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The number of people with diabetes worldwide has increased to 537 million, with a 3.6-fold increase occurring in the last 20 years. Various medications are used in the treatment of diabetes, and glucagon-like peptide-1 (GLP-1) receptor agonists have been recommended in major overseas guidelines. Although the main route of administration of GLP-1 receptor agonists is subcutaneous, orally administered GLP-1 receptor agonists were approved in 2019. Therefore, gastrointestinal epithelial cells are exposed to GLP-1 receptor agonists with poor bioavailability; however, it currently remains unclear whether this luminal approach damages these cells. The present study investigated the effects of GLP-1 receptor agonists on gastrointestinal epithelial cells. The gastrointestinal epithelial cell lines HGC-27, IEC-6, and Caco-2 were treated with Liraglutide, a GLP-1 receptor agonist. The protein expression of the GLP-1 receptor was confirmed in these cell lines, and Liraglutide did not significantly affect their proliferation. Although no inhibitory effects on oxidative stress were noted, Liraglutide appeared to alter the expression of drug absorption-regulating factors. In conclusion, since no significant changes were detected in the cell lines examined, even at higher concentrations of Liraglutide, there were no significant effects at the cellular level. However, since the present results were contradictory to previous findings, further studies using different conditions and cells are warranted.

This study aimed to clarify the genetic features of endometrioid-type endometrial cancer arising in adenomyosis (EC-AIA) using targeted sequencing and immunohistochemistry (IHC) for both carcinoma and adjacent adenomyosis tissues. We identified three endometrioid-type EC-AIAs in 689 patients with endometrial cancer; two exhibited grade 3 endometrioid carcinoma. IHC revealed retained expression of PMS2, MSH6, ARID1A, and PAX2. Two of them showed diffuse strong p53 expression only in the carcinoma. PTEN expression was lost in carcinoma of only one of these cases. Carcinoma had many gene mutations than adjacent adenomyosis in all cases. KRAS and TP53 mutations were found in two of them. The other patient had mutations in KRAS, PIK3CA, and PPP2R1A. They were classified as two "p53-mutated" and one "non-specific molecular profile." These molecular alterations in endometrioid-type EC-AIA imply similar carcinogenesis to a subset of endometrial endometrioid carcinoma and might be used as targets of liquid biopsy after further validation.

Peutz-Jeghers syndrome (PJS) is associated with female genital lesions, such as cervical gastric-type adenocarcinoma and lobular endocervical glandular hyperplasia (LEGH). However, ovarian mucinous borderline tumors (OMBT) with atypical LEGH-like histology have not been described. The patient was a 60-year-old female with PJS clinically diagnosed at 23 years old with gastrointestinal polyposis. Abdominal distension was noted, and computed tomography scan revealed bilateral breast masses, multiple lung nodules, and a multicystic ovarian tumor. A needle biopsy revealed invasive ductal carcinoma of the breast. For the ovarian tumor, simple hysterectomy and bilateral salpingo-oophorectomy were performed. The left ovarian tumor was 25 × 20 × 12 cm in size and a multicystic tumor containing yellowish mucus without a solid part. Histologically, the cyst wall was covered with mucus cells with focal mild-to-moderate cellular atypia, forming LEGH-like architectures. The glandular cells were immunohistochemically positive for MUC5AC, MUC6 (focal), HIK1083 (focal), and HNF4α. Stromal invasion was not observed. Cervical lesions were not observed. The final pathological diagnosis was OMBT showing atypical LEGH morphology. Targeted sequencing of nontumor tissues revealed the germline STK11 p.F354L variant. Six months later, peritoneal dissemination of adenocarcinoma showing features similar to those of the ovarian tumor was observed, and the patient died of the disease. In summary, we report a case of OMBT with an atypical LEGH-like appearance in a patient with germline STK11 p.F354L variant. This case provides us with unresolved questions regarding the pathogenicity of this STK11 variant and the malignant potential of OMBT with this unusual morphology.

Objective The prognosis of and optimal treatment for grade 3 endometrioid endometrial carcinoma (G3EEC) currently remain unclear. This study aimed to clarify the baseline recurrence risk in patients with early-stage (stage I–II) G3EEC without adjuvant therapy and the prognosis of patients with advanced-stage (stage III–IV) G3EEC. Materials and methods A total of 101 patients with pathologically confirmed G3EEC from 1997 to 2018 were identified. Their clinicopathological characteristics and survival outcomes were reviewed retrospectively. Disease-free survival and overall survival values were estimated according to the Kaplan–Meier method and compared using a log-rank test. Results Recurrence was observed in eight (13%) of 63 patients with early-stage G3EEC, none of whom had received adjuvant therapy. The 5-year disease-free survival and 5-year overall survival rates for these patients were 86.7% and 96.4%, respectively. Recurrence was also observed in 12 (41%) of 29 patients with stage III G3EEC. The 5-year overall survival rates for stage III patients who underwent adjuvant chemotherapy and adjuvant radiotherapy were 85.6% and 42.9%, respectively. The 3-year overall survival rate among stage IVB patients was only 12.7% despite multidisciplinary treatment provision. Conclusion Our study newly demonstrates that patients with early-stage G3EEC have a favorable prognosis and a low recurrence rate in the absence of adjuvant therapy. In patients with stage III G3EEC, adjuvant chemotherapy was more beneficial than adjuvant radiotherapy. The poor prognosis of patients with stage IV G3EEC indicates the need for more effective treatments. Unique therapeutic approaches based on staging are recommended for treatment of G3EEC.

Obstructed hemivagina and ipsilateral renal agenesis (OHVIRA) syndrome is a rare Mullerian duct anomaly characterized by an obstructed hemivagina, ipsilateral renal agenesis, and uterine didelphys. There are only a few published case reports of OHVIRA syndrome, and cases of OHVIRA syndrome associated with cancer have rarely been reported. In fact, there is only one published report of a case with clear cell carcinoma (CCC) of the cervix. Here, we report a case of CCC of the cervix with OHVIRA syndrome that underwent abdominal radical hysterectomy; we also provide a short literature review of this topic. A 52-year-old woman presented with abnormal vaginal bleeding for 1 month 2 years after menopause. A pelvic examination and preoperative imaging showed uterine didelphys, an obstructed hemivagina with a mass measuring approximately 2 cm located in her left cervix, and an absence of her left kidney. A colposcopy biopsy reported CCC of the cervix. Clinical staging classified her with stage IB1 disease. Abdominal radical hysterectomy was performed. Her left ectopic ureter led to the left cervix and opened in the endometrium, resulting in a so-called ectopic ureter. Macroscopic examination of the excised specimens showed two cervixes, two corpora of the uterus, and a tumor measuring 1.0 × 2.0 cm on the left cervix. In addition to typical OHVIRA symptoms including uterine didelphys, obstructed hemivagina, and renal agenesis, several anatomical variants were present. The current case included those variants as well as an atrophic kidney with an ectopic ureter to the obstructed hemivagina. Based on the results of our case, clinicians should be aware of the risks of cancer and anatomical variants associated with OHVIRA syndrome.

Microcystic stromal tumors (MCSTs) of the ovary are rare sex cord-stromal tumors that are considered benign neoplasms because almost all cases display unilateral, localized lesions and have benign outcomes, except for one recurrent case with familial adenomatous polyposis and another initial metastatic case with a CTNNB1 mutation. We report herein a sporadic case that relapsed as intra-abdominal spread 9 years and 1 month after primary left salpingo-oophorectomy for torsion of the ovarian tumor pedicle. The tumor relapsed as multiple disseminations at the subabdominal wall, Douglas pouch, and omentum. Histologically, the tumor cells formed microcysts and infiltrated the surrounding adipose tissue, similar to the invasive implants of ovarian epithelial borderline tumors. Mutation analysis of the recurrent tumor revealed a somatic CTNNB1 p.S33Y activated missense mutation and a germline KDR p.Q472H variant. In conclusion, long-term clinical follow-up may be needed to detect any recurrence of MCST, irrespective of familial adenomatous polyposis.

Background This study examined the accuracy and pitfalls associated with frozen section diagnosis of primary ovarian tumors and ovarian metastases based on the 2014 World Health Organization classification (WHO) criteria and proposed improvements from a pathologist’s perspective. Methods We microscopically reviewed 871 cases of primary ovarian tumor (N = 802) and ovarian metastasis (N = 69) and compared the results of frozen sections with the final diagnosis. Malignant potential concordance (benign, borderline, or malignant) and specific discordant diagnosis rates were analyzed. Finally, we conducted a unique literature review of specific diagnostic errors in the frozen section diagnosis of primary ovarian tumors. Results Of 802 primary ovarian tumors, 50 (6.2%) cases showed discordant diagnoses in which mucinous carcinoma (40.5%), low-grade serous carcinoma (LGSC; 31.3%), and mucinous borderline tumor (18.4%) were frequently misinterpreted. Of 69 ovarian metastases, all 4 cases of low-grade appendiceal mucinous neoplasm (LAMN) were misdiagnosed as primary ovarian mucinous tumor. A literature review revealed that mucinous/serous borderline tumor or carcinoma accounted for approximately 70% of 217 reported discordant diagnoses. Conclusion In the present study, the concordance rate of malignant potential of the tumor was comparable to that previously reported. Even in the 2014 WHO classification, primary ovarian mucinous borderline tumor/carcinoma and LGSC still comprised the majority of discordant cases. Grossing methods that reduce sampling error are required. LAMN was frequently misinterpreted as a benign or borderline ovarian mucinous tumor. To prevent this error, a differential algorithm integrating clinical information and gross findings should be developed.

To safely perform minimally invasive hysterectomy (MIH), including laparoscopic hysterectomy and robot-assisted hysterectomy, partial ureterolysis, or visualizing only the ureter without dissection is often inadequate. Moreover, careless blunt dissection could injure the blood vessels. We present our surgical method for ureterolysis using sharp dissection during MIH. First, the outer portion of the ureter is dissected. Dissecting between the pelvic sidewall and the posterior leaf of the broad ligament creates a pararectal space outside the ureter, enabling the easy identification of the ureter running on the posterior leaf. Second, the inner portion of the ureter is dissected. After determining the location of the ureter, a better partial dissection of the ureter can be performed from the posterior leaf, instead of dissecting along the entire circumference. If fine surgery has to be performed, the ureter can be dissected by enclosing it within its sheath. We primarily perform dissections using a monopolar device, which allows a sharp dissection. Furthermore, in our method, we often include the dissection of the ureteral tunnel. It is important to understand the anatomy and membrane structure of the ureter in each patient and adjust the extent of ureterolysis based on individual differences.

Adenoid basal carcinoma (ABC) is rare cancer with a favorable prognosis. However, some ABCs are associated with other histological types, such as squamous cell carcinoma. Here, we present a case of a mixed tumor of ABC and adenoid cystic carcinoma (ACC) of the cervix, with a detailed immunohistochemical study and literature review. We describe a case of a 66-year-old woman who underwent cervical cancer screening that led to the detection of a 0.7 cm nodular lesion. Cervical punch biopsies revealed a high-grade squamous intraepithelial lesion. Cervical conization revealed a mixed carcinoma composed of ABC and ACC, showing stromal invasion, lymphovascular invasion, and positive resection margins. Immunohistochemically, the ACC components were positive for KIT and αSMA and negative for NKX3.1. The tumor presented with proficient mismatch repair (MMR) and was negative for HER2, PD-L1, and TRKA (NTRK1). Subsequent radical hysterectomy with pelvic lymph node dissection revealed the presence of residual tumor cells in the cervix. Our literature review identified six similar cases, including one patient who died of disease recurrence. We report a rare tumor comprising both ABC and ACC. Prognostic data on mixed tumors are scarce; however, given the aggressive nature of ACC, attention should be paid to the detection of mixed tumors. Since ABC and ACC histology may overlap, adequate sampling and IHC for detecting ACC would be helpful.

Uterine sarcomas with myomelanocytic differentiation have been reported to be diagnostically challenging. We report a case of uterine leiomyosarcoma with extensive perivascular epithelioid cell tumor (PEComa)-like areas and extrauterine metastases. The patient was a 49-year-old gravida 3 para 2 Japanese woman with no relevant medical history. She noticed a vaginal mass with bleeding. Imaging examination revealed a uterine tumor and multiple liver and lung metastases. The vaginal tumor (3.5 cm) was resected and diagnosed as a malignant PEComa based on morphology and myomelanocytic marker expression. Clinically used targeted sequencing (FoundationOneCDx™) revealed gene alterations in RB1, TP53, and ATRX but not TSC1/2. Despite administration of an mTOR inhibitor, the tumor size increased, and subsequently, hysterectomy was performed to relieve the symptoms. The uterine tumor was composed of conventional leiomyosarcoma showing RB1 loss, wild-type TP53 staining, and retained ATRX expression, as well as adjacent predominant PEComa-like components with RB1 loss, TP53 overexpression, and ATRX loss, identical to the characteristics of the vaginal tumor. In the uterine tumor, both HMB-45 and MITF were weak to moderately positive for approximately 40% of tumor cells while Melan-A was negative. The tumor was finally diagnosed as leiomyosarcoma with PEComa-like features. This case exemplifies the tumorigenesis of diagnostically challenging tumors with myomelanocytic differentiation and demonstrates the importance of integrating multiple types of information, including genomic profiling, in making a correct diagnosis leading to appropriate treatment.

This study aimed to clarify the genetic features of endometrioid-type endometrial cancer arising in adenomyosis (EC-AIA) using targeted sequencing and immunohistochemistry (IHC) for both carcinoma and adjacent adenomyosis tissues. We identified three endometrioid-type EC-AIAs in 689 patients with endometrial cancer; two exhibited grade 3 endometrioid carcinoma. IHC revealed retained expression of PMS2, MSH6, ARID1A, and PAX2. Two of them showed diffuse strong p53 expression only in the carcinoma. PTEN expression was lost in carcinoma of only one of these cases. Carcinoma had many gene mutations than adjacent adenomyosis in all cases. KRAS and TP53 mutations were found in two of them. The other patient had mutations in KRAS, PIK3CA, and PPP2R1A. They were classified as two "p53-mutated" and one "non-specific molecular profile." These molecular alterations in endometrioid-type EC-AIA imply similar carcinogenesis to a subset of endometrial endometrioid carcinoma and might be used as targets of liquid biopsy after further validation.

Folate receptor α (FRα) is a membrane protein expressed in various solid tumors but has limited expression in normal cells. Therefore, FRα is an attractive target for cancer treatment. This study aimed to investigate the relationship between FRα expression and the clinicopathological characteristics and survivals of cervical cancer.This retrospective study included patients with cervical cancer who underwent primary surgery between 2000 and 2020 at our institution. Immunohistochemical staining of FRα was performed using an anti-folate-binding protein/FBP antibody. FRα-positive staining was defined as ≥5% of tumor staining and FRα-high as ≥50% tumor staining with ≥2+ intensity. The association between FRα expression and survival was assessed using multivariate Cox regression analysis, adjusting for established prognostic factors.Overall, 123 patients were identified, and 140 tumor samples, including 17 paired primary and metastatic samples, were evaluated. As histological types, 67 patients had squamous cell carcinoma (SCC), and 56 patients had non-SCC. All primary tumors were FRα-positive. High FRα expression was observed in 25% of the cases and differed according to histology (SCC vs. non-SCC, 14.9% vs. 37.5%, p=0.004). FRα expression was significantly higher in metastatic tumors than in primary (170 [IQR, 140-205] vs. 125 [IQR, 110-150], p=0.0006). High FRα expression was significantly associated with worse overall survival (hazard ratio, 6.73; 95% confidence interval, 2.21-20.53; p=0.001).In cervical cancer, FRα expression was elevated in metastatic tumors and high expression was associated with a worse prognosis. Our study supports the development of FRα-targeted therapy for advanced cervical cancer.

Background and Objectives The aim of this study was to determine whether peritoneal washing cytology (PWC) during interval debulking surgery (IDS) could predict the prognosis of patients with pelvic high‐grade serous carcinoma (HGSC) achieving R0 status. Methods Between January 2007 and May 2018, 110 patients with ovarian/tubal/primary peritoneal HGSC received platinum‐based neo‐adjuvant chemotherapy, followed by IDS at National Cancer Center Hospital, Japan. All the patients achieved R0 debulking status, defined as no macroscopic residual tumor in the peritoneal cavity at the completion of IDS. PWC was performed before debulking during IDS. The survival outcomes were compared between the PWC‐positive and PWC‐negative groups. Results The median progression free survival (PFS) for the entire cohort was 17 months (range, 5‐133 months). The median PFS for the PWC‐positive group was significantly shorter than that of the PWC‐negative group (16 vs 19 months, HR 2.04, 95% CI 1.22‐3.41, P‐value

Background: HER3 (ErbB-3) is a member of the epidermal growth factor receptor family of receptor tyrosine kinases, and its overexpression is associated with poorer prognosis in several cancer types. It is unclear whether HER3 expression status changes in tumor tissue at relapse. The purpose of this study is to evaluate changes in HER3 expression between initial diagnosis and recurrence in gynecologic cancers. Methods: This retrospective study included gynecologic cancer patients with matched paired tissues at the time of initial diagnosis and at the time of recurrence between 1999 and 2019 at National Cancer Center Hospital, Japan. Immunohistochemical (IHC) staining for HER3 was performed using formalin-fixed paraffin-embedded specimens. The primary antibody was HER3/ErbB3 (D22C5) XP Rabbit mAb (Cell Signaling Technology). HER3-positive was defined as an IHC score of 2+ or 3+, and HER3-negative was an IHC score of 0 or 1+, scored according to HER2 testing guidelines for gastroesophageal cancer. The H-score (range, 0-300) was calculated using the following formula: 3X+2Y+Z, where X, Y, and Z are the percentage of tumor cells showing strong, moderate, and weak staining intensity. The difference in HER3 expression between initial diagnosis and recurrence was evaluated using the χ2 test. Results: Eighty-six patients with gynecologic cancers were included (40 ovarian; 32 endometrial; 14 cervical). In ovarian cancer, 67.5% and 80.0% of the patients were HER3-positive at initial diagnosis and recurrence, respectively. There was a statistically significant increase in H-Score at recurrence (p=0.004). The HER3-positive rate in patients with endometrial cancer increased from 46.9% at initial diagnosis to 68.8% at recurrence, and H-Score tended to increase at recurrence (p=0.08). Twelve of the 14 patients (85.7%) with cervical cancer were HER3-positive, both at initial diagnosis and at recurrence, and H-Score tended to increase at recurrence (p=0.19). The discordance rate of HER3 expression determination in samples at initial diagnosis and recurrence was 27.5%, 46.9%, and 14.3% for ovarian, endometrial, and cervical cancers, respectively. Conclusion: Our findings suggest that HER3 expression may increase at recurrence in patients with gynecologic cancers. HER3-targeted therapy may represent a promising option to overcome treatment failure and improve patient outcomes. Citation Format: Yuki Kojima, Kazuki Sudo, Hiroshi Yoshida, Shu Yazaki, Momoko Tokura, Shosuke Kita, Kasumi Yamamoto, Chiharu Mizoguchi, Hitomi S Okuma, Tadaaki Nishikawa, Emi Noguchi, Tatsunori Shimoi, Yasuhito Tanase, Masaya Uno, Mitsuya Ishikawa, Tomoyasu Kato, Kumiko Koyama, Maki Kobayashi, Tomoya Kakegawa, Yasuhiro Fujiwara, Kan Yonemori. Changes in HER3 expression profiles between initial diagnosis and recurrence in gynecologic cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5083.

Simple Summary This review investigated the prevalence, clinical characteristics, clinical presentation, diagnosis, treatment, and prognosis of patients with brain metastases from uterine cervical carcinoma (CC) and uterine endometrial carcinoma (EC). The findings of this review indicate the factors that can facilitate better treatment selection and, consequently, better outcomes in patients with CC and EC. Abstract Reports on brain metastases (BMs) from uterine cervical carcinoma (CC) and uterine endometrial carcinoma (EC) have recently increased due to the development of massive databases and improvements in diagnostic procedures. This review separately investigates the prevalence, clinical characteristics, clinical presentation, diagnosis, treatment, and prognosis of BMs from CC and uterine endometrial carcinoma EC. For patients with CC, early-stage disease and poorly differentiated carcinoma lead to BMs, and elderly age, poor performance status, and multiple BMs are listed as poor prognostic factors. Advanced-stage disease and high-grade carcinoma are high-risk factors for BMs from EC, and multiple metastases and extracranial metastases, or unimodal therapies, are possibly factors indicating poor prognosis. There is no “most effective” therapy that has gained consensus for the treatment of BMs. Treatment decisions are based on clinical status, number of the metastases, tumor size, and metastases at distant organs. Surgical resection followed by adjuvant radiotherapy appears to be the best treatment approach to date. Stereotactic ablative radiation therapy has been increasingly associated with good outcomes in preserving cognitive functions. Despite treatment, patients died within 1 year after the BM diagnosis. BMs from uterine cancer remain quite rare, and the current evidence is limited; thus, further studies are needed.

Gastric-type adenocarcinoma (GAS) of the cervix is a human papilloma virus (HPV)–independent, aggressive, and chemo-resistant adenocarcinoma. However, although the histopathological features of GAS have been extensively investigated, squamous differentiation has not been mentioned. This study aimed to elucidate the frequency of GAS with squamous differentiation and describe their clinicopathological characteristics. We retrospectively evaluated 78 patients with GAS (n = 13) and adenosquamous carcinoma (n = 65) diagnosed between 2000 and 2020. Two patients with GAS with squamous differentiation were identified. Both tumors showed advanced stage (pT2bN1) and had predominant GAS and merged squamous cell carcinoma components without p16-block positivity and HPV DNA. Gastric-type adenocarcinoma in situ was confirmed in both cases. Some cases of GAS could show squamous differentiation mimicking the usual, HPV-associated, adenosquamous carcinoma. GAS with squamous differentiation is recognized as an HPV-independent cancer.

HER3 (erbB3) signaling serves an important role in the development and chemoresistance of ovarian cancer, and is activated by chemotherapy. To evaluate the influence of neoadjuvant chemotherapy and other clinical factors on the expression of HER3, as well as to examine its role as a prognostic marker, the present study evaluated archived tissues from patients who underwent surgery for ovarian cancer between 2011 and 2018 at our hospital. Immunohistochemical staining for HER3 was performed using formalin-fixed paraffin-embedded surgical specimens and biopsy samples. In total, data from 111 patients with sufficient surgically resected tumor samples were extracted. A total of 28 patients with histology type high-grade serous carcinoma (HGSC) had specimens available from both pre-chemotherapy biopsies and post-chemotherapy surgery. High HER3 expression (HER3-high) was observed in 64 patients (58%), whereas low HER3 expression (HER3-low) was observed in 47 patients (42%). Multivariate logistic regression analysis identified neoadjuvant chemotherapy [odds ratio (OR), 7.49; 95% confidence interval (CI), 2.48–22.64; P

Ovarian metastases of low-grade appendiceal mucinous neoplasms (LAMNs) show grossly abundant nodular mucous cells, with a gross mucinous multinodular appearance and a histological resemblance to primary ovarian mucinous tumors (POMTs). This study aimed to elucidate the utility of gross features including the gross mucinous multinodular appearance and available clinical information at the time of intraoperative consultation, in distinguishing the ovarian metastases of LAMNs from POMTs or the ovarian metastases of colorectal cancer (CRC). In total, 776 patients with primary ovarian tumor and 68 patients with ovarian metastases underwent intraoperative consultation during 1998-2018. Of the total cases, 4 ovarian metastases of LAMNs, 19 ovarian metastases of CRC, and 50 POMTs (36 borderline tumors and 14 carcinomas) were identified. The gross features including the gross mucinous multinodular appearance were analyzed based on the gross photographs obtained before formalin fixation and the available clinical information collected during intraoperative consultation. The analysis indicated that the ovarian metastases of LAMNs significantly presented with gross mucinous multinodular appearance (4/4 vs. 0/50, P 0.0001), extraovarian disease (4/4 vs. 2/50, P 0.0001), ovarian surface involvement (3/4 vs. 2/50, P = 0.0016), and abnormal appendix (4/4 vs. 0/50, P 0.0001) as compared to POMT. Moreover, the gross mucinous multinodular appearance was a distinguishable feature between the ovarian metastases of LAMNs and ovarian metastases of CRC (4/4 vs. 0/19, P = 0.0001). Based on these results, we proposed an algorithm to diagnose ovarian tumors using the gross mucinous multinodular appearance. Thus, recognizing unique gross features including the gross mucinous multinodular appearance would be useful for both pathologists and surgeons to accurately diagnose ovarian metastases of LAMNs during intraoperative consultation.

This study aimed to retrospectively evaluate the efficacy and safety of ifosfamide plus paclitaxel(IT)in Japanese patients with recurrent or metastatic uterine carcinosarcoma.This study included 15 patients who received IT(ifosfamide [1.6 g/m / 2 on days 1-3]and paclitaxel[135mg/m2 on day 1]every 3 weeks)for recurrent or metastatic uterine carcinosarcoma.The overall response rate was 38.4%, and the disease control rate was 92.3%. The median progression- free survival was 7.0 months, and the median overall survival was 9.0 months after initiation of IT therapy. The most common hematological adverse event was Grade 1-2 neutropenia. Peripheral neuropathy of Grade 1 or 2 was observed in 33.3% of cases. There was no treatment-related death.IT therapy showed good efficacy and tolerability in Japanese patients with recurrent or metastatic uterine carcinosarcoma.

The formation of gastrointestinal-type epithelium is found in 7–13% of mature cystic teratomas, which are the most common germ cell tumors of the ovary. Few cases harboring organized gastrointestinal tract formation have been reported, and a mucinous neoplasm arising in them is further rare. Here, we report a case of an ovarian mature cystic teratoma with intestinal structures harboring intestinal-type mucinous neoplasm, mimicking low-grade appendiceal mucinous cystadenoma. A 66-year-old female, with remarkably increased serum carcinoembryonic antigen (CEA) level, underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy due to the ovarian tumor. The immunoprofile of the tumor showed CK7−/CK20+. We review the past literatures, and then consider that the existence of mucinous neoplasm should be kept in mind if we find elevated level of serum CEA and the organized gastrointestinal development in an ovary. The immunoprofile of CK7/CK20 is useful to determine the origin of mucinous tumors associated with mature cystic teratomas.

The majority of cervical adenocarcinomas are associated with human papillomavirus (HPV) mainly HPV types 18 and 16. Patients with gastric-type endocervical adenocarcinoma (GAS) have an aggressive clinical behavior, resulting in poor prognosis compared to those with HPV-associated usual type adenocarcinoma. Chemotherapy resistance to taxane and carboplatin-based regimen has also been reported, which poses a difficulty in managing GAS patients with metastatic lesion. We established patient-driven xenografts (PDX) of two GAS patients and evaluated protein biomarkers for drug development using immunohistochemistry staining. The pathological findings of the established PDX were confirmed by HE staining and special staining to be similar to the pathological findings obtained from the patients' surgical specimens. PDX was established 78 and 48 days after transplantation of patient tumor tissue into immunodeficient mice, respectively. HER2, HER3, PMS2, MSH6, PanTrk, and ARID1A were stained for both PDX and patient-tumor samples to evaluate biomarkers for therapeutic targets. All staining results were consistent between patient tumor samples and PDX for both patients. Staining results for HER3 showed that both patients' tumors and the corresponding PDXs were 3+. Staining for HER2 was 1+ in both cases. In all PDX and patient-tumor samaples, PMS2, MSH6 and ARID1A showed no loss of protein expression, and PanTrk showed no protein expression. In addition, nine additional tumor tissue specimens from GAS patients diagnosed at our institution were stained for HER3 and HER2. HER3 was 3+ in 3 cases and 2+ in 6 cases, and HER2 was 3+ in 1 case, 2+ in 3 cases and 1+ in 5 cases. The present study showed overexpression of HER2 and HER3, suggesting a therapeutic potential of targeting HER2 and/or HER3 in GAS patients. We are next planning an in vivo study to develop therapies in GAS patients. Citation Format: Yuki Kojima, Hiroshi Yoshida, Toshihiro Okuya, Hitomi S. Okuma, Tadaaki Nishikawa, Maki Tanioka, Kazuki Sudo, Emi Noguchi, Tatsunori Shimoi, Yasuhito Tanase, Masaya Uno, Mitsuya Ishikawa, Yasuhiro Fujiwara, Kan Yonemori, Tomoyasu Kato. Characterization based on therapeutic target biomarkers of patients-driven xenografts model of gastric-type cervical adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2930.

OBJECTIVE To treat advanced ovarian cancer, interval debulking surgery (IDS) is performed after 3 cycles each of neoadjuvant chemotherapy (NAC) and postoperative chemotherapy (IDS group). If we expect that complete resection cannot be achieved by IDS, debulking surgery is performed after administering additional 3 cycles of chemotherapy without postoperative chemotherapy (Add-C group). We evaluated the survival outcomes of the Add-C group and determined their serum cancer antigen 125 (CA125) levels to predict complete surgery. METHODS A retrospective chart review of all stage III and IV ovarian, fallopian tube, and peritoneal cancer patients treated with NAC in 2007-2016 was conducted. RESULTS About 117 patients comprised the IDS group and 26 comprised the Add-C group. Univariate and multivariate analyses revealed that Add-C group had an equivalent effect on progression-free survival (PFS; p=0.09) and overall survival (OS; p=0.94) compared with the IDS group. Multivariate analysis revealed that patients who developed residual disease after surgery had worse PFS (hazard ratio [HR]=2.18; 95% confidence interval [CI]=1.45-3.28) and OS (HR=2.33; 95% CI=1.43-3.79), and those who received

Objectives Incidentally discovered lymphangioleiomyomatosis (LAM) in sampled lymph nodes are infrequent but intractable issues for gynecologists. The aims of this study were to elucidate the prevalence of incidental nodal LAM in a consecutive cohort of gynecologic surgical specimens from Japanese patients, to document clinicopathological features of nodal LAM cases, and to investigate the association between the subsequent development of pulmonary LAM and tuberous sclerosis complex (TSC). Study design We retrospectively reviewed 1732 consecutive Japanese patients who underwent gynecologic surgery with lymph node sampling in the National Cancer Center Hospital between January 2004 and April 2017. The pathological diagnosis of LAM was performed by pathologists. Clinicopathological data were obtained from patients’ electronic medical records. Results We found that 0.46% (8/1732) of gynecologic surgical specimens with lymph node sampling showed incidental nodal LAM. The size of the lesions was less than 10 mm, and external iliac and obturator nodes were frequently affected. Although there has been no report of a case of incidental nodal LAM developing pulmonary LAM, we identified the first case of a 36-year-old woman who developed pulmonary LAM 7 years after the diagnosis of incidental nodal LAM. None of the 8 patients had a personal or family history of TSC. Conclusions Our case brings attention to the risk of developing subsequent pulmonary LAM. To date, insufficient long-term follow-up data of young patients have hindered us from drawing a definite conclusion that patients with incidental nodal LAM are not at risk for subsequent pulmonary LAM. Future studies should collect and share long-term follow-up data to elucidate the true risk of developing pulmonary LAM in women with incidental nodal LAM.

A 64-year-old Japanese woman had rapidly progressing bilateral palmar contracture associated with severe pain on both palms over the previous 8 weeks, without a history of arthritis in any joints. We suspected palmar fibromatosis or fasciitis without polyarthritis. Because palmar fibromatosis is known to be associated with cancer, we performed cancer screening and the patient was subsequently diagnosed with fallopian tube cancer. This is the first case report of palmar fibromatosis or fasciitis without polyarthritis associated with fallopian tube cancer. The characteristic rapid progression of palmar contracture is a key finding that suggests the potential existence of a malignancy.

Few reports on malignant transformation of adenomyosis are available, and endometrioid adenocarcinoma arising from cystic adenomyosis is further rarely reported. We report a case of a 67-year-old asymptomatic woman who was referred to our hospital for evaluation of a cystic lesion in the pelvis, which had been diagnosed as cystic degeneration of leiomyoma for 3 years. Magnetic resonance imaging revealed a cystic mass measuring 11 cm in diameter, which was contiguous with uterine myometrium. The lesion contained solid areas enhanced on gadolinium-enhanced T1 -weighted imaging. Transabdominal simple total hysterectomy with bilateral salpingo-oophorectomy was performed. Pathological examination revealed endometrioid adenocarcinoma arising from cystic adenomyosis. The patient underwent six courses of adjuvant combination chemotherapy with paclitaxel and carboplatin. No metastasis or recurrence has been demonstrated for 16 months following surgery. Our case demonstrates that cystic adenomyoma possesses the risk of malignant transformation, indicating the importance of long-term follow-up with imaging examination.

Objective To evaluate the role of follow-up after curative treatment in endometrial carcinoma, we determined predictive factors for prolonged survival after recurrence. Methods We retrospectively studied patients with endometrioid endometrial carcinoma who had a follow-up appointment consisting of pelvic examination, vaginal cytology, imaging and CA-125 measurements and who developed recurrence. Possible prognostic factors were evaluated by univariate and multivariate analyses. Results Fifty-one patients developed recurrence. The median time from initial treatment to recurrence was 12months (range, 3–119months). A total of 25 (49%) and 45 (88%) recurrences were detected within 1 and 3years of initial treatment, respectively. Twenty (39%) patients were symptomatic, while 31 (61%) were asymptomatic. The median survival time of symptomatic patients was longer than that of asymptomatic patients (27 vs. 12months); however, the difference was not statistically significant ( P =0.42). No recurrences were detected by vaginal cytology. Of asymptomatic patients with low/intermediate risk (stage I/II), patients with recurrence detected by imaging or CA-125 measurements tended to have shorter survival than patients with recurrence detected by physical examination (7 vs. 31+ months, P =0.057). Multivariate analysis revealed that site of recurrence (vaginal vs. extravaginal, P 1year vs. ≤1year, P =0.01) were significant independent predictors of prolonged survival after recurrence. Conclusion In endometrial carcinoma, site of and time to recurrence are significant predictive factors of prolonged survival after recurrence, suggesting that early detection of recurrence by imaging studies and CA-125 measurements cannot improve prognosis. Although intensive follow-up using these methods may provide psychological reassurance to some patients, the use of these methods must be balanced against the wise use of limited health care resources.

Adult T-cell leukemia (ATL) arises from a human T-cell leukemia virus type I (HTLV-I)-infected cell and has few therapeutic options. Here, we have uncovered a previously unrecognized role for a ubiquitin-editing enzyme A20 in the survival of HTLV-I-infected cells. Unlike in lymphomas of the B-cell lineage, A20 is abundantly expressed in primary ATL cells without notable mutations. Depletion of A20 in HTLV-I-infected cells resulted in caspase activation, cell death induction and impaired tumorigenicity in mouse xenograft models. Mechanistically, A20 stably interacts with caspase-8 and Fas-associated via death domain (FADD) in HTLV-I-infected cells. Mutational studies revealed that A20 supports the growth of HTLV-I-infected cells independent of its catalytic functions and that the zinc-finger domains are required for the interaction with and regulation of caspases. These results indicate a pivotal role for A20 in the survival of HTLV-I-infected cells and implicate A20 as a potential therapeutic target in ATL.

We evaluated renal functions by urinary biochemical parameters in normotensive pregnancy and preeclampsia. The parameters are expected to be altered resulting from different abnormalities of renal glomeruli and tubules. We chose N-acetyl-beta-d-glucosaminidase (NAG), beta2-microglobulin (beta2MG), total protein (TP), albumin (Alb), urea nitrogen (UN), uric acid (UA), and creatinine (Cr). Urinary excretion of these biochemical parameter concentrations (relative to Cr) was measured simultaneously in first morning fasting urine samples from 27 healthy nonpregnant women (group 1), 32 women with normotensive pregnancies (group 2), and 26 women with preeclampsia (group 3). The average gestational age at entry was 36 weeks. Serum UN and serum UA also were measured. All the ratios were significantly higher in group 2 than in group 1. The NAG-to-Cr, TP-to-Cr, and Alb-to-Cr ratios were significantly higher in group 3 than in group 2. In contrast, the UN-to-Cr and UA-to-Cr ratios were significantly lower in group 3 than in group 2. The percent increase in the beta2MG-to-Cr ratio in group 2 relative to that in group 1 was the highest, followed by percent increases in the NAG-to-Cr, TP-to-Cr, Alb-to-Cr, UA-to-Cr, and UN-to-Cr ratios. In contrast, the percent increase in the Alb-to-Cr ratio in group 3 relative to that in group 2 was the highest, followed by percent increases in the TP-to-Cr, NAG-to-Cr, beta2MG-to-Cr, UA-to-Cr, and UN-to-Cr ratios. The percent increases in the NAG-to-Cr and beta2MG-to-Cr ratios rose markedly in normotensive pregnancy, whereas percent increases of the Alb-to-Cr and TP-to-Cr ratios were far greater in preeclampsia than in normotensive pregnancy. Renal tubular damage and reabsorption dysfunction may be impaired markedly even in normotensive pregnancy, and further deterioration in reabsorption dysfunction may be slight in preeclampsia. Renal glomerular permeability of TP and Alb may be enhanced in normotensive pregnancy and markedly enhanced in preeclampsia.

Few reports on malignant transformation of adenomyosis are available, and endometrioid adenocarcinoma arising from cystic adenomyosis is further rarely reported. We report a case of a 67-year-old asymptomatic woman who was referred to our hospital for evaluation of a cystic lesion in the pelvis, which had been diagnosed as cystic degeneration of leiomyoma for 3 years. Magnetic resonance imaging revealed a cystic mass measuring 11 cm in diameter, which was contiguous with uterine myometrium. The lesion contained solid areas enhanced on gadolinium-enhanced T1 -weighted imaging. Transabdominal simple total hysterectomy with bilateral salpingo-oophorectomy was performed. Pathological examination revealed endometrioid adenocarcinoma arising from cystic adenomyosis. The patient underwent six courses of adjuvant combination chemotherapy with paclitaxel and carboplatin. No metastasis or recurrence has been demonstrated for 16 months following surgery. Our case demonstrates that cystic adenomyoma possesses the risk of malignant transformation, indicating the importance of long-term follow-up with imaging examination.

Ovarian cancer is one of the leading causes of female death and the development of novel therapeutic approaches is urgently required. Nuclear factor-κB (NF-κB) is constitutively activated in several types of cancer including ovarian cancer and is known to support the survival of cancer cells. However, molecular mechanisms of persistent activation of NF-κB in ovarian cancer remain largely unknown. We report here that, in addition to the previously reported canonical activation, NF-κB is activated through the noncanonical pathway in ovarian cancer cells. RNA interference-mediated silencing of NF-κB inducing kinase (NIK), a central regulator of the noncanonical pathway, reduced the NF-κB2/p52 DNA binding activity and NF-κB-dependent reporter gene expression as well as NF-κB target gene expression. Notably, anchorage-dependent and -independent cell growth was impaired in NIK-depleted cells. Depletion of NIK also suppressed tumor formation in the nude mouse xenograft assay. These results indicate that NIK plays a key role in constitutive NF-κB activation and the progression of ovarian cancer cells and suggest that NIK represents an attractive therapeutic target for ovarian cancer.