Gynecological malignant tumors can develop in the vulva, vagina, uterus, fallopian tubes, or ovaries in the female reproductive tract. The cervix, uterine body, and ovaries are particularly common ...sites for malignant tumors. Surgery, radiation, and drug therapy are the main treatment modalities for gynecological cancers, with surgery being the most important of them. We started laparoscopic surgery for uterine endometrial cancer as an advanced medical treatment in 2011 and contributed to its insurance coverage. We were able to reproduce our laparoscopic surgery more easily using the da Vinci Xi system for robotic surgery. We have now switched from laparoscopic surgery for endometrial cancer to robotic surgery and have been able to perform them safely and reliably. In the case of cervical cancer, the results of the Laparoscopic Approach to Cervical Cancer (LACC) trial, which compared the prognosis of two groups of radical hysterectomy for early-stage cervical cancer: conventional open surgery and laparoscopic/robotic (minimally invasive) surgery, showed that minimally invasive surgery resulted in more pelvic recurrences and had a worse prognosis compared with open surgery. The trend toward minimally invasive surgery for cervical cancer has stagnated worldwide. Ovarian cancer has few symptoms in the early stages and is often found at stage III or IV, when the cancer has spread throughout the abdominal cavity. As residual tumor after surgery correlates with prognosis in ovarian cancer, debulking surgery should be performed to achieve complete resection. Therefore, peritoneal or bowel resection is often required to remove disseminated or metastatic tumors. We also performed prophylactic salpingo-oophorectomy to prevent ovarian and fallopian tube cancers in patients with BRCA1/2 gene variants. The uterus and ovaries are organs necessary for pregnancy and childbirth, and cancer of the uterus or ovaries in women of childbearing age may result in infertility. Surgery and adjuvant treatment may affect marriage, childbirth, and sexual life; therefore, it is important to ensure the cure of cancer and to provide patients with treatment methods that allow them to live their lives as women.
Uterine adenomyosis is a benign disorder that often co-occurs with endometriosis and/or leiomyoma, and impairs quality of life. The genomic features of adenomyosis are unknown. Here we apply ...next-generation sequencing to adenomyosis (70 individuals and 192 multi-regional samples), as well as co-occurring leiomyoma and endometriosis, and find recurring KRAS mutations in 26/70 (37.1%) of adenomyosis cases. Multi-regional sequencing reveals oligoclonality in adenomyosis, with some mutations also detected in normal endometrium and/or co-occurring endometriosis. KRAS mutations are more frequent in cases of adenomyosis with co-occurring endometriosis, low progesterone receptor (PR) expression, or progestin (dienogest; DNG) pretreatment. DNG's anti-proliferative effect is diminished via epigenetic silencing of PR in immortalized cells with mutant KRAS. Our genomic analyses suggest that adenomyotic lesions frequently contain KRAS mutations that may reduce DNG efficacy, and that adenomyosis and endometriosis may share molecular etiology, explaining their co-occurrence. These findings could lead to genetically guided therapy and/or relapse risk assessment after uterine-sparing surgery.
Gene expression is controlled at the transcriptional and post-transcriptional levels. The TACC2 gene was known to be associated with tumors but the control of its expression is unclear. We have ...reported that activity of the intronic promoter p10 of TACC2 in primary lesion of endometrial cancer is indicative of lymph node metastasis among a low-risk patient group. Here, we analyze the intronic promoter derived isoforms in JHUEM-1 endometrial cancer cells, and primary tissues of endometrial cancers and normal endometrium. Full-length cDNA amplicons are produced by long-range PCR and subjected to nanopore sequencing followed by computational error correction. We identify 16 stable, 4 variable, and 9 rare exons including 3 novel exons validated independently. All variable and rare exons reside N-terminally of the TACC domain and contribute to isoform variety. We found 240 isoforms as high-confidence, supported by more than 20 reads. The large number of isoforms produced from one minor promoter indicates the post-transcriptional complexity coupled with transcription at the TACC2 locus in cancer and normal cells.
Mesonephric-like adenocarcinoma is a rare neoplasm of the uterine corpus and ovary. Unlike prototypical mesonephric adenocarcinoma of the uterine cervix, which is considered of Wolffian origin, ...recent evidence suggests that mesonephric-like adenocarcinoma is a Mullerian tumor associated with endometriosis. We report here on a 48-year-old woman with a mixed carcinoma of the ovary that consisted of mesonephric-like adenocarcinoma, clear cell carcinoma, and endometrioid carcinoma, arising from an endometriotic cyst. The mesonephric-like adenocarcinoma consisted of cuboidal cells with vesicular nuclei presenting with a tubular, ductal, papillary, and solid architecture forming nodules. Each component showed distinct immunophenotypes that were consistent with their morphology. The mesonephric-like adenocarcinoma showed diffuse positive staining for paired box 8 and GATA binding protein 3, and negative staining for estrogen and progesterone receptors. A p53 stain exhibited wild-type immunoreactivity. A complete loss of AT-rich interactive domain-containing protein 1A (ARID1A) expression was suggestive of an ARID1A mutation. Manual macrodissection and Sanger sequencing revealed identical KRAS and PIK3CA mutations in all three components. To the best of our knowledge, this is the first report of mesonephric-like adenocarcinoma combined with a clear cell carcinoma and endometrioid carcinoma, which supports the hypothesis that mesonephric-like adenocarcinoma is an endometriosis-associated neoplasm. The report also highlights a potential pitfall in diagnosing mesonephric-like adenocarcinoma combined with clear cell carcinoma.
We sought dosimetric predictors of a decreasing estimated glomerular filtration rate (eGFR) in gynecological oncology patients receiving extended-field radiation therapy (EFRT).
Between July 2012 and ...April 2020, 98 consecutive cervical or endometrial cancer patients underwent EFRT or whole-pelvis radiation therapy (WPRT) with concurrent cisplatin chemotherapy in our institution. To explore the effect of concurrent cisplatin chemotherapy on renal function, the renal function of the WPRT patients was examined. Of the 98 patients, 34 cervical or endometrial cancer patients underwent EFRT including extended-field intensity-modulated radiation therapy (EF-IMRT) and 64 cervical cancer patients underwent WPRT with cisplatin. Of the 34 EFRT patients, 32 underwent concurrent cisplatin chemotherapy. Excluding patients exhibiting recurrences within 6 months, 31 EFRT patients were analyzed in terms of the dose-volume kidney histograms (the percentages of kidney volumes receiving 12, 16, 20, and 24 Gy) and the post- to pre-treatment eGFR ratios. We calculated Pearson correlation coefficients between the renal dose volume and the percentage eGFR reductions of the 31 EFRT patients, and those treated via EF-IMRT. Renal dose constraint significance was evaluated using the Mann-Whitney U test.
The eGFR value after WPRT with cisplatin remained largely unchanged for 12 months, unlike that after EFRT. In EFRT patients, a strong correlation was evident between the KV
dose and the post- to pre-treatment eGFR ratio (correlation coefficients - 0.80 for all patients and - 0.74 for EF-IMRT patients). In EF-IMRT patients, the kidney volume receiving 20 Gy tended to correlate negatively with the eGFR reduction. The Mann-Whitney U test showed that patients with KV
values < 10% retained significantly better renal function than did patients with KV
values > 10% (P = 0.002).
Imposition of a severe kidney dose constraint during EF-IMRT may reduce nephrotic toxicity. Future prospective investigations of kidney-sparing EF-IMRT are required.
Evaluation of a cancer cell fraction is important for accurate molecular analysis, and pathological analysis is the gold standard for evaluation. Despite the potential convenience, no established ...molecular markers for evaluation are available. In this study, we aimed to identify ovarian cancer cell fraction markers using DNA methylation highly specific to ovarian cancer cells. Using genome-wide DNA methylation data, we screened candidate marker genes methylated in 30 ovarian cancer FFPE samples and 12 high-grade serous ovarian cancer cell lines, and unmethylated in two female leucocytes and two normal fallopian epithelial cell samples. Methylation levels of two genes,
SIM1
, and
ZNF154
, showed high correlation with pathological cancer cell fractions among the 30 ovarian cancer FFPE samples (
R
= 0.61 for
SIM1
, 0.71 for
ZNF154
). For cost-effective analysis of FFPE samples, pyrosequencing primers were designed, and successfully established for
SIM1
and
ZNF154
. Correlation between a pathological cancer cell fraction and methylation levels obtained by pyrosequencing was confirmed to be high (
R
= 0.53 for
SIM1
, 0.64 for
ZNF154
). Finally, an independent validation cohort of 29 ovarian cancer FFPE samples was analyzed.
ZNF154
methylation showed a high correlation with the pathological cancer cell fraction (
R
= 0.77,
P
< 0.0001). Therefore, the
ZNF154
methylation level was considered to be useful for the estimation of ovarian cancer cell fraction, and is expected to help accurate molecular analysis.
Coplanar extended-field intensity-modulated radiation therapy (EF-IMRT) targeting the whole-pelvic and para-aortic lymph nodes in patients with advanced cervical cancer results in impaired creatinine ...clearance. An improvement in renal function cannot be expected unless low-dose (approximately 10 Gy) kidney exposure is reduced. The dosimetric method should be considered during EF-IMRT planning to further reduce low-dose exposure to the kidneys. To assess the usefulness of non-coplanar EF-IMRT with kidney-avoiding beams to spare the kidneys during cervical carcinoma treatment in dosimetric analysis between non-coplanar and coplanar EF-IMRT, we compared the doses of the target organ and organs at risk, including the kidney, in 10 consecutive patients. To estimate the influence of EFRT on renal dysfunction, creatinine clearance values after treatment were also examined in 18 consecutive patients. Of these 18 patients, 10 patients who were included in the dosimetric analysis underwent extended field radiation therapy (EFRT) with concurrent chemotherapy, and eight patients underwent whole-pelvis radiation therapy with concurrent chemotherapy to treat cervical carcinoma between April 2012 and March 2015 at our institution. In the dosimetric analysis, non-coplanar EF-IMRT was effective at reducing low-dose (approximately 10 Gy) exposure to the kidneys, thus maintaining target coverage and sparing other organs at risk, such as the small bowel, rectum, and bladder, compared with coplanar EF-IMRT. Renal function in all 10 patients who underwent EFRT, including coplanar EF-IMRT (with kidney irradiation), was low after treatment, and differed significantly from that of the eight patients who underwent WPRT (no kidney irradiation) 6 months after the first day of treatment (P = 0.005). In conclusion, non-coplanar EF-IMRT should be considered in patients with advanced cervical cancer, particularly in patients with a long life expectancy or with pre-existing renal dysfunction.
Solitary fibrous tumors (SFTs) are rare mesenchymal cell‐derived tumors that can cause substantial bleeding during surgery due to hyper‐vascularization. We report a case of a large retroperitoneal ...SFT resected completely using an intra‐aortic balloon. A 71‐year‐old female with a history of type 2 diabetes mellitus presented with a tumor that was diagnosed as an insulin‐like growth factor‐II‐producing benign SFT using computed tomography‐guided biopsy. The tumor had grown from 6 to 20 cm in diameter within 4 years, with concurrent and severe hypoglycemia. Preoperative computed tomography findings showed substantial blood flow toward the tumor. The retroperitoneal tumor was observed to be widely attached. Substantial hemorrhaging during tumor resection was observed despite vascular embolism. We inflated the intra‐aortic balloon for 45 min and resected the tumor completely. In conclusion, large SFT resection requires preoperative tumor blood flow evaluation and preparation of both a vascular embolism and an intra‐aortic balloon.
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