Clinical Significance of Serum SCC Levels Before Treatment for Locally Advanced Cervical Squamous Cell Carcinoma.

BACKGROUND/AIM: Although serum squamous cell carcinoma (SCC) antigen values are known to be useful in predicting the prognosis of cervical SCC, they have only been examined in a cursory manner. This study aimed to meticulously investigate the clinical significance of serum SCC antigen levels in patients with locally advanced cervical squamous cell carcinoma (LACSC). PATIENTS AND METHODS: The study included patients who were diagnosed with local stage (T-stage) 1b3/2/3 LACSC and underwent initial treatment at our institute between January 2006 and December 2016 (T-1b3: n=30; T-2: n=75; T-3: n=34). The patients were divided into three groups based on pre-treatment SCC values, and differences in clinical background, laboratory and pathology findings, and prognosis were examined. RESULTS: No significant difference in the SCC distribution was observed among the T-1b3/2/3 cases with elevated SCC levels. In stages T-1b3, T-2, and T-3, most recurrences in the SCC-High group were distant (T-1b3: three out of five recurrences; T-2: six out of seven recurrences; T-3: four out of eight recurrences), while most recurrences in the SCC-Low group were pelvic (T-1b3: two out of three recurrences; T-2: eight out of eight recurrences; T-3: three out of three recurrences). CONCLUSION: In LACSC, serum SCC antigen levels before treatment correlate strongly with the recurrence site. Patients with low levels should be closely monitored for local recurrence, whereas those with high levels warrant vigilance for distant recurrence.

Successful correction of the transverse vaginal septum with a pinhole vaginal foramen using Y-V plasty: A case report.

The transverse vaginal septum, a rare Müllerian duct anomaly, presents diagnostic and therapeutic challenges owing to its variable location, thickness, and potential association with uterine malformations. Therefore, an accurate diagnosis and selection of an appropriate treatment are important. Herein, the case of a 28-year-old nonpregnant woman with sexual dysfunction attributable to a transverse vaginal septum is presented. The septum, approximately 5 mm thick, was situated low on the vaginal wall near the urethral opening, with a small central aperture. Employing Y-V plasty, full extension of the posterior and lateral vaginal walls was achieved while minimizing the manipulation of the anterior wall to avoid urethral injury. Postoperatively, the patient achieved sexual function without vaginal stenosis. Y-V plasty is a minimally invasive and effective approach for preventing postoperative stenosis in the treatment of a thin transverse vaginal septum located low on the vaginal wall.

Clinical significance of initial symptoms in endometriosis-associated ovarian cancer.

Objective: Endometriosis is associated with various symptoms, but their severity varies from case to case. In this study, we investigated the reality of symptoms presented by patients with clinically early-stage endometriosis-associated ovarian cancer (EAOC) and explored the relationship between symptoms and laboratory/imaging findings, pathological findings, and prognosis. Materials and Methods: This was a retrospective case-control study of patients who received initial surgical treatment and were diagnosed with clinically early-stage EAOC, including ovarian endometrioid carcinoma (OEC), ovarian clear cell carcinoma (OCCC), and seromucinous borderline tumor (SMBT). Patients with OEC/OCCC diagnosed between 2006 and 2016 and those with SMBT diagnosed between 2006 and 2020 were included. Chi-square and Kaplan-Meier estimates were used for statistical analyses. Results: One hundred-seven patients (OEC, n=31; OCCC, n=39; SMBT, n=37) were included. Fifty-nine (55.1%) patients presented with symptoms, and the proportion of patients with OEC who presented with symptoms was significantly higher than that of others (OEC, 77.4%; OCCC, 43.6%; SMBT, 48.6%). The details of symptoms differed significantly among the pathological types (lower abdominal pain/abdominal discomfort/abnormal bleeding, OEC: 11/8/9; OCCC: 6/12/1; SMBT: 15/5/3). Only in the OEC group did symptomatic patients show significantly higher white blood cell (WBC) count and neutrophil/lymphocyte (N/L) ratio (symptomatic vs. asymptomatic, median: WBC count: 7250 vs. 5000, p=0.008; N/L ratio: 4.6 vs. 1.7, p=0.013). None of the asymptomatic patients showed recurrence during follow-up. Conclusion: Patients with EAOC show varying symptoms depending on the histological type of the tumor. Laboratory findings underlying symptoms also vary by histopathological type, which may reflect differences in the carcinogenesis process.

A Deep Learning-Based Assessment Pipeline for Intraepithelial and Stromal Tumor-Infiltrating Lymphocytes in High-Grade Serous Ovarian Carcinoma.

Tumor-infiltrating lymphocytes (TILs) are associated with improved survival in patients with epithelial ovarian cancer. However, the evaluation of TILs has not been applied to routine clinical practice because of reproducibility issues. We developed two convolutional neural network models to detect TILs and to determine their spatial location in whole slide images, and established a spatial assessment pipeline to objectively quantify intraepithelial and stromal TILs in patients with high-grade serous ovarian carcinoma. The predictions of the established models showed a significant positive correlation with the number of CD8+ T cells and immune gene expressions. We demonstrated that patients with a higher density of intraepithelial TILs had a significantly prolonged overall survival and progression-free survival in multiple cohorts. On the basis of the density of intraepithelial and stromal TILs, we classified patients into three immunophenotypes: immune inflamed, excluded, and desert. The immune-desert subgroup showed the worst prognosis. Gene expression analysis showed that the immune-desert subgroup had lower immune cytolytic activity and T-cell-inflamed gene-expression profile scores, whereas the immune-excluded subgroup had higher expression of interferon-γ and programmed death 1 receptor signaling pathway. Our established evaluation method provides detailed and comprehensive quantification of intraepithelial and stromal TILs throughout hematoxylin and eosin-stained slides, and has potential for clinical application for personalized treatment of patients with ovarian cancer.

Neuroendocrine carcinoma of the uterine cervix with extensive pagetoid spread pattern.

There have been no reported cases of neuroendocrine carcinoma (NEC) of the cervix with pagetoid spread (Pag-S). A 44-year-old woman came to our department because of abnormal cytology that persisted immediately after a radical hysterectomy for NEC of the cervix. A mapping biopsy in a large area from the vaginal wall to the vulva revealed that synaptophysin/Ki-67-positive tumor cells were scattered within the epithelium in multiple areas, suggesting a wide Pag-S of NEC. Because tumor cells were found beyond the vaginal wall, the anterior pelvic exenteration was performed. Since we could pathologically confirm the complete resection and no distant metastases were detected, no adjuvant therapy was performed. Four years have passed since the initial treatment without any tumor recurrence. It is known that the prognosis of NEC of the cervix that invades beyond the cervix is poor; however, if there is a Pag-S pattern, a radical surgical treatment can be considered.

Investigation of the Effect of Puncture Order and Position on the Difficulty of Lower and Middle Abdominal Port Placement.

Objectives: Port placements at the mid-abdomen (mainstay of robotic surgery [Rob]) appear to be difficult compared to that at lower abdomen (mainstay of conventional laparoscopy [Con-Lap]). We hypothesized that the reason for this may be the difference in port puncture places. Materials and Methods: We examined how the differences between the place and puncture order of ports affected Con-Lap cases with ports mainly placed in the lower abdomen and Rob cases with ports mainly placed in the middle abdomen. The trocar time was measured from the time when the puncture position and skin incision were determined and initiated, respectively, to the time when the port was punctured and fixed and used as the indicator of difficulty. Results: In the Con-Lap group analysis, the trocar time of the left lower port was longer (right lower: 77 s, middle lower: 117.5 s, and left lower: 138 s, P < 0.0001). In the Rob group analysis, the trocar time of the left most port was significantly longer (right-most: 89.0 s, right-middle: 92.5 s, left-middle: 121.0 s, and left-most: 197.0 s; P < 0.0001). In addition, the total trocar time was significantly longer in the first puncture at the right-middle port in the Rob group (right-most first: 8.4 min, right-middle first: 12.4 min, and left-middle first: 8.5 min, P = 0.0063). Conclusion: In the mid-abdomen port placement, mainstay of Rob cases, the puncture order, and port site have a significant impact on the difficulty of the procedure. It is preferable to avoid initially puncturing the right-middle port in case of the Rob.

Nodal infiltration in endometrial cancer: a prediction model using best subset regression.

OBJECTIVES: To build preoperative prediction models with and without MRI for regional lymph node metastasis (r-LNM, pelvic and/or para-aortic LNM (PENM/PANM)) and for PANM in endometrial cancer using established risk factors. METHODS: In this retrospective two-center study, 364 patients with endometrial cancer were included: 253 in the model development and 111 in the external validation. For r-LNM and PANM, respectively, best subset regression with ten-time fivefold cross validation was conducted using ten established risk factors (4 clinical and 6 imaging factors). Models with the top 10 percentile of area under the curve (AUC) and with the fewest variables in the model development were subjected to the external validation (11 and 4 candidates, respectively, for r-LNM and PANM). Then, the models with the highest AUC were selected as the final models. Models without MRI findings were developed similarly, assuming the cases where MRI was not available. RESULTS: The final r-LNM model consisted of pelvic lymph node (PEN) ≥ 6 mm, deep myometrial invasion (DMI) on MRI, CA125, para-aortic lymph node (PAN) ≥ 6 mm, and biopsy; PANM model consisted of DMI, PAN, PEN, and CA125 (in order of correlation coefficient ß values). The AUCs were 0.85 (95%CI: 0.77-0.92) and 0.86 (0.75-0.94) for the external validation, respectively. The model without MRI for r-LNM and PANM showed AUC of 0.79 (0.68-0.89) and 0.87 (0.76-0.96), respectively. CONCLUSIONS: The prediction models created by best subset regression with cross validation showed high diagnostic performance for predicting LNM in endometrial cancer, which may avoid unnecessary lymphadenectomies. CLINICAL RELEVANCE STATEMENT: The prediction risks of lymph node metastasis (LNM) and para-aortic LNM can be easily obtained for all patients with endometrial cancer by inputting the conventional clinical information into our models. They help in the decision-making for optimal lymphadenectomy and personalized treatment. KEY POINTS: •Diagnostic performance of lymph node metastases (LNM) in endometrial cancer is low based on size criteria and can be improved by combining with other clinical information. •The optimized logistic regression model for regional LNM consists of lymph node ≥ 6 mm, deep myometrial invasion, cancer antigen-125, and biopsy, showing high diagnostic performance. •Our model predicts the preoperative risk of LNM, which may avoid unnecessary lymphadenectomies.

Clinical impact of age­specific distribution of combination patterns of cytology and high­risk HPV status on cervical intraepithelial neoplasia grade 2 or more.

To the best of our knowledge, the present study is the first to elucidate the significance of cytology and high-risk human papillomavirus (hrHPV) status in different age groups for the detection of cervical intraepithelial neoplasia (CIN)2, CIN3 and squamous cell carcinoma (SCC). There were 12 combinations based on cytology and hrHPV status [cytology: Atypical squamous cells (ASC) of undetermined significance, low-grade squamous intraepithelial lesion, ASC not excluding high-grade squamous intraepithelial lesion (HSIL) and HSIL; hrHPV status: HPV16/18-positive (16/18+), hrHPV positive for subtypes other than 16/18 (others+) and hrHPV-negative (hrHPV-)]. All patients were categorized into four groups based on age (18-29, 30-39, 40-49 and ≥50 years). For patients with CIN2, CIN3 and SCC (CIN2+) (n=107), the distribution of cytology and hrHPV was investigated in each age group. In addition, for all patients (n=446), the occurrence of CIN2+ in each of the 12 combinations was investigated in each age group. In the 18-29-year age group, the most common combination was HSIL and 16/18+, followed by HSIL and others+, which accounted for 73% of CIN2+ cases. The occurrence of HSIL and 16/18+ decreased with increasing age, and no cases occurred in the 50-year age group. In the 18-29-year age group, all patients with HSIL and 16/18+ were diagnosed with CIN2+. CIN2+ was predominantly detected in patients with HSIL in the 18-29-year age group, as well as hrHPV- and others+. This definite distinction was not observed in any other age group. For CIN2+, the distribution patterns of cytology and hrHPV status combinations varied significantly among different age groups. Accordingly, the clinical impact of the combination of cytological findings and hrHPV status can vary among age groups.

Imiquimod for Cervical and Vaginal Intraepithelial Neoplasia: A Systematic Review and Meta-analysis.

OBJECTIVE: To evaluate the treatment efficacy and the risk of adverse events of imiquimod for cervical intraepithelial neoplasia (CIN) and vaginal intraepithelial neoplasia (VAIN), compared with placebo or no intervention. DATA SOURCES: We searched Cochrane, PubMed, ISRCTN registry, ClinicalTrials.gov , and the World Health Organization International Clinical Trials Registry Platform up to November 23, 2022. METHODS OF STUDY SELECTION: We included randomized controlled trials and prospective nonrandomized studies with control arms that investigated the efficacy of imiquimod for histologically confirmed CIN or VAIN. The primary outcomes were histologic regression of the disease (primary efficacy outcome) and treatment discontinuation due to side effects (primary safety outcome). We estimated pooled odds ratios (ORs) of imiquimod, compared with placebo or no intervention. We also conducted a meta-analysis of the proportions of patients with adverse events in the imiquimod arms. TABULATION, INTEGRATION, AND RESULTS: Four studies contributed to the pooled OR for the primary efficacy outcome. An additional four studies were available for meta-analyses of proportions in the imiquimod arm. Imiquimod was associated with increased probability of regression (pooled OR 4.05, 95% CI 2.08-7.89). Pooled OR for CIN in the three studies was 4.27 (95% CI 2.11-8.66); results of one study were available for VAIN (OR, 2.67, 95% CI 0.36-19.71). Pooled probability for primary safety outcome in the imiquimod arm was 0.07 (95% CI 0.03-0.14). The pooled probabilities (95% CI) of secondary outcomes were 0.51 (0.20-0.81) for fever, 0.53 (0.31-0.73) for arthralgia or myalgia, 0.31 (0.18-0.47) for abdominal pain, 0.28 (0.09-0.61) for abnormal vaginal discharge or genital bleeding, 0.48 (0.16-0.82) for vulvovaginal pain, and 0.02 (0.01-0.06) for vaginal ulceration. CONCLUSION: Imiquimod was found to be effective for CIN, whereas data on VAIN were limited. Although local and systemic complications are common, treatment discontinuation is infrequent. Thus, imiquimod is potentially an alternative therapy to surgery for CIN. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42022377982.

High-grade vaginal intraepithelial neoplasia after hysterectomy for high-grade cervical intraepithelial neoplasia: Is hysterectomy a "definitive" treatment compared to conization?

AIM: We investigated the frequency of early recurrence of vaginal intraepithelial neoplasia grade 2/3 (VaIN 2/3) (within 2 years) after hysterectomy for cervical intraepithelial neoplasia grade 3 (CIN3). The characteristics of the clinicopathological factors common to them were explored including different surgical methods. METHODS: As a retrospective observational study, a total of 647 CIN3 patients were divided into a conization and hysterectomy group (C group, n = 492; H group, n = 155), and HSIL (CIN2/3 or VaIN2/3) recurrence within 2 years after surgery was evaluated. A stratified analyses was performed. Surgical methods were divided into trans-abdominal, trans-vaginal, and laparoscopic. RESULTS: The recurrence of VaIN3 was detected in four cases (2.6%) in the H group, which was similar to that of CIN2/3 in the C group, 12 out of 491 patients (2.4%). The patients who developed VaIN3 were significantly older than those who did not (median, VaIN3: 71.0; VaIN1 and less: 48.0; p < 0.0001). All VaIN3 cases were detected within 5 months, although majority of cases were negative in the margin (3/4 cases; margin negative). The method of hysterectomy was not related to the VaIN3 recurrence. CONCLUSION: For CIN3 patients for whom hysterectomy is the main treatment, VaIN3 can develop in 2.6% within very shortly after operation even if surgical margin was negative. The elder the age, the higher the risk of early recurrence could be. Laparoscopic surgery is considered to be acceptable methods of hysterectomy.

A case of solitary lymph node recurrence 9 years after initial treatment for advanced premenopausal endometrioid endometrial cancer; clinical usefulness of hormonal replacement therapy.

There is no consensus on the use of hormone replacement therapy (HRT) after treatment of advanced corpus cancer. We report a case of advanced corpus cancer at a young age, in which HRT was initiated 7 years after surgery, and regional lymph node recurrence was later detected. The patient was 35 years old at the time of initial treatment in X year, when she was diagnosed with stageIIIC2 corpus cancer and underwent a hysterectomy with bilateral salpingo-oophorectomy and a retroperitoneal lymphadenectomy. HRT was started at X + 7 years, and at X + 9 years, a 25 × 12-mm-sized mass was found in the hilum of the right kidney. A laparoscopic resection revealed regional lymph node recurrence of the corpus cancer. A retrospective study further revealed that a tumor measuring 12 × 3 mm was found at X + 3 years and grew to 18 × 7 mm in X + 6 years, just before the start of the HRT. We hypothesize that HRT did not induce tumor recurrence; instead, it allowed for long-term follow-up and early diagnosis.

ATM mutation in aggressive uterine adenosarcoma in which systemic chemotherapies had remarkable effects.

Uterine adenosarcoma is a rare gynecologic malignancy, and 10-25% of the cases exhibit clinically aggressive behaviors. Although TP53 mutations are frequently identified in high-grade adenosarcomas of the uterus, definitive gene alterations have not been identified in uterine adenosarcomas. Specifically, no reports have described mutations in homologous recombination deficiency-related genes in uterine adenosarcomas. This study presents a case of uterine adenosarcoma without sarcomatous overgrowth but with TP53 mutation that exhibited clinically aggressive behaviors. The patient had an ATM mutation, which is a gene associated with homologous recombination deficiency, and exhibited a good response against platinum-based chemotherapy and possible therapeutic target by poly(ADP-ribose) polymerase inhibitors.

A case of paraovarian tumor of borderline malignancy with decrease of apparent diffusion coefficient value and marked 18F-fluorodeoxyglucose accumulation.

Para-ovarian cysts are occasionally encountered in clinical practice; however, malignant tumors derived from them are rare. Due to its rarity, the characteristic imaging findings of para-ovarian tumors with borderline malignancy (PTBM) are largely unknown. Herein, we report a case of PTBM, along with imaging findings. A 37-year-old woman came to our department with a suspected malignant adnexal tumor. Pelvic contrast-enhanced magnetic resonance imaging (MRI) revealed a solid part within the cystic tumor with a decrease in the apparent diffusion coefficient (ADC) value (1.16 × 10-3 mm2/s). We also performed Positron Emission Tomography-MRI and showed a strong accumulation of 18F-fluorodeoxyglucose (FDG) in the solid part (SUVmax = 14.8). In addition, the tumor appeared to develop independently of the ovary. Because tumor was derived from para-ovarian cyst, we suspected PTBM preoperatively and planned fertility sparing treatment. Pathological examination revealed a serous borderline tumor and PTBM was confirmed. PTBM can have unique imaging characteristics, including a low ADC value and high FDG accumulation. When a tumor appears to develop from para-ovarian cysts, borderline malignancy can be suspected, even if imaging findings suggest malignant potential.

Nivolumab for malignant transformation of ovarian mature cystic teratoma.

Mature cystic teratoma of the ovary (MCT) occasionally undergoes malignant transformation (MT) that is resistant to chemotherapy and has a poor prognosis. We experienced a case of clinically aggressive MCT-MT that invades surrounding organs and tissues. Although tumor was resected entirely, a rapid tumor recurrence occurred during postoperative chemotherapy (paclitaxel + ifosfamide + cisplatin). The results of comprehensive genomic profiling test performed early in the postoperative period showed a high tumor mutational burden of 23 mutations/Mb. Treatment with nivolumab monotherapy has promptly been initiated and has been very successful for more than one year.

Peritoneal dissemination of high-grade serous ovarian cancer: pivotal roles of chromosomal instability and epigenetic dynamics.

Epithelial ovarian cancer remains the lethal gynecological malignancy in women. The representative histotype is high-grade serous carcinoma (HGSC), and most patients with HGSC present at advanced stages with peritoneal dissemination. Since the peritoneal dissemination is the most important factor for poor prognosis of the patients, complete exploration for its molecular mechanisms is mandatory. In this narrative review, being based on the clinical, pathologic, and genomic findings of HGSC, chromosomal instability and epigenetic dynamics have been discussed as the potential drivers for cancer development in the fallopian tube, acquisition of cancer stem cell (CSC)-like properties, and peritoneal metastasis of HGSC. The natural history of carcinogenesis with clonal evolution, and adaptation to microenvironment of peritoneal dissemination of HGSC should be targeted in the novel development of strategies for prevention, early detection, and precision treatment for patients with HGSC.

Mutation burden-orthogonal tumor genomic subtypes delineate responses to immune checkpoint therapy.

BACKGROUND: In cancer therapy, higher-resolution tumor-agnostic biomarkers that predict response to immune checkpoint inhibitor (ICI) therapy are needed. Mutation signatures reflect underlying oncogenic processes that can affect tumor immunogenicity, and thus potentially delineate ICI treatment response among tumor types. METHODS: Based on mutational signature analysis, we developed a stratification for all solid tumors in The Cancer Genome Atlas (TCGA). Subsequently, we developed a new software (Genomic Subtyping and Predictive Response Analysis for Cancer Tumor ICi Efficacy, GS-PRACTICE) to classify new tumors submitted to whole-exome sequencing. Using existing data from 973 pan-cancer ICI-treated cases with outcomes, we evaluated the subtype-response predictive performance. RESULTS: Systematic analysis on TCGA samples identified eight tumor genomic subtypes, which were characterized by features represented by smoking exposure, ultraviolet light exposure, APOBEC enzyme activity, POLE mutation, mismatch repair deficiency, homologous recombination deficiency, genomic stability, and aging. The former five subtypes were presumed to form an immune-responsive group acting as candidates for ICI therapy because of their high expression of immune-related genes and enrichment in cancer types with FDA approval for ICI monotherapy. In the validation cohort, the samples assigned by GS-PRACTICE to the immune-reactive subtypes were significantly associated with ICI response independent of cancer type and TMB high or low status. CONCLUSIONS: The new tumor subtyping method can serve as a tumor-agnostic biomarker for ICI response prediction and will improve decision making in cancer treatment.

Development of healthy lifestyle consciousness index for gynecological cancer patients.

PURPOSE: Healthy lifestyle is related to quality of life (QOL) after cancer diagnosis and prognosis. However, there are few reports on patients conscious of healthy lifestyle and patients requiring medical providers' attention regarding healthy lifestyle. We aimed to develop a healthy lifestyle consciousness index (HLCI) for cancer patients and evaluated its validity in gynecological cancer patients. METHODS: The HLCI was designed to assess degree of healthy lifestyle consciousness, including items regarding "diet," "exercise," "body weight," and "sleep." Exploratory factor analysis was performed for dimensionality of the scale; Cronbach's alpha was calculated to assess internal-consistency reliability. For criterion-based validity, we calculated proportions of stage III/IV gynecological malignancies in those with categorized HLCI scores based on tertiles. Concurrent validity was evaluated between HLCI and other quality of life (QOL) scales including European Organization for Research and Treatment of Cancer QLQ-C30 in limited patients. RESULTS: HLCI comprised five 10-point items (0-45); higher values implied improved healthy lifestyle consciousness. Data from 108 gynecological malignancy patients at Kyoto University Hospital were analyzed. The mean age of subjects was 55.8 years; 36.1% of them had uterine corpus cancer; 34.3% were at stage III/IV of gynecological malignancy. The factor analysis revealed HLCI was unidimensional; the reliability based on Cronbach's alpha was satisfactory (0.88). The proportions of stage III/IV gynecological malignancies were 25.7%, 33.3%, and 44.4% in those with first (7-24 points), second (25-30 points), and third (31-46 points) tertiles of HLCI score, respectively. For patients with other QOL scales (n = 25), the mean scores of global health status of QLQ-C30 were 33.3, 50.0, and 83.3 for first, second, and third tertiles of HLCI score, respectively. CONCLUSION: HLCI was successfully validated; thus, patients with advanced stages or higher QOL might have strong consciousness regarding healthy lifestyle. HLCI may be useful in precision care for improved lifestyles and QOL.