Evaluation of ARID1A as a Potential Biomarker for Predicting Response to Immune Checkpoint Inhibitors in Patients with Endometrial Cancer.

BACKGROUND: AT-rich interaction domain 1A (ARID1A) has been proposed as a new biomarker for predicting response to immune checkpoint inhibitors (ICIs). The predictive value of ARID1A for predicting ICI effectiveness has not been reported for endometrial cancer. Therefore, we investigated whether ARID1A negativity predicts ICI effectiveness for endometrial cancer treatment. METHODS: We evaluated ARID1A expression, tumor-infiltrating lymphocytes (CD8+), and immune checkpoint molecules (PD-L1/PD-1) by immunostaining endometrial samples from patients with endometrial cancer. Samples in which any of the four mismatch repair proteins (MLH1, MSH2, MSH6, and PMS2) were determined to be negative via immunostaining were excluded. In the ARID1A-negative group, microsatellite instability (MSI) status was confirmed via MSI analysis. RESULTS: Of the 102 samples investigated, 25 (24.5%) were ARID1A-negative. CD8 and PD-1 expression did not differ significantly between the ARID1A-negative group and the ARID1A-positive group; however, the ARID1A-negative group showed significantly lower PD-L1 expression. Only three samples (14.2%) in the ARID1A-negative group showed high MSI. Sanger sequencing detected three cases of pathological mutation in the MSH2-binding regions. We also established an ARID1A-knockout human ovarian endometriotic epithelial cell line (HMOsisEC7 ARID1A KO), which remained microsatellite-stable after passage. CONCLUSION: ARID1A negativity is not suitable as a biomarker for ICI effectiveness in treating endometrial cancer.

Association between KRAS and PIK3CA Mutations and Progesterone Resistance in Endometriotic Epithelial Cell Line.

Although endometriosis is a benign disease, it is associated with cancer-related gene mutations, such as KRAS or PIK3CA. Endometriosis is associated with elevated levels of inflammatory factors that cause severe pain. In a previous study, we demonstrated that KRAS or PIK3CA mutations are associated with the activation of cell proliferation, migration, and invasion in a patient-derived immortalized endometriotic cell line, HMOsisEC10. In this study, we investigated the effects of these mutations on progesterone resistance. Since the HMOsisEC10 had suppressed progesterone receptor (PR) expression, we transduced PR-B to HMOsisEc10 cell lines including KRAS mutant and PIK3CA mutant cell lines. We conducted a migration assay, invasion assay, and MTT assay using dienogest and medroxyprogestrone acetate. All cell lines showed progesterone sensitivity with or without mutations. Regarding inflammatory factors, real-time quantitative RT-PCR revealed that the KRAS mutation cell line exhibited no suppression of Cox-2 and mPGES-1 on progesterone treatment, whereas IL-6, MCP-1, VEGF, and CYP19A1 were significantly suppressed by progesterone in both mutated cell lines. Our results suggest that KRAS mutation and PIK3CA mutation in endometriotic cells may not be associated with progesterone resistance in terms of aggressiveness. However, KRAS mutations may be associated with progesterone resistance in the context of pain.

Economic effects of dietary salt reduction policies for cardiovascular disease prevention in Japan: a simulation study of hypothetical scenarios.

Objective: Reducing dietary salt intake is an essential population strategy for cardiovascular disease (CVD) prevention, but evidence on healthcare costs and outcomes is limited in Japan. We aimed to conduct a pilot economic evaluation under hypothetical scenarios of applying the salt reduction policies of England to Japan. Methods: We examined salt reduction policies in England: media health promotion campaigns, front-of-pack labeling, and voluntary and mandatory reformulation with best-case and worst-case policy cost scenarios. We assumed that these policies were conducted in Japan for 10 years from 2019. We used published data on epidemiology and healthcare expenditures in Japan and the costs and effects of salt reduction policies in England, and defined the benefits as a decrease in national medical expenditures on CVD. We developed a Markov cohort simulation model of the Japanese population. To estimate the annual net benefits of each policy over 10 years, we subtracted monitoring and policy costs from the benefits. We adopted a health sector perspective and a 2% discount rate. Results: The cumulative net benefit over 10 years was largest for mandatory reformulation (best case) at 2,015.1 million USD (with costs of USD 48.3 million and benefits of USD 2063.5 million), followed by voluntary reformulation (net benefit: USD 1,895.1 million, cost: USD 48.1 million, benefit: USD 1,943.2 million), mandatory reformulation (worst case, net benefit: USD 1,447.9 million, cost: USD 1,174.5 million, benefit: USD 2,622.3 million), labeling (net benefit: USD 159.5 million, cost: USD 91.6 million, benefit: USD 251.0 million), and a media campaign (net benefit: USD 140.5 million, cost: USD 110.5 million, benefit: USD 251.0 million). There was no change in the superiority or inferiority of policies when the uncertainty of model parameters was considered. Conclusion: Mandatory reformulation with the best-case cost scenario might be economically preferable to the other alternatives in Japan. In future research, domestic data on costs and effects of salt reduction policies should be incorporated for model refinement.

Histological and Genetic Diversity in Ovarian Mucinous Carcinomas: A Pilot Study.

Tumor heterogeneity remains an ongoing challenge in the field of cancer therapy. Intratumor heterogeneity significantly complicates the diagnosis of cancer and presents challenging clinical problems due to resistance to drug therapy. This study aimed to elucidate the genetic changes histologically (mucinous cystadenoma (MCA), mucinous borderline tumor (MBT), and mucinous ovarian carcinoma (MOC)) in a portion of mucinous ovarian tumors within the same sample. Seven tumor samples obtained from different patients were used to evaluate the genetic mutations in each component. Intratumor genetic heterogeneity was observed in all patients; among them, BRAF (V600E) and p53 (T118I, P142S, T150I, and T170M) point mutations were observed in the MBT component, while KRAS (G12D and G13D) and PIK3CA (E545K) mutations were found in the MOC component. The current findings suggest that diverse genetic alterations occur in mucinous tumors, according to tumor histology. Tumor heterogeneity and genetic diversity in mucinous ovarian tumors might be the cause of treatment failure. Knowledge of intertumor heterogeneity may lead to an increased understanding of the tumor response to treatment.

The Case of an Endometrial Cancer Patient with Breast Cancer Who Has Achieved Long-Term Survival via Letrozole Monotherapy.

Herein, we present the successful treatment of a 92-year-old woman who experienced recurrent EC in the vaginal stump and para-aortic lymph nodes. The patient was first treated with paclitaxel and carboplatin for recurrent EC, which was abandoned after two cycles of chemotherapy because of G4 hematologic toxicity. Later, the patient was treated with letrozole for early-stage breast cancer, which was diagnosed simultaneously with EC recurrence. After four months of hormonal therapy, a partial response was observed not only in the lesions in the breast, but also those in the vaginal stump and para-aortic lymph nodes. She had no recurrence of breast cancer or EC, even after six years of treatment with letrozole-based hormonal therapy. Subsequent whole-exome sequencing using the genomic DNA isolated from the surgical specimen in the uterine tumor identified several genetic variants, including actionable mutations, such as CTNNB1 (p.S37F), PIK3R1 (p.M582Is_10), and TP53 c.375 + 5G>T. These data suggest that the efficacy of letrozole is mediated by blocking the mammalian target of the rapamycin pathway. The findings of this study, substantiated via genetic analysis, suggest the possibility of long-term disease-free survival, even in elderly patients with recurrent EC, which was thought to be difficult to cure completely.

Promising Therapeutic Impact of Immune Checkpoint Inhibitors in Type II Endometrial Cancer Patients with Deficient Mismatch Repair Status.

Type II endometrial cancer (EC) is responsible for most endometrial cancer-related deaths due to its aggressive nature, late-stage detection, and high tolerance to standard therapies. Thus, novel treatment strategies for type II EC are imperative. For patients with mismatch repair-deficient (dMMR) tumors, immunotherapy with immune checkpoint inhibitors represents a promising therapeutic strategy. However, the prevalence of dMMR tumors in type II EC patients remains unclear. In this study, using immunohistochemistry, we evaluated the expression of mismatch repair (MMR) proteins, tumor-infiltrating lymphocytes (CD8+), and immune checkpoint molecules (PD-L1) in 60 patients with type II EC (16, 5, 17, and 22 were endometrioid G3, serous, de-differentiated, and carcinosarcoma cases, respectively) to investigate the therapeutic effect of immune checkpoint inhibitors. Approximately 24 cases (40%) had a loss of MMR protein expression. The positivity rate of CD8+ (p = 0.0072) and PD-L1 (p = 0.0061) expression was significantly associated with the dMMR group. These results suggest immune checkpoint inhibitors (anti-PD-L1/PD-1 antibodies) could effectively treat type II EC with dMMR. The presence of dMMR might be a biomarker for a positive response to PD-1/PD-L1 immunotherapy in type II EC.

Identifying the Carcinogenic Mechanism of Malignant Struma Ovarii Using Whole-Exome Sequencing and DNA Methylation Analysis.

BACKGROUND: Since malignant struma ovarii is a very rare disease, its carcinogenic mechanism has not been elucidated. Here, we sought to identify the genetic lesions that may have led to the carcinogenesis of a rare case of malignant struma ovarii (follicular carcinoma) with peritoneal dissemination. METHODS: DNA was extracted from the paraffin-embedded sections of normal uterine tissues and malignant struma ovarii for genetic analysis. Whole-exome sequencing and DNA methylation analysis were then performed. RESULTS: Germline variants of RECQL4, CNTNAP2, and PRDM2, which are tumor-suppressor genes, were detected by whole-exome sequencing. Somatic uniparental disomy (UPD) was also observed in these three genes. Additionally, the methylation of FRMD6-AS2, SESN3, CYTL1, MIR4429, HIF3A, and ATP1B2, which are associated with tumor growth suppression, was detected by DNA methylation analysis. CONCLUSIONS: Somatic UPD and DNA methylation in tumor suppressor genes may be associated with the pathogenesis of malignant struma ovarii. To our knowledge, this is the first report of whole-exome sequencing and DNA methylation analysis in malignant struma ovarii. Genetic and DNA methylation analysis may help elucidate the mechanism of carcinogenesis in rare diseases and guide treatment decisions.

Frequent PIK3CA mutation in normal endometrial gland drives spheroid formation and may be involved in stem cell propagation.

Recent studies reported the presence of oncogenic mutations in normal endometrial glands, but the biological significance remains unclear. The present study investigated the status of KRAS/PIK3CA driver mutations in normal endometrial glands as well as spheroids derived from single glands. The normal endometria of surgically removed uteri (n = 3) were divided into nine regions, and 40 endometrial single glands were isolated from each region. The DNAs of 10 glands in each region were extracted and subjected to Sanger sequencing for KRAS or PIK3CA driver mutations, while the remaining 30 glands were conferred to a long-term spheroid culture, followed by Sanger sequencing. Immunohistochemical analyses of stem cell (Axin2, ALDH1A1, SOX9) markers were undertaken for spheroids. Sanger sequencing successfully detected oncogenic mutations of KRAS or PIK3CA in a single gland. Twenty-five of the 270 glands (9.3%) had mutations in either KRAS or PIK3CA, and the mutation frequency in each endometrial region varied from 0% to 50%. The droplet digital PCR showed high mutation allele frequency (MAF) of PIK3CA mutation, suggestive of clonal expansion of mutated cells within a gland. Over 60% of the collected spheroids had PIK3CA mutations, but no KRAS mutations were detected. Immunohistochemically, spheroids were mainly composed of cells with stem cell marker expressions. High MAF of PIK3CA mutation in a single gland as well as frequent PIK3CA mutation in stem cell-rich spheroids that originated from a single gland suggest the role of PIK3CA mutation in stem cell propagation. This information could improve our understanding of endometrial physiology as well as stem cell-oriented endometrial regeneration and carcinogenesis.

Functions of neuronal Synaptobrevin in the post-Golgi transport of Rhodopsin in Drosophila photoreceptors.

Polarized transport is essential for constructing multiple plasma membrane domains in the cell. Drosophila photoreceptors are an excellent model system to study the mechanisms of polarized transport. Rab11 is the key factor regulating the post-Golgi transport of rhodopsin 1 (Rh1; also known as NinaE), a photoreceptive protein, to the rhabdomere, a photoreceptive plasma membrane. Here, we found that neuronal Synaptobrevin (nSyb) colocalizes with Rab11 on the trans-side of Golgi stacks and post-Golgi vesicles at the rhabdomere base, and nSyb deficiency impairs rhabdomeric transport and induces accumulation of Rh1 and vesicles in the cytoplasm; this is similar to the effects of Rab11 loss. These results indicate that nSyb acts as a post-Golgi SNARE toward rhabdomeres. Surprisingly, in Rab11-, Rip11- and nSyb-deficient photoreceptors, illumination enhances cytoplasmic accumulation of Rh1, which colocalizes with Rab11, Rabenosyn5, nSyb and Arrestin 1 (Arr1). Arr1 loss, but not Rab5 dominant negative (Rab5DN) protein expression, inhibits the light-enhanced cytoplasmic Rh1 accumulation. Rab5DN inhibits the generation of Rh1-containing multivesicular bodies rather than Rh1 internalization. Overall, these results indicate that exocytic Rh1 mingles with endocytosed Rh1 and is then transported together to rhabdomeres.

Reduction of Cardiovascular Events and Related Healthcare Expenditures through Achieving Population-Level Targets of Dietary Salt Intake in Japan: A Simulation Model Based on the National Health and Nutrition Survey.

Reducing population dietary salt intake is expected to help prevent cardiovascular disease and thus constrain increasing national healthcare expenditures in Japan's super-aged society. We aimed to estimate the impact of achieving global and national salt-reduction targets (8, <6, and <5 grams/day) on cardiovascular events and national healthcare spending in Japan. Using published data including mean salt intake and systolic blood pressure from the 2019 National Health and Nutrition Survey, we developed a Markov model of a closed cohort of adults aged 40−79 years in 2019 (n = 66,955,000) transitioning among six health states based on the disease course of ischemic heart disease (IHD) and stroke. If mean salt intake were to remain at 2019 levels over 10 years, cumulative incident cases in the cohort would be approximately 2.0 million for IHD and 2.6 million for stroke, costing USD 61.6 billion for IHD and USD 104.6 billion for stroke. Compared with the status quo, reducing mean salt intake towards the targets over 10 years would avert 1−3% of IHD and stroke events and save up to 2% of related national healthcare costs. Attaining dietary salt-reduction goals among adults would yield moderate health economic benefits in Japan.

Effects of a rework program in a university hospital and predictors of work restoration and maintenance in the participants.

During sickness absence, it appears necessary for psychiatric patients suffering from depression or bipolar disorder to undergo a psychiatric rehabilitation called the rework program that aids in work restoration and maintenance. However, few studies have investigated the effects of such a program and predictors of work restoration and maintenance in the participants. Here, we aimed to investigate the effects of a rework program as well as to examine whether cognitive function and mental state at the end of the rework program predict the probability of work restoration and maintenance and whether the frequency of rework program participation predicts successful work restoration and maintenance. The rework program included both patients absent from work and unemployed patients. Patients completed assessments including Trail Making Test Type B (TMT-B), the Wisconsin Card Sorting Test, and the Social Adaptation Self-Evaluation Scale just before graduating from the rework program. Simultaneously, their depressive state was assessed using the Hamilton Depression Rating scale. The patients were divided into the job group, comprising 94 patients who were able to restore their work or get a new job, and the non-job group, comprising 34 patients who were not able to do so. We found that the program was more effective in patients absent from work than in unemployed patients, TMT-B could predict work restoration and maintenance, and the frequency of rework program participation could predict work restoration but not work maintenance. Based on the findings, we propose "Yamashita's criterion" where a TMT-B completion time of 70 s is the cut-off point for work restoration. The present findings may provide useful evidence that could aid in the further development of rework program(s).

Promising Therapeutic Impact of a Selective Estrogen Receptor Downregulator, Fulvestrant, as Demonstrated In Vitro upon Low-Grade Serous Ovarian Carcinoma Cell Lines.

Few studies have reported hormonal agent use in the treatment of low-grade serous ovarian carcinomas (LGSOCs), which are chemoresistant. Considering the need for novel effective therapies, we investigated the hormone receptor expression and hormonal inhibition efficacy in LGSOCs. Using immunohistochemistry, we assessed the estrogen receptor (ER) expression status in 33 cases of histologically confirmed serous ovarian tumors, including 10, 11, and 12 cases of LGSOCs, serous borderline tumors (SBTs), and serous cystadenomas (SCAs), respectively. The genetic background reported in our previous study was used in the current study. MPSC1 cells, which were established from LGSOCs, were used in cell proliferation assays. We observed a higher ER expression in LGSOCs and SBTs than in SCAs (70%, 81%, and 50%, respectively). Thus, LGSOCs and SBTs exhibit higher ER expression than SCAs. Moreover, the PIK3CA mutation positively correlated with ER expression in LGSOCs (p = 0.0113). MPSC1 cells showed low ER expression on Western blotting. MPSC1 cell proliferation was significantly inhibited by fulvestrant (a selective ER downregulator). The activation of ER and PI3K/AKT signaling pathways may play an important role in LGSOC carcinogenesis. ER downregulation with fulvestrant or combination therapy with PI3K inhibitors is a possible novel treatment for patients with LGSOCs.

Stratum is required for both apical and basolateral transport through stable expression of Rab10 and Rab35 in Drosophila photoreceptors.

Post-Golgi transport for specific membrane domains, also termed polarized transport, is essential for the construction and maintenance of polarized cells. Highly polarized Drosophila photoreceptors serve as a good model system for studying the mechanisms underlying polarized transport. The Mss4 Drosophila ortholog, Stratum (Strat), controls basal restriction of basement membrane proteins in follicle cells, and Rab8 acts downstream of Strat. We investigated the function of Strat in fly photoreceptors and found that polarized transport in both the basolateral and the rhabdomere membrane domains was inhibited in Strat-deficient photoreceptors. We also observed 79 and 55% reductions in Rab10 and Rab35 levels, respectively, but no reduction in Rab11 levels in whole-eye homozygous clones of Stratnull. Moreover, Rab35 was localized in the rhabdomere, and loss of Rab35 resulted in impaired Rh1 transport to the rhabdomere. These results indicate that Strat is essential for the stable expression of Rab10 and Rab35, which regulate basolateral and rhabdomere transport, respectively, in fly photoreceptors.

Clinical Landscape of PARP Inhibitors in Ovarian Cancer: Molecular Mechanisms and Clues to Overcome Resistance.

The survival of patients with advanced or recurrent ovarian cancer has improved tremendously in the past decade, mainly due to the establishment of maintenance therapy with poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis) after conservative chemotherapies. Despite their superior efficacy, resistance to PARPis has been reported, and patients with resistance have a much worse prognosis. Therefore, the development of novel treatment strategies to overcome PARPi resistance is urgently needed. The present review article focuses on the molecular mechanisms of how PARPis exert cytotoxic effects on cancer cells through DNA repair processes, especially the genetic background and tumor microenvironment favored by PARPis. Furthermore, currently available information on PARPi resistance mechanisms is introduced and discussed to develop a novel therapeutic approach against them.

Mutation Profiles of Ovarian Seromucinous Borderline Tumors in Japanese Patients.

Ovarian seromucinous tumors (SMBTs) are relatively rare, and their carcinogenesis is largely unknown. In this study, the molecular features of SMBTs in Japan are assessed. DNA was extracted from microdissected paraffin-embedded sections from 23 SMBT cases. Genetic mutations (KRAS, BRAF, PIK3CA, and ERBB2) were evaluated using Sanger sequencing. Immunohistochemistry for p53, ARID1A, and PTEN was also performed as a surrogate for the loss of functional mutations in these tumor suppressor genes. The prevalence of KRAS, BRAF, PIK3CA, and ERBB2 mutations was 4.3% (1/23), 8.6% (2/23), 8.6% (2/23), and 17.3% (4/23), respectively. Overexpression or loss of p53 expression occurred in 26% (6/23), loss of ARID1A expression in 4.3% (1/23), and none of the cases showed expression of PTEN loss. These findings suggest that KRAS/BRAF/PIK3CA and PTEN mutations are rare carcinogenic events in SMBTs. The high frequency of positive p53 staining and a low frequency of loss of ARID1A staining suggests that SMBT carcinogenesis may be related to the alteration of p53 rather than that of ARID1A. ERBB2 oncogenic mutations may play an important role in the tumorigenesis of Japanese SMBTs.

Ovarian Endometrioid and Clear Cell Carcinomas with Low Prevalence of Microsatellite Instability: A Unique Subset of Ovarian Carcinomas Could Benefit from Combination Therapy with Immune Checkpoint Inhibitors and Other Anticancer Agents.

Ovarian cancer has the highest mortality rate among all gynecological malignancies; therefore, a novel treatment strategy is needed urgently. Utilizing immune checkpoint inhibitors has been considered for microsatellite instability (MSI)-high (MSI-H) tumors. However, the prevalence of MSI-H tumors in ovarian endometrioid and clear cell carcinomas remains unclear. Here, polymerase chain reaction was used to analyze 91 cases of ovarian endometrioid and clear cell carcinomas for the MSI status and the relationship between MSI-H, immune checkpoint molecules, and clinicopathological factors (including patient survival). Only 5 of 91 (5%) cases were MSI-H endometrioid carcinomas. In these cases, CD-8 expression was significantly higher (p = 0.026), confirming an enhanced immune response. From the survival curve, no statistical correlations were found between the MSI-H group and the microsatellite stable (MSS) group; however, the MSS group trended towards better progression-free survival than the MSI-H group (p = 0.056). Patients with PD-L1 expression had shorter overall survival than those without (p = 0.022). Thus, MSI-H is a rare event and not a favorable prognostic factor in ovarian endometrioid and clear cell carcinomas. Thus, to improve the prognosis of ovarian endometrioid carcinoma and clear cell carcinomas, a combination therapy of immune checkpoint inhibitors and other molecular targeted therapies may be required.

Development of Low-Grade Serous Ovarian Carcinoma from Benign Ovarian Serous Cystadenoma Cells.

Despite the knowledge about numerous genetic mutations essential for the progression of low-grade serous ovarian carcinoma (LGSOC), the specific combination of mutations required remains unclear. Here, we aimed to recognize the oncogenic mutations responsible for the stepwise development of LGSOC using immortalized HOVs-cyst-1 cells, developed from ovarian serous cystadenoma cells, and immortalized via cyclin D1, CDK4R24C, and hTERT gene transfection. Furthermore, oncogenic mutations, KRAS and PIK3CA, were individually and simultaneously introduced in immortalized HOV-cyst-1 cells. Cell functions were subsequently analyzed via in vitro assays. KRAS or PIK3CA double mutant HOV-cyst-1 cells exhibited higher cell proliferation and migration capacity than the wild-type cells, or those with either a KRAS or a PIK3CA mutation, indicating that these mutations play a causative role in LGSOC tumorigenesis. Moreover, KRAS and PIK3CA double mutants gained tumorigenic potential in nude mice, whereas the cells with a single mutant exhibited no signs of tumorigenicity. Furthermore, the transformation of HOV-cyst-1 cells with KRAS and PIK3CA mutants resulted in the development of tumors that were grossly and histologically similar to human LGSOCs. These findings suggest that simultaneous activation of the KRAS/ERK and PIK3CA/AKT signaling pathways is essential for LGSOC development.

Clinical Outcomes of Genotype-Matched Therapy for Recurrent Gynecological Cancers: A Single Institutional Experience.

Recent advances in next-generation sequencing and genome medicine have contributed to treatment decisions in patients with cancer. Most advanced gynecological cancers develop resistance to chemotherapy and have a poor prognosis. Therefore, we conducted genomic tests in gynecological tumors to examine the efficacy and clinical feasibility of genotype-matched therapy. Target sequencing was performed in 20 cases of gynecological cancers (cervical cancer, 6; endometrial cancer, 6; and ovarian cancer, 6). Both actionable and druggable genes were identified in 95% (19/20) of the cases. Among them, seven patients (35%) received genotype-matched therapy, which was effective in three patients. Of the three patients, one patient with a PTEN mutation received everolimus, another patient with a TSC2 mutation received everolimus and letrozole, and the patient with a BRIP1 mutation received olaparib. Subsequently, disease control in these three patients lasted for more than half a year. However, all patients relapsed between 9 and 13 months after the initiation of genotype-matched therapy. In this study, the response rate of genotype-matched therapy was 43% (3/7), which may have contributed to improved prognoses. Therefore, genotype-matched therapies may help patients with refractory gynecological cancers achieve better outcomes.

Underdiagnosis of early cervical cancer with an invisible cervical transformation zone in an elderly patient: A case report.

The treatment of cervical intraepithelial neoplasia (CIN) can result in under- or overtreatment. The current report describes a case of undertreatment of a cervical tumor. A 72-year-old woman was preoperatively diagnosed with CIN3. Following surgery, the final diagnosis of the excised specimen was keratinizing squamous cell carcinoma that measured 2.5 cm in size. The exocervical margin and deep margin were negative. The patient received adjuvant therapy with concurrent chemoradiotherapy and never had disease recurrence. In elderly patients, making an accurate preoperative diagnosis based on specimens from cervical biopsies with or without colposcopy is difficult. MRI may be an accurate preoperative indicator of early cervical tumor, although some studies have demonstrated that MRI has a limitation with respect to its diagnostic ability. Other studies have reported that it is necessary to perform conization prior to hysterectomy. Physicians must reconsider the determined preoperative diagnosis of an early cervical tumor and establish standard guidelines for deciding when to use surgical treatment in elderly patients.

P16INK4A expression might be associated with a favorable prognosis for cervical adenocarcinoma via dysregulation of the RB pathway.

Previous studies have largely failed to clarify the relationship between p16INK4A status and cervical adenocarcinoma prognosis. The current study aimed to examine the clinical and pathological significance of p16INK4A expression in several cervical adenocarcinoma subtypes. Eighty-two samples collected from patients with cervical adenocarcinoma were formalin fixed and paraffin embedded. Next, p16INK4A levels were analyzed with immunohistochemistry. Additionally, the relationship between p16INK4A expression and clinicopathological factors as well as prognosis was evaluated. The expression of p16INK4A was mostly detected in all usual cervical adenocarcinoma subtypes. In the gastric type, only a few cases were positive for p16INK4A expression. Results of the Kaplan-Meier analysis indicated that the positive p16INK4A expression in tumor cells was significantly associated with favorable progression-free survival and overall survival in patients with cervical adenocarcinoma (p = 0.018 and p = 0.047, respectively, log-rank test). Our findings suggest that the status of p16INK4A expression may influence prognosis. Thus, p16INK4A expression could be used as a biomarker for improving the prognosis of patients with cervical adenocarcinoma.