Hideaki Yahata

Olaparib maintenance therapy for recurrent adult granulosa cell tumors: A case report

Abstract Poly (ADP‐ribose) polymerase inhibitors (PARPi) are now available for advanced or recurrent epithelial ovarian cancer after platinum‐based chemotherapy; however, there is little known concerning the use of PARPi for adult granulosa cell tumors (AGCT). A 49‐year‐old woman, who previously had primary debulking surgery and a second surgery for a first intraperitoneal recurrence, received a surgery for a second intraperitoneal recurrence of AGCT. Although she received paclitaxel–carboplatin combination chemotherapy and a combination of bleomycin, etoposide, and cisplatin after the surgeries for the first and the second recurrences, respectively, the risk of a third recurrence was considered very high due to microscopic peritoneal dissemination. Olaparib administration was initiated based on a FANCA mutation, which results in homologous recombination deficiency. The patient has been recurrence‐free for over 4 years since the initiation of olaparib. This case highlights the possibility of using olaparib for AGCT with a homologous recombination gene mutation.

The BHLHE40‒PPM1F‒AMPK pathway regulates energy metabolism and is associated with the aggressiveness of endometrial cancer

BHLHE40 is a basic helix-loop-helix transcription factor that is involved in multiple cell activities including differentiation, cell cycle, and epithelial-to-mesenchymal transition. While there is growing evidence to support the functions of BHLHE40 in energy metabolism, little is known about the mechanism. In this study, we found that BHLHE40 expression was downregulated in cases of endometrial cancer of higher grade and advanced disease. Knockdown of BHLHE40 in endometrial cancer cells resulted in suppressed oxygen consumption and enhanced extracellular acidification. Suppressed pyruvate dehydrogenase (PDH) activity and enhanced lactated dehydrogenase (LDH) activity were observed in the knockdown cells. Knockdown of BHLHE40 also led to dephosphorylation of AMPKα Thr172 and enhanced phosphorylation of pyruvate dehydrogenase E1 subunit alpha 1 (PDHA1) Ser293 and lactate dehydrogenase A (LDHA) Tyr10. These results suggested that BHLHE40 modulates PDH and LDH activity by regulating the phosphorylation status of PDHA1 and LDHA. We found that BHLHE40 enhanced AMPKα phosphorylation by directly suppressing the transcription of an AMPKα-specific phosphatase, PPM1F. Our immunohistochemical study showed that the expression of BHLHE40, PPM1F, and phosphorylated AMPKα correlated with the prognosis of endometrial cancer patients. Because AMPK is a central regulator of energy metabolism in cancer cells, targeting the BHLHE40‒PPM1F‒AMPK axis may represent a strategy to control cancer development.

Tumor-derived ARHGAP35 mutations enhance the Gα13-Rho signaling axis in human endometrial cancer

Dysregulated G protein-coupled receptor signaling is involved in the formation and progression of human cancers. The heterotrimeric G protein Gα

Impact of obesity on robotic‐assisted surgery in patients with stage IA endometrial cancer and a low risk of recurrence: An institutional study

AbstractAimWesternization of lifestyle has increased the numbers of patients with endometrial cancer and obesity. This study aimed to compare the clinical outcomes of robotic‐assisted surgery according to whether patients are obese, morbidly obese, or nonobese.MethodsSixty‐three patients with endometrial cancer who underwent robotic‐assisted surgery between March 2014 and June 2022 were categorized according to whether they had a body mass index (BMI) <30 (group A, nonobese, n = 40), ≥30 and <35 (group B, obese, n = 13), or ≥35 (group C, morbidly obese, n = 10). Operation time, blood loss, perioperative complications, and recurrence rate were investigated.ResultsConversion to laparotomy was required in one case in group A and one in group C. There was no difference in total operation time, time for setting (including trocar installation and docking of the da Vinci robot), console time, or time for wound closure between the groups; however, there was a significant between‐group difference in the total time for setting and wound closure. There was no significant difference in blood loss or complications between the groups. Three patients in group A and two in group B received adjuvant treatment; none have shown evidence of recurrent disease during a mean observation time of 21 months (range, 2–29). Two cases in group A and one in group B had recurrence during a mean observation time of 38 months (range, 19–46).ConclusionPatients with endometrial cancer who are obese can be treated safely by robotic‐assisted surgery with a low risk of complications and few relapses.

Claudin‐18 expression in gastric type adenocarcinoma and HPV ‐associated adenocarcinoma of the uterine cervix

Aims Claudin‐18 (CLDN18) is both a marker for the gastric phenotype and a therapeutic target. However, little is known about its immunoexpression in endocervical adenocarcinomas (ECAs), particularly as detected using the clone 43‐14A antibody, or about the gene expression of its isoforms in ECAs. Methods and results We examined CLDN18, HIK1083, p16 and Rb expression by immunohistochemistry and high‐risk human papillomavirus (HR‐HPV) mRNA by in situ hybridization (ISH) in 121 ECAs, including 35 HPV‐independent adenocarcinomas (gastric type [GAS], n  = 24; non‐GAS, n  = 11) and 86 HPV‐associated ECAs. We also analysed mRNA expression of the CLDN18.1 (lung type) and CLDN18.2 (gastric type) isoforms by quantitative polymerase chain reaction (qPCR) in selected cases. CLDN18 positivity was detected in 8/24 (33%) GASs, 0/11 (0%) non‐GASs and 2/86 (2%) HPV‐associated ECAs, with positivity defined as staining in ≥75% of tumour cells, as in gastric cancer. When a 5% cut‐off was used, CLDN18 positivity was detected in 22/24 (92%) GASs, 0/11 (0%) non‐GASs and 6/86 (7%) HPV‐associated ECAs; CLDN18 expression was thus significantly associated with GAS histology ( P  < 0.0001). Among the 6 cases of HPV‐associated ECAs with CLDN18 expression (ranging from 5% to 80%), the histological patterns included a mix of usual and mucinous features in 4 cases, pure usual type in 1 and villoglandular variant in 1. Otherwise features such as p16 overexpression and the Rb partial loss pattern were consistent with those of HPV‐associated ECAs. Six of 22 (27%) CLDN18‐positive GASs were also positive for p16, but their other features—such as CLDN18 expression and the Rb preserved pattern—were the same as in p16 negative GASs. Expression of CLDN18.2 mRNA but not CLDN18.1 mRNA was confirmed in both GASs and HPV‐associated ECAs. Conclusions CLDN18 (43‐14A) emerged as a potential diagnostic and therapeutic marker for GAS. A minor subset of HPV‐associated ECAs also can be immunoreactive for CLDN18 and express CLDN18.2 mRNA, suggesting divergent gastric phenotypic differentiation. The caution is that GAS and HPV‐associated ECAs can share overlapping histological features and similar expression of CLDN18 and p16.

Obstetric Outcome After Trachelectomy for Cervical Cancer Without Uterine Artery Preservation

ABSTRACT Aim A trachelectomy is a fertility‐preserving surgery that is performed for cervical cancer. Transecting the uterine arteries (UAs) during abdominal radical trachelectomy (ART) or abdominal modified radical trachelectomy (AmRT) has the advantage of simplifying other surgical procedures. However, the effect of UA transection on subsequent pregnancy outcome is unknown. The purpose of this study was to clarify the pregnancy outcomes in post‐RT pregnancies in which the UAs were not preserved. Methods This was a retrospective cohort study of electronic case records involving pregnant women after ART and AmRT, which were managed at Kyushu University Hospital from January 2008 to July 2024. Results Complications that often occur in pregnancies after ART and AmRT, such as antepartum bleeding, premature birth, and preterm premature rupture of membranes, were noted to the same degree after UA‐sparing ART. In contrast, abnormalities related to placental attachment, such as placenta previa and adherent placenta, occurred at a high rate after UA transection. Furthermore, compared to pregnancies with normal placentation, pregnancies with abnormal placentation had more blood loss during cesarean section (1150 g vs. 2289 g; p  = 0.0004) and required blood transfusion more frequently (5.7% vs. 64.2%; p  < 0.0001). Conclusions Although ART and AmRT with UA transection may increase the risk of abnormal placentation and bleeding‐related complications during cesarean section, UA transection may not increase the risk of major obstetric complications after ART and AmRT. Therefore, UA transection should be considered during ART and AmRT due technical advantages.

Retrospective analysis of treatment and prognosis for clear cell carcinoma of the uterine cervix: 15‐year experience at a single institution

AbstractAimClear cell carcinoma of the uterine cervix (CCCUC) is a rare disease, accounting for 4% to 9% of cervical adenocarcinomas. Because it is so rare, its pathogenesis is largely unknown, and the standard treatment is unclear due to a lack of prospective studies. Our aim is to investigate the clinical features, treatment, and prognosis of CCCUC.MethodsWe retrospectively evaluated the clinical characteristics, treatment choices, and outcomes of 12 patients with CCCUC treated at our institution between January 2009 and July 2024.ResultsThe median patient age was 62.5 years (range, 14–90 years). The most common stage was IB (IA, n = 3; IB, n = 4; IIB, n = 1; IIIC, n = 2; IVB, n = 2). Ten patients underwent surgery as initial treatment: 6 underwent radical hysterectomy plus pelvic lymphadenectomy (PLD) or sentinel lymph node biopsy (SLNB), with or without para‐aortic lymphadenectomy (PALD); 3 underwent modified radical hysterectomy plus PLD with or without PALD; and 1 underwent radical trachelectomy with SLNB as fertility‐preserving surgery. All patients underwent bilateral salpingo‐oophorectomy except for the patient who opted for radical trachelectomy. Five patients received adjuvant treatment: 3 received platinum‐based systemic chemotherapy (2 of whom had combination therapy with bevacizumab), and 2 received concurrent chemoradiotherapy. The median follow‐up was 43.5 months (range, 1–123 months). The 5‐year progression‐free survival rate was 64.5%.ConclusionSystemic platinum‐based chemotherapy with bevacizumab may be more effective than concurrent chemoradiotherapy as adjuvant therapy for CCCUC.

Immunohistochemical p16 overexpression and Rb loss correlate with high‐risk human papillomavirus infection in endocervical adenocarcinomas

Aimsp16 is a sensitive surrogate marker for transcriptionally active high‐risk human papillomavirus (HR‐HPV) infection in endocervical adenocarcinoma (ECA); however, its specificity is not perfect.Methods and resultsWe examined p16 and Rb expressions by immunohistochemistry (IHC) and the transcriptionally active HR‐HPV infection by mRNA in‐situ hybridisation (ISH) with histological review in 108 ECA cases. Thirteen adenocarcinomas of endometrial or equivocal origin (six endometrioid and seven serous carcinomas) were compared as the control group. HR‐HPV was detected in 83 of 108 ECA cases (77%), including five HPV‐associated adenocarcinomas in situ and 78 invasive HPV‐associated adenocarcinomas. All 83 HPV‐positive cases showed consistent morphology, p16 positivity and partial loss pattern of Rb. Among the 25 cases of HPV‐independent adenocarcinoma, four (16%) were positive for p16, and of these four cases, three of 14 (21%) were gastric type adenocarcinomas and one of 10 (10%) was a clear cell type adenocarcinoma. All 25 HPV‐independent adenocarcinomas showed preserved expression of Rb irrespective of the p16 status. Similarly, all 13 cases of the control group were negative for HR‐HPV with preserved expression of Rb, even though six of 13 (46%) cases were positive for p16. Compared with p16 alone, the combination of p16 overexpression and Rb partial loss pattern showed equally excellent sensitivity (each 100%) and improved specificity (100 versus 73.6%) and positive predictive values (100 versus 89.2%) in the ECA and control groups. Furthermore, HR‐HPV infection correlated with better prognosis among invasive ECAs.ConclusionsThe results suggest that the combined use of p16 and Rb IHC could be a reliable method to predict HR‐HPV infection in primary ECAs and mimics. This finding may contribute to prognostic prediction and therapeutic strategy.

Safety evaluation of abdominal trachelectomy in patients with cervical tumors ≥2 cm: a single-institution, retrospective analysis

For oncologic safety, vaginal radical trachelectomy is generally performed only in patients with cervical cancers smaller than 2 cm. However, because inclusion criteria for abdominal trachelectomy are controversial, we evaluated the safety of abdominal trachelectomy for cervical cancers ≥2 cm. We began performing abdominal trachelectomies at our institution in 2005, primarily for squamous cell carcinoma ≤3 cm or adenocarcinoma/adenosquamous carcinoma ≤2 cm. If a positive sentinel lymph node or cervical margin was diagnosed intraoperatively by frozen section, the trachelectomy was converted to a hysterectomy. Medical records of these patients were reviewed retrospectively. Patients who had undergone simple abdominal trachelectomy were excluded from this study. We attempted trachelectomy in 212 patients. Among the 135 patients with tumors <2 cm, trachelectomy was successful in 120, one of whom developed recurrence and none of whom died of their disease. Among 77 patients with tumors ≥2 cm, trachelectomy was successful in 62, 2 of whom developed recurrence and 1 of whom died of her disease. The overall relapse rate after trachelectomy was 1.6% (0.8% in <2 cm group and 3.2% in ≥2 cm group), and the mortality rate was 0.5% (0% in <2 cm group and 1.6% in ≥2 cm group). Recurrence-free survival (p=0.303) and overall survival (p=0.193) did not differ significantly between the <2 cm and ≥2 cm groups. Abdominal trachelectomy with intraoperative frozen sections of sentinel lymph nodes and cervical margins is oncologically safe, even in patients with tumors ≥2 cm.

Prognostic outcomes and risk factors for recurrence after laser vaporization for cervical intraepithelial neoplasia: a single-center retrospective study

Cervical intraepithelial neoplasia (CIN) is a precancerous lesion that may progress to invasive cervical cancer without intervention. We aim to examine the prognostic outcomes and risk factors for recurrence after laser vaporization for CIN 3, CIN 2 with high-risk human papillomavirus (HPV) infection, and CIN 1 persisting for more than 2 years. Between 2008 and 2016, a total of 1070 patients underwent cervical laser vaporization using a carbon dioxide laser. We performed a retrospective review of their medical records to assess their clinical characteristics, pathologic factors, and prognostic outcomes. The mean patient age was 34 years (range 18-64 years). The preoperative diagnosis was CIN 1 in 27 patients, CIN 2 in 485 patients, and CIN 3 in 558 patients. Over a median follow-up period of 15 months, the 2-year recurrence rate was 18.9%, and the 5-year recurrence rate was 46.5%. The 2-year retreatment rate was 12.6%, and the 5-year retreatment rate was 30.5%. We diagnosed 9 patients with invasive cancer after treatment; all patients underwent combined multidisciplinary treatment, and there were no deaths during follow-up. The recurrence-free interval was correlated with patient age (hazard ratio [HR], 1.028; 95% CI 1.005-1.051; P = 0.0167), body mass index (HR, 1.052; 95% CI 1.008-1.098; P = 0.0191), and glandular involvement (HR, 1.962; 95% CI 1.353-2.846; P = 0.0004). Cervical laser vaporization is effective and useful for patients with CIN who wish to preserve fertility. However, patients with glandular involvement, older age, and higher body weight require close follow-up for recurrence.

Regional differences in human papillomavirus type 52 prevalence among Japanese women with cervical intraepithelial neoplasia

Abstract Although geographical differences in the distribution of human papillomavirus genotypes have been observed worldwide, no studies have reported on national differences in the prevalence of human papillomavirus types in Japan. Here, we report a cross-sectional study to explore regional differences in the prevalence of human papillomavirus types among Japanese women with cervical intraepithelial neoplasia or invasive cervical cancer. Using human papillomavirus genotyping data from the nationwide prospective study on human papillomavirus vaccine effectiveness, we compared the frequency of detection of 15 high-risk and two low-risk human papillomavirus types in each disease category between the women who visited hospitals located in eastern Japan and those who visited hospitals located in western Japan. The risk of cervical intraepithelial neoplasia progression was assessed by calculating a prevalence ratio of each human papillomavirus type for cervical intraepithelial neoplasia grade 2/3 versus grade 1. Among the human papillomavirus types studied, human papillomavirus 52 was detected significantly more frequently in western hospitals than in eastern hospitals in cervical intraepithelial neoplasia grade 1 patients, but was less frequent in cervical intraepithelial neoplasia grade 2/3. The prevalence of particular human papillomavirus types was not significantly different between patients in hospitals in eastern Japan and those in hospitals in western Japan for invasive cervical cancer. In both eastern and western hospitals, a higher risk of cervical intraepithelial neoplasia progression was observed in patients infected with human papillomavirus 16, 31 or 58. In contrast, there was a significantly higher prevalence of human papillomavirus 52 infection in women with cervical intraepithelial neoplasia grade 2/3 than in those with cervical intraepithelial neoplasia grade 1 in eastern hospitals (prevalence ratio, 1.93; 95% confidence interval, 1.48–2.58), but not in western hospitals (prevalence ratio, 1.03; 95% confidence interval, 0.83–1.30). Regional differences of human papillomavirus 52 prevalence in cervical intraepithelial neoplasia lesions may exist and emphasize the importance of continuous monitoring of human papillomavirus type prevalence throughout the country in order to accurately assess the efficacy of human papillomavirus vaccines.

Diagnostic accuracy and prognostic factors of uterine serous carcinoma in Japanese women: a multi-center study

This multi-center retrospective study aimed to clarify the characteristics, diagnostic accuracy, treatment outcomes, and prognostic factors of uterine serous carcinoma (USC) in Japanese women. The medical records of 193 patients who were treated between 2006 and 2008 at 24 participating institutions in the Japanese Clinical Oncology Group were examined, and pathological slides of 188 patients were re-checked through central pathology review (CPR), hematoxylin-eosin staining, and immunohistochemistry. USC was confirmed in 144 of the 188 (76.6%) patients using CPR, and only 50% were correctly diagnosed preoperatively. Forty-three patients were diagnosed with non-serous carcinoma, whereas one patient had metastasis from another organ. The average age was 65.7 years, and 19% of patients had a history of other cancers. The incidence of stage III-IV disease was 52.8%, and lymph node metastasis was found in 28.5% of patients. Extrauterine spread and distant metastasis occurred in 39% and 14% of patients, respectively. The 2-year overall survival and progression-free survival (PFS) rates were 56% and 42%, respectively. The PFS of patients with stage I and II who underwent complete staging surgery was 92.3%, and that of those without lymph node dissection or omentectomy was 33.3%. Patients with USC had a significantly worse prognosis than 43 patients with non-serous carcinoma. USC in Japanese women has characteristics different from those of endometrioid carcinoma, worse prognosis, and is difficult to diagnose preoperatively. Complete surgical staging is necessary even for early-stage disease. Additionally, new adjuvant treatment strategies, including molecular targeted therapy, should be explored.