chemoradiotherapy with nedaplatin after radical hysterectomy in patients with stage IB and II cervical cancer.

Although radical hysterectomy is the standard surgical treatment for patients with stage IB and II cervical cancer, it does not improve the prognosis of high-risk patients even if postoperative radiotherapy is added. There is therefore a need to establish some other therapeutic regimen. In the present retrospective study, the efficacy of concurrent nedaplatin after radical hysterectomy in high-risk stage IB to II cervical cancer was analyzed. From 1995 through 2005, patients with an International Federation of Gynecology and Obstetrics stage of IB2 and II cervical cancer who were given only radiotherapy (RT; n = 17) or postoperative concurrent chemoradiotherapy with biweekly nedaplatin at 70 mg/m(2) (p-CCRT; n = 13) were entered. All of the patients had at least one of the following risk factors: lymphovascular space infiltration, positive lymph nodes, or parametrial invasion. There was no significant difference between the RT and p-CCRT groups with regard to mean age and risk factors, except that more patients in the p-CCRT group had positive lymph nodes (P < 0.05). Five-year progression-free survival and overall survival after RT versus p-CCRT were 76.0% versus 83.3%, and 81.9% versus 83.3%, respectively. Although many patients in the p-CCRT group had positive lymph nodes, there was no significant difference in either PFS or OS. No grade 4 myelosuppression or other severe side effects were seen in the p-CCRT group. As CCRT with nedaplatin might have some benefit, a randomized control trial should be conducted in the future.

Expression of paralogs of cytochrome P 450 21a1 pseudogene (Cyp21a1-ps) and endogenous retrovirus SC1 (SC1) in the rat ovary during the ovulatory process.

This study assesses the relatively high incidence of the expression of paralogs of several pseudogenes within the cascade of expression of functional genes in the rat ovary in response to an ovulation-stimulating dose of gonadotropin. Immature Wistar rats were primed with 10 IU equine chorionic gonadotropin subcutaneously, and 48 h later the 12-h ovulatory process was initiated by 10 IU hCG subcutaneously. Ovarian RNA was extracted at 0, 2, 4, 8, 12, and 24 h after injecting the animals with hCG. The RNA extracts were used for RT-PCR differential display to detect gene expression in the ovarian tissue. Sequence analyses of differentially expressed cDNAs revealed that approximately 27% (i.e. 22/82 clones) of the transcripts were fragments of paralogs of known pseudogenes. Out of the 22 clones reported here, 12 have high sequence similarity to the cytochrome P450 pseudogene Cyp21a1-ps, and 5 have high sequence similarity to both the Cyp21a1-ps and the aldo-keto reductase gene Akr1c6. The remaining five clones were paralogs of the endogenous retrovirus SC1 that has heavily infested the rat genome. Northern analyses reveal that peak expression of all the 22 paralogs occurs at 4-8 h into the ovulatory process. In situ hybridization shows that expression of these pseudogenes is primarily in the granulosa layer of ovulatory follicles. In summary, the results reveal that ovarian expression of Cyp21a1-ps- and SC1-like pseudogenes occurs concurrently with the ovulatory process.

Establishment and characterization of a cell line derived from a human serous surface papillary carcinoma of the ovary.

A novel serous surface papillary carcinoma of the ovary (SSPC) cell line, HYKSSPC, was established successfully. Carcinoma cells were obtained from ascitic fluid of a 60-year-old Japanese woman. The population doubling time was 51.4 h. A phase contrast micrograph showed a pavement stone-like arrangement without contact inhibition. The chromosome number showed a wide distribution of aneuploidy, and the mode was in 46-47. An immunocytochemical study showed that CA125, BerER4 and cytokeratin were positive and that CEA, calretinin and thrombomodulin were negative. This cell line preserved some characters of the adenocarcinoma while growing in vitro. A chemosensitivity test revealed that HYKSSPC cells were sensitive to CDDP (cis-platinum), 5-fluorouracil, mitomycin C, paclitaxel and irinotecan. To our knowledge, HYKSSPC is the first established cell line derived from SSPC, and it may offer some useful information for investigating this disease.

Melatonin binding sites in estrogen receptor-positive cells derived from human endometrial cancer.

Our previous work showed that melatonin (N-acetyl-5-methoxytryptamine) inhibits proliferation of the human endometrial cancer cell line, Ishikawa, which is estrogen receptor-positive. The aim of the present study was to determine whether Ishikawa cells possess membrane melatonin receptors. Binding of the radioligand 2-[125I]-iodomelatonin to membrane preparations obtained from Ishikawa cells was detectable, saturable and stable. Scatchard analysis revealed that the dissociation constant (Kd) of the binding sites was 179.0 pm (similar to that of the MT2 [Mel1b] melatonin receptor subtype), and that the concentration (Bmax) of the binding sites was 12.9 fmol/mg protein. Luzindole, a selective MT2 melatonin receptor antagonist, significantly suppressed binding of 2-[125I]-iodomelatonin at all concentrations tested (10(-8) to 10(-4) m). These results suggest that the MT2 melatonin receptor subtype is present in the membranes of Ishikawa cells, and that the antiproliferative effect of melatonin on Ishikawa cells is mediated via the MT2 receptor. This may have implications for the use of melatonin in endometrial cancer therapy.

Establishment and characterization of a human ovarian granulosa tumor cell line (HSOGT).

We successfully established a novel ovarian granulosa tumor cell line (HSOGT). The tumor tissue of the ovary was derived from a 25 year-old Japanese woman under her consent. The cell line was maintained for over 14 months, subcultured more than 73 times, and had a population doubling time of 18.9 hours. Phase contrast microscopy displayed a pavement-like arrangement without contact inhibition. The chromosome number showed a wide distribution of aneuploidy and the mode was 83; many marker chromosomes were observed. The HSOGT was also successfully xenotransplanted into nude mice. The cell line produced estradiol and has preserved some characters of granulosa cells with stable growth in vitro. We firmly believe that this cell line will be a most useful tool for endocrinological investigation of human granulosa cells.

Correlation between expression of oncogene products and resistance to anticancer drugs in cultured ovarian cancer cell lines.

Despite recent advances in the application of chemotherapy to ovarian cancer, the development of alternative therapies that retain activity against drug-resistant-tumors remains a high priority. We analyzed a number of cultured ovarian cancer cell lines of different tissue types for the presence or absence of sensitivity to various anticancer drugs as well as expression patterns of oncogene products (erbB-2, EGFR, bcl-2). As a result, we identified oncogene products that were related to resistance. Using 9 cultured cell lines of ovarian cancers (serous, mucinous, endometrioid, clear, undifferentiated), sensitivities to anticancer drugs were investigated using the MTT assay. The phenotypes of oncogene products expressed by the above cultured cell lines were analyzed by Western blotting. The oncogene products involved in resistance to anticancer drugs were identified by multivariate analysis. Positive correlation between the resistance to anticancer drugs and the oncogene products was obtained by multivariate analysis for (a) CDDP and erbB-2 (b) x p-16 and erbB-2, and (c) MMC and EGFR. Correlation between resistance to anticancer drugs and expression of certain oncogene products was obtained in ovarian cancers, suggesting that sensitivity to anticancer drugs could be predicated prior to chemotherapy.

Establishment and characterization of a cell-line originated from human mucinous cystadenocarcinoma of the ovary.

We recently established a cell line (designated 371M) derived from an ovarian mucinous cystadenocarcinoma. The tumor cells were obtained from the ascitic fluid of a 54-year-old Japanese woman while she was undergoing surgery. Adjuvant chemotherapy (combined paclitaxel and carboplatin) was administered, but was ineffective, and she died about 4 months after surgery. The 371M cells continuously propagated in vitro over a period of about 50 months and, to date, have undergone over 100 passages. They proliferated in a monolayered sheet with doubling times of 84 h and 37 h in the 10th and 34th passages, respectively. When transplanted into nude mice, the tumor histopathologically resembled the structure of the original tumor. The 371M cells secreted high levels of CA125 and CA19-9 into the culture medium. There were several abnormal chromosomes in all karyotypes selected at random. Sensitivity of 371M cells to a variety of anti-cancer drugs was examined by in vitro MTT assay, and the results suggested that CPT-11 and CDDP were more effective against 371M cells than other anti-cancer agents.