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.

Are HPV-negative lesions concerned for the introduction of primary HPV testing for cervical cancer screening in Japan?

AIM: In Japan, primary human papilloma virus (HPV) testing has not been introduced for cervical cancer screening due to concerns that HPV-negative lesions may be missed and a lack of Japanese data. The purpose of this study was to evaluate the validity of primary HPV testing in Japan by analyzing cervical intraepithelial neoplasia 2 (CIN2) or more/high-risk HPV- (CIN2+/hrHPV-) cases in cervical cancer screening. METHODS: Data from 35 525 cervical cancer screenings with HPV testing and cervical cytology from 2011 to 2019 in Saga City, Japan, were reviewed. The cases with low-grade squamous intraepithelial lesion (LSIL+)/hrHPV- were analyzed in detail. RESULTS: The results of the 35 525 examinees were as follows: 31 123 were negative for intraepithelial lesion or malignancy (NILM)/hrHPV-, 2612 were NILM/hrHPV+, 262 were atypical squamous cells of undetermined significance (ASC-US)/hrHPV-, 213 were ASC-US/hrHPV+, 291 were LSIL+/hrHPV-, and 1024 were LSIL+/hrHPV+. Of the 256 LSIL+/hrHPV- examinees for whom histology was available, CIN2+ were CIN2 9.4% (24/256), CIN3 3.9% (10/256), cervical adenocarcinoma 0.4% (1/256), uterine corpus cancer 1.2% (3/256), and uterine sarcoma 0.4% (1/256). Overall, the rate of LSIL+/hrHPV- was 0.82% (291/35.525), 0.1% (36/35525) of which were cervical lesions with CIN2+. Only one cervical adenocarcinoma was detected, but gastric-type adenocarcinoma was not included. CONCLUSION: HPV-negative CIN2+ or cervical adenocarcinoma is not a concern for the introduction of primary HPV screening in Japan. Primary HPV testing in cervical cancer screening is considered a feasible method that can be used in Japan, although an algorithm suitable for Japan and a national-level management system need to be established.

Development of novel tracers for sentinel node identification in cervical cancer.

Indocyanine green (ICG) with near-infrared (NIR) fluorescence imaging is used for lymphatic mapping. However, binding of ICG to blood proteins like serum albumin can shorten its retention time in sentinel lymph nodes (SLNs). Here, we investigated the efficacy and safety of a new fluorescence tracer comprising phytate and liposome (LP)-encapsulated ICG. Coadministration of phytate with LP containing phosphatidic acid promotes chelation mediated by Ca2+ in bodily fluids to enhance SLN retention. Uniformly sized LPs (100 nm) encapsulating ICG under conditions that minimized fluorescence self-quenching during storage were produced. We analyzed the behavior of the new tracer (ICG-phytate-LP) and control tracers (ICG and ICG-LP) in the lymphatic flow of mice in terms of lymph node retention time. We also tested lymphatic flow and safety in pigs that have a more human-like lymphatic system. LPs encapsulating stabilized ICG were successfully prepared. Mixing LP with phytate in the presence of Ca2+ increased both the particle size and negative surface charge. In mice, ICG-phytate-LP had the best lymph node retention, with a fluorescence intensity ratio that increased over 6 h and then decreased slowly over the next 24 h. In pigs, administration of ICG and ICG-phytate-LP resulted in no death or weight loss. There were no obvious differences between blood test results for the ICG and ICG-phytate-LP groups, and the overall safety was good. ICG-phytate-LP may be a useful new tracer for gynecological cancers that require time for lymph node identification due to a retroperitoneal approach.

Decision-making for Subsequent Therapy for Patients With Recurrent or Advanced Endometrial Cancer Based on the Platinum-free Interval.

OBJECTIVE: The aim of this study was to evaluate the progression-free survival (PFS) and overall response rate (ORR) of patients with recurrent endometrial cancer (REC) or advanced endometrial cancer (AEC) retreated with platinum-containing chemotherapy (PCC) based on the platinum-free interval (PFI). We compared our results with those reported in the KEYNOTE-775 study (that used pembrolizumab plus lenvatinib). METHODS: A retrospective analysis was conducted of 65 patients with REC or AEC retreated with PCC between 2005 and 2020 at our hospital. Various clinicopathologic variables were analyzed: (1) age, (2) performance status, (3) histology, (4) history of pelvic irradiation in the adjuvant setting, (5) PFI, (6) chemotherapy regimen, (7) PFS and overall survival after retreatment with PCC, and (8) best ORR. Survival analyses were performed using Kaplan-Meier curves and log-rank tests. RESULTS: The best ORR and PFS were 43.3% and 9.5 months, respectively, in patients with REC/AEC with a PFI ≥6 months. These results were comparable with those of patients treated with pembrolizumab and lenvatinib. The best ORR and PFS of patients with a PFI of <6 months appeared to be inferior to those of patients treated with pembrolizumab plus lenvatinib. CONCLUSIONS: Pembrolizumab plus lenvatinib seems to be a better treatment choice for patients with REC or AEC with a PFI of <6 months. For a PFI of ≥6 months, pembrolizumab plus lenvatinib or PCC can be used depending on the degree of residual side -effects associated with cytotoxic agents.

An update of oncologic and obstetric outcomes after abdominal trachelectomy using the FIGO 2018 staging system for cervical cancer: a single-institution retrospective analysis.

OBJECTIVE: To apply the International Federation of Gynecology and Obstetrics (FIGO) 2018 staging system to all patients who underwent trachelectomy in our previous study and to update the oncologic and obstetric results. METHODS: We retrospectively reviewed the medical records of patients in whom abdominal trachelectomy was attempted between June 2005 and September 2021. The FIGO 2018 staging system for cervical cancer was applied to all patients. RESULTS: Abdominal trachelectomy was attempted for 265 patients. Trachelectomy was converted to hysterectomy in 35 patients, and trachelectomy was completed successfully in 230 (conversion rate: 13%). Applying the FIGO 2018 staging system, 40% of the patients who underwent radical trachelectomy had stage IA tumors. Among 71 patients who had tumors measuring ≥2 cm, 8 patients were classified as stage IA1 and 14 as stage IA2. Overall recurrence and mortality rates were 2.2% and 1.3%, respectively. One hundred twelve patients attempted to conceive after trachelectomy; 69 pregnancies were achieved in 46 patients (pregnancy rate: 41%). Twenty-three pregnancies ended in first-trimester miscarriage, and 41 infants were delivered between gestational weeks 23 and 37; 16 were deliveries at term (39%) and 25 were premature deliveries (61%). CONCLUSION: This study suggested that patients judged to be ineligible for trachelectomy and patients receiving overtreatment will continue to appear using the current standard eligibility criteria. With the revisions to the FIGO 2018 staging system, the preoperative eligibility criteria for trachelectomy, which were based on the FIGO 2009 staging system and tumor size, should be changed.

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 Gα13 is highly expressed in various cancers and regulates diverse cancer-related transcriptional networks and cellular functions by activating Rho. Herein, we demonstrate that increased expression of Gα13 promotes cell proliferation through activation of Rho and the transcription factor AP-1 in human endometrial cancer. Of interest, the RhoGTPase activating protein (RhoGAP), ARHGAP35 is frequently mutated in human endometrial cancers. Among the 509 endometrial cancer samples in The Cancer Genome Atlas database, 108 harbor 152 mutations at 126 different positions within ARHGAP35, representing a somatic mutation frequency of 20.2%. We evaluated the effect of 124 tumor-derived ARHGAP35 mutations on Gα13-mediated Rho and AP-1 activation. The RhoGAP activity of ARHGAP35 was impaired by 55 of 124 tumor-derived mutations, comprised of 23 nonsense, 15 frame-shift, 15 missense mutations, and two in-frame deletions. Considering that ARHGAP35 is mutated in >2% of all tumors, it ranks among the top 30 most significantly mutated genes in human cancer. Our data suggest potential roles of ARHGAP35 as an oncogenic driver gene, providing novel therapeutic opportunities for endometrial cancer.

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

AIM: Westernization 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. METHODS: Sixty-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. RESULTS: Conversion 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). CONCLUSION: Patients with endometrial cancer who are obese can be treated safely by robotic-assisted surgery with a low risk of complications and few relapses.

Prognostic impact of adding bevacizumab to carboplatin and paclitaxel for recurrent, persistent, or metastatic cervical cancer.

OBJECTIVE: Recent randomized phase III trial has shown significant benefit in overall survival (OS) for patients with advanced cervical cancer by adding bevacizumab to conventional chemotherapy. The aim of this study was to evaluate the prognostic impact for Japanese recurrent, persistent, or metastatic cervical cancer patients where bevacizumab was added to paclitaxel plus carboplatin. MATERIALS AND METHODS: A retrospective analysis was performed on 90 patients with recurrent, persistent, or metastatic cervical cancer mainly treated by paclitaxel plus carboplatin between 2005 and 2019 at our hospital. Data for the following clinicopathological variables were analyzed: (1) bevacizumab use; (2) histology; (3) disease presentation; (4) performance status; (5) prior chemotherapy containing platinum agent; (6) pelvic disease; (7) prior pelvic radiotherapy; (8) location of target lesions. Survival analysis was performed using Kaplan-Meier curves, log-rank tests, Wilcoxon tests, and Cox proportional hazards models combined with propensity score matching. RESULTS: Adding bevacizumab to paclitaxel plus carboplatin showed significantly increased complete response to compared with that of non-users. In a Cox regression hazard model, bevacizumab use tended to show better OS though without statistically significance. After propensity score matching, adding bevacizumab to paclitaxel plus carboplatin showed a significant better OS by univariate analysis using Wilcoxon test, not by log-rank test. CONCLUSION: Adding bevacizumab to paclitaxel plus carboplatin showed a limited prognostic impact for recurrent, persistent or advanced cervical cancer patients in the real world. Further effective second-line treatments are needed to prolong OS of patients with recurrent, persistent or advanced cervical cancer.

Cyclin-dependent kinase 8 is an independent prognosticator in uterine leiomyosarcoma.

Cyclin-dependent kinase 8 (CDK8) is associated with the transcriptional mediator complex and regulates several transcription factors implicated in cancer. CDK8 expression is a poor prognostic marker in colon and breast cancer by immunohistochemistry. However, somatic mutations in exon 2 of the RNA polymerase II transcriptional mediator subunit MED12 occur in 7-30% of cases of uterine leiomyosarcoma (ULMS), suggesting that these alterations contribute to tumorigenesis. Public genomic mutation data of 80 patients with ULMS were used for MED12 and CDK8 mutation analysis. The expression of MED12, CDK8 and ß-catenin was evaluated by immunohistochemistry in our cohort of 60 patients with ULMS, in addition with MED12 mutation status and survival stage. Univariate analysis was performed using the log-rank test, and Cox regression was used to identify independent prognostic factors. Multivariate Cox regression analysis revealed that advanced stage (p < 0.0001) and high CDK8 expression (p = 0.0014) were independent predictors of poor prognosis. MED12 mutation status was not significantly associated with CDK8 expression (p = 0.6873) and DSS (p = 0.8075). In conclusion, our data suggest that CDK8 expression may identify a subset of ULMS patients with a poor prognosis.

Long-term follow up after sentinel node biopsy alone for early-stage cervical cancer.

OBJECTIVE: Sentinel node biopsy alone (SNB) reduces the postoperative complications of pelvic lymphadenectomy, such as lymphedema and lymphangitis; however, the long-term prognosis after SNB is unclear. The objective of this study was to evaluate the long-term outcome and complications of patients with early-stage cervical cancer who underwent SNB for hysterectomy or trachelectomy. METHODS: We performed SNB for cervical cancer using a radioisotope method in 181 patients between 2009 and 2017. If the intraoperative sentinel lymph node evaluation was negative for metastasis, no further lymph nodes were removed. RESULTS: The median age of the patients was 34 years (range, 21-73 years). The International Federation of Gynecology and Obstetrics 2008 stage was IA1 in 6 patients, IA2 in 18, IB1 in 154, and IIA1 in 3. Of the 181 patients (44 with hysterectomy, 137 with trachelectomy), 8 did not undergo pelvic lymphadenectomy because of a false-negative intraoperative diagnosis, 20 received adjuvant therapy after surgery, and 4 (2.2%) experienced recurrence over a median follow-up period of 83.5 months (range, 25-145 months). In the four recurrent cases, recurrence occurred in the pelvis, lung, and bone in one patient each, while the remaining patient developed pelvic and para-aortic lymph node metastases. Of these four patients, one died, and the remaining three are alive without disease after multidisciplinary therapy. The 5-year progression-free and overall survival rates were 98.8% and 99.4%, respectively. Postoperative complications, such as lymphedema, were very low rate. CONCLUSIONS: SNB for early-stage cervical cancer might be safe and effective, with no increase in the recurrence and postoperative complications rate.

A Case of Malignant Phyllodes Tumor of the Breast Metastasizing to the Ovary.

Phyllodes tumors of the breast are uncommon, and 6.2% of phyllodes tumors behave in a malignant fashion. The metastatic spread of malignant phyllodes tumor is mainly hematogenous to lung and bone, and malignant phyllodes tumor metastasizing to the ovary is rare, with only 2 cases reported. We report the third case of metastatic malignant phyllodes tumor to the ovary with a focus on the differential diagnosis of ovarian cancer.

Evaluation of Clinical Significance of Lymphovascular Space Invasion in Stage IA Endometrial Cancer.

INTRODUCTION: The prognostic significance of lymphovascular space invasion (LVSI) in stage IA endometrial cancer remains unclear. The aim of this study was to evaluate the clinical significance of LVSI in stage IA endometrial cancer. METHODS: Clinical data of patients with stage IA endometrial cancer who underwent initial surgery at our institution between January 2008 and December 2018 were reviewed retrospectively. Information of patients, surgery, and characteristics of cancer were obtained from medical records and pathological reports. RESULTS: Two hundred ninety-seven patients were enrolled in this study. With a median follow-up of 60 months, 15 patients experienced recurrence (5.1%) and 4 patients died of endometrial cancer (1.3%). The recurrence and mortality rates did not differ significantly between the LVSI-positive and -negative groups (p = 0.07 and p = 0.41, respectively). Recurrence-free survival and endometrial cancer-specific survival also did not differ significantly between these groups (p = 0.11 and p = 0.49, respectively). The 5-year endometrial cancer-specific survival rates for tumors with and without LVSI were 97.0% and 98.9%, respectively. Among patients with low-grade tumors, recurrence-free survival and endometrial cancer-specific survival did not differ significantly between patients with tumors with and without LVSI (p = 0.92 and p = 0.72, respectively). The 5-year endometrial cancer-specific survival rates for low-grade tumors with and without LVSI were 100% and 99.3%, respectively. CONCLUSION: LVSI was not a prognostic factor of not only stage IA endometrial cancer but also stage IA low-grade cancer.

Prognostic impact of the subclassification of Müllerian cancer stage IV in the FIGO 2014 staging system with a focus of extra-abdominal lymph node metastases.

BACKGROUND: The International Federation of Gynecology and Obstetrics (FIGO) staging system for Müllerian cancer was changed in 2014. Our objective was to evaluate the prognostic impact of stage IV subclassification in this new staging system, especially focusing on extra-abdominal lymph node metastasis. METHODS: Eighty-two patients with stage IV Müllerian cancer treated between 2005 and 2016 at our hospital were retrospectively analyzed. Data for the following clinicopathological variables were analyzed: (1) FIGO stage; (2) tumor stage; (3) lymph node status; (4) histologic type; (5) neoadjuvant chemotherapy; (6) optimal surgery; and (7) bevacizumab use. Survival analysis was performed using Kaplan-Meier curves, log-rank tests, and Cox proportional hazards models. RESULTS: In accordance with the new classification, 28 and 54 patients were classified as FIGO IVA and IVB, respectively. In the Cox proportional hazards model, early-stage tumors (T1b-3b) and optimal surgery were statistically significant favorable prognostic factors. However, the new FIGO system did not discriminate prognostically between stage IVA and IVB. Median overall survival of stage IVB patients diagnosed with extra-abdominal lymph node metastasis only was better than that of stage IVA and stage IVB patients diagnosed with solid organ metastasis. CONCLUSIONS: In this analysis of the revised FIGO system of patients reclassified as FIGO stage IVA or IVB, no new prognostic information was obtained. There is a possibility that stage IVB patients diagnosed with extra-abdominal lymph node metastasis only can be classified as an earlier stage. Further modification of the FIGO staging system may be needed to improve the prediction of patient prognosis.

Evaluation of the efficacy of vaginal progesterone in preventing preterm birth after abdominal trachelectomy.

OBJECTIVE: To determine whether vaginal progesterone (VP) reduces the rate of preterm birth in pregnant women after abdominal trachelectomy (AT) for early-stage cervical cancer STUDY DESIGN: This is an interventional study with a historical cohort. For the interventional study participants who had singleton pregnancies after AT between October 2016 and September 2020, the administration of vaginal progesterone was started between 16+ and 19+6 weeks of gestation and discontinued at 34 weeks of gestation or at the time of delivery, rupture of membranes, or massive uterine bleeding. We investigated obstetric and neonatal outcomes among the study participants and compared them with outcomes of the historical control group participants, included women with singleton pregnancies after AT who were managed without VP at our institution between January 2007 and September 2016, using Fisher's exact test and the Mann-Whitney U test The main outcomes were the gestational age at delivery and incidence of preterm birth before 37 weeks and 34 weeks of gestation. RESULT: Twelve pregnancies in ten women were included in the VP group. In contrast, 19 pregnancies in 17 women were included in the historical control group. The incidence of preterm birth at <37 weeks was 10/12 (83 %) in the VP group and 11/19 (58 %) in the control group. The incidence of preterm birth at <34 weeks was 6/12 (50 %) in the VP group and 9/19 (48 %) in the control group. The incidence of preterm birth in the two groups was similar, and the difference between the two groups was not statistically significant. CONCLUSION: The administration of vaginal progesterone did not reduce the rate of preterm birth among pregnant women after AT.

Difficulty of cervical cancer diagnosis during pregnancy: A case series analysis of the clinicopathological characteristics and prognosis of cervical cancer diagnosed during pregnancy or within 6 months after parturition.

Due to the recent trend of women having children at an older age, the number of pregnancies complicated by cervical cancer has increased. In the present study, the clinical characteristics of patients with cervical cancer complicated by pregnancy were analyzed. The clinicopathological characteristics and prognosis of patients with cervical cancer during pregnancy who underwent treatment at Kyushu University Hospital from January 2008 to December 2017 were assessed retrospectively from their medical records. The medical information of patients diagnosed within 6 months after parturition was also evaluated as these patients were considered to be affected by cervical cancer during pregnancy. A total of 19 women were diagnosed with cervical cancer during pregnancy (median age, 33 years), three of whom were diagnosed as negative for intraepithelial lesion or malignancy at the initial visit to a previous clinic after pregnancy. The tumor stage was IA1 in one patient, IB1 in 16 patients, IB2 in one patient and IVB in one patient. The median gestational age at the time of cervical cancer diagnosis was 13 weeks. One patient died of cervical cancer during the follow-up period. An additional 12 patients were diagnosed within 6 months after parturition. The median age of these patients was 35.5 years. Cancer screening was performed in 10 patients during pregnancy, none of whom were diagnosed with cervical cancer, including three patients who were negative for intraepithelial lesion or malignancy. Of the 12 patients, one had tumor stage IA1, eight had IB1, two had IB2 and one had IIB. Three patients experienced recurrence, of whom one died of cervical cancer. Advanced cervical cancer was diagnosed both during pregnancy and within 6 months after parturition. Diagnosis of cervical cancer during pregnancy is difficult even at an advanced stage; however, rapid diagnosis and prompt multidisciplinary treatment are critical. Therefore, it is necessary to improve the accuracy of cervical cancer diagnosis, and to characterize tumor cells and their microenvironment, during pregnancy.

The validity of the subsequent pregnancy index score for fertility-sparing trachelectomy in early-stage cervical cancer.

OBJECTIVE: To evaluate timing and a prediction model for pregnancy in early-stage cervical cancer patients who underwent fertility-sparing trachelectomy. DESIGN: Retrospective cohort. SETTING: Academic multicenter. PATIENT(S): Women ages <45 years with clinical stage I-II cervical cancer were enrolled between 2009 and 2013 (n = 393). INTERVENTION(S): Planned fertility-sparing trachelectomy. MAIN OUTCOME MEASURE(S): Cumulative incidences and clinicopathological characteristics of those who developed subsequent pregnancy were examined. RESULT(S): There were 77 (21.6%) women who had subsequent pregnancies after fertility-sparing trachelectomy with 1-, 2-, and 5-year cumulative pregnancy rates of 2.8%, 6.2%, and 17.4%, respectively. The median time to develop subsequent pregnancy was 3.2 years. In a competing risk analysis, women had a higher risk of recurrent cancer than conception during the first 11 months postsurgery. On multivariable analysis, younger age, being married, and postoperative reproductive treatment were independently associated with an increased chance of developing a subsequent pregnancy. The subsequent pregnancy index (SPI) score to predict the likelihood of having pregnancy was proposed, and it was calculated based on age, marital status, and reproductive treatment (2, 2, and 4 points, respectively). Women with a higher SPI score had significantly higher subsequent pregnancy rates (5-year pregnancy rate; the score was 3 in 4.7% of cases; 4 to 5 in 11.3%; 6 to 7 in 27.4%; and 8 in 50.8%), but they had similar recurrence rates (5.0%). CONCLUSION(S): The SPI score proposed in our study is useful in predicting subsequent pregnancy in women with early-stage cervical cancer undergoing fertility-sparing trachelectomy.

Fibronectin mediates activation of stromal fibroblasts by SPARC in endometrial cancer cells.

BACKGROUND: Matricellular glycoprotein, SPARC is a secreted molecule, that mediates the interaction between cells and extracellular matrix. SPARC functions as a regulator of matrix organization and modulates cell behavior. In various kinds of cancer, strong SPARC expression was observed in stromal tissues as well as in cancer epithelial cells. The function of SPARC in cancer cells is somewhat controversial and its impact on peritumoral stromal cells remains to be resolved. METHODS: We investigated the effects of SPARC expression in endometrial cancer cells on the surrounding stromal fibroblasts using in vitro co-culture system. Changes in characteristics of fibroblasts were examined by analysis of fibroblast-specific markers and in vitro contraction assay. RESULTS: SPARC induced AKT phosphorylation and epithelial-to-mesenchymal transition, consistent with previous reports. Cancer-associated fibroblasts of endometrial cancer expressed higher levels of mesenchymal- and fibroblast-associated factors and had a stronger contraction ability. Unexpectedly, cancer-associated fibroblasts expressed comparable levels of SPARC compared with fibroblasts from normal endometrium. However, co-culture of normal fibroblasts with SPARC-expressing Ishikawa cells resulted in activation of the fibroblasts. Immunodepletion of SPARC did not affect the activation of fibroblasts. CONCLUSIONS: Our data indicated that SPARC activated fibroblasts only in the presence of fibronectin, which was abundantly secreted from SPARC-expressing endometrial cancer cells. These results suggested that a SPARC-fibronectin-mediated activation of fibroblasts might be involved in enhanced mobility and invasion of cancer cells.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Hypersensitivity reaction to pegylated liposomal doxorubicin administration for Mullerian carcinoma in Japanese women.

AIM: PEGylated liposomal doxorubicin (PLD) is a therapeutic agent for gynecological malignancy. Hypersensitivity reaction (HSR) is a major adverse effect that usually disappears after halting administration of PLD. Premedication is usually not necessary before administration of PLD to prevent HSR. Here, we evaluated the frequency of HSR during administration of PLD following premedication in Japanese women. METHODS: We performed PLD administration in 78 patients (386 cycles) between 2013 and 2018. Granisetron hydrochloride and dexamethasone sodium phosphate were administered 30 min before PLD administration. Then, PLD (40 or 30 mg/m2 combined usage with carboplatin) was administered. We retrospectively reviewed the medical records of 78 patients and examined the frequency of HSR. RESULTS: Seven of 78 (9%) patients showed HSR by PLD administration following premedication. One patient showed cardiopulmonary arrest in 13 min after PLD administration (grade 4). The other six patients showed grade 2 HSR. All patients developed HSR in the first course. The incidence of HSR was significantly higher in patients with allergic history than in patients without allergic history (p = 0.0151). CONCLUSIONS: Clinicians should be aware of the potential for HSR in patients administered PLD, particularly those with allergic history and those receiving the first cycle of PLD, even following premedication.

Evaluation of adjuvant chemotherapy after abdominal trachelectomy for cervical cancer: a single-institution experience.

BACKGROUND: To avoid the loss of fertility, chemotherapy should be chosen as an adjuvant treatment after trachelectomy. Our study evaluated the effectiveness and safety of adjuvant chemotherapy after abdominal trachelectomy for cervical cancer. METHODS: Our institutional review board approved this clinical study, and informed consent was obtained from each patient. We began performing abdominal trachelectomy at our institution in 2005. Deep stromal invasion (more than two-thirds) with lymphovascular space invasion, diffuse cervical invasion, skip lesions in the vagina, and lymphovascular space invasion in the cardinal ligament and vagina were defined as intermediate-risk factors, and parametrial invasion and pelvic lymph node metastasis were defined as high-risk factors. Patients who had intermediate- or high-risk factors received post-trachelectomy adjuvant treatment. The medical records and information of the patients were reviewed retrospectively. RESULTS: Through January 2020, we performed 212 trachelectomies. Among the included patients, 16 and 7 patients with intermediate- and high-risk cancer, respectively, received adjuvant chemotherapy after trachelectomy (2 and 21 patients underwent abdominal modified radical trachelectomy and radical trachelectomy, respectively). Among these patients, only one (4.3%) experienced relapse and subsequent death of the disease after a median postoperative follow-up of 80 months (range 12-146 months). The 5-year survival rate was 95.5%. Chemotherapy-related life-threatening acute adverse events were not observed. Persistent ovarian dysfunction and late adverse events did not occur. One woman achieved three pregnancies, and two infants were delivered. CONCLUSION: Adjuvant chemotherapy after abdominal trachelectomy could be an alternative treatment option from the aspects of effectiveness, safety, and fertility preservation.