Genetic and epigenetic alterations in precursor lesions of endometrial endometrioid carcinoma.

The hyperplasia-carcinoma sequence is a stepwise tumourigenic programme towards endometrial cancer in which normal endometrial epithelium becomes neoplastic through non-atypical endometrial hyperplasia (NAEH) and atypical endometrial hyperplasia (AEH), under the influence of unopposed oestrogen. NAEH and AEH are known to exhibit polyclonal and monoclonal cell growth, respectively; yet, aside from focal PTEN protein loss, the genetic and epigenetic alterations that occur during the cellular transition remain largely unknown. We sought to explore the potential molecular mechanisms that promote the NAEH-AEH transition and identify molecular markers that could help to differentiate between these two states. We conducted target-panel sequencing on the coding exons of 596 genes, including 96 endometrial cancer driver genes, and DNA methylome microarrays for 48 NAEH and 44 AEH lesions that were separately collected via macro- or micro-dissection from the endometrial tissues of 30 cases. Sequencing analyses revealed acquisition of the PTEN mutation and the clonal expansion of tumour cells in AEH samples. Further, across the transition, alterations to the DNA methylome were characterised by hypermethylation of promoter/enhancer regions and CpG islands, as well as hypo- and hyper-methylation of DNA-binding regions for transcription factors relevant to endometrial cell differentiation and/or tumourigenesis, including FOXA2, SOX17, and HAND2. The identified DNA methylation signature distinguishing NAEH and AEH lesions was reproducible in a validation cohort with modest discriminative capability. These findings not only support the concept that the transition from NAEH to AEH is an essential step within neoplastic cell transformation of endometrial epithelium but also provide deep insight into the molecular mechanism of the tumourigenic programme. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Preoperative diagnosis of cervical cystic lesions using magnetic resonance imaging: a retrospective study.

BACKGROUND: We conducted this study to clarify the magnetic resonance imaging (MRI) characteristics of lobular endocervical glandular hyperplasia (LEGH) and Nabothian cysts. METHODS: This study included 48 patients who underwent hysterectomy at our institution between 2016 and 2020 for suspected LEGH. Histopathological studies confirmed the presence of 25 Nabothian cysts and 23 cases of LEGH. We retrospectively analyzed five characteristic MRI findings: (1) located at the upper cervical canal, (2) positioned within the cervical stroma, (3) not circumscribing the cervical canal, (4) low- to iso-intensity on T1-weighted images (T1WI), and (5) "cosmos" or "microcystic" pattern. We compared the diagnostic accuracy of these findings for LEGH and Nabothian cysts using sensitivity, specificity, and predictive values. Combinations of findings were also calculated. RESULTS: The characteristics "cosmos" or "microcystic" pattern, lesion not circumscribing the cervical canal, and low/iso-intensity on T1WI had a sensitivity and specificity greater than 50%. The sensitivity was 73.9% and specificity 84.0% when a combination of "cosmos" or "microcystic" pattern and lesion not circumscribing the cervical canal was present. CONCLUSION: The coexistence of a "cosmos" or "microcystic" pattern and not circumscribing the cervical canal was the most characteristic finding that distinguished LEGH from Nabothian cysts. When neither of these findings is present, Nabothian cyst can be suspected.

Incidence and Prognostic Value of Lavage Cytology in Colorectal Cancer.

BACKGROUND: Lavage cytology is a method to detect cancer cells released within the abdominal cavity. It has been widely utilized, in particular, for gastric cancer. However, its clinical significance has not yet been determined in colorectal cancer. OBJECTIVE: This study aimed to investigate the frequency of lavage cytology positivity and its influence on the prognosis of patients with colorectal cancer. DESIGN: This is a single-institution retrospective observational study. SETTING: This study was conducted at a comprehensive cancer center. PATIENTS: We retrospectively analyzed 3135 colorectal cancer cases from 2007 to 2013 at our institution. Intraoperative peritoneal washing cytology was performed just after the start of the operation. Fluids were centrifuged for 5 minutes at 2500 rotations per minute, cell pellets were smeared on microscope glass slides, and Papanicolaou staining was performed. MAIN OUTCOME MEASURES: The primary outcome was the 5-year overall survival rate. The secondary outcome was the 5-year recurrence rate. RESULTS: Lavage cytology positivity was detected in 19 (2.0%) and 86 (16.9%) cases of stage III and IV colorectal cancer; however, no positive cases were found in stage I and II colorectal cancer. Lavage cytology positivity was an independent prognostic factor in stage III and IV colorectal cancer in the multivariate analysis (5-year mortality HR 3.59 [1.69-7.64] in stage III, 2.23 [1.15-4.31] in stage IV). The prognosis of the 5-year survival rate was significantly worse in the lavage cytology-positive group in stages III and IV. In terms of recurrence, the results of the lavage cytology-positive group in stage III were similar to those of the lavage cytology-positive/negative group in stage IV (73.7%, 70.0%, and 75.0%). LIMITATIONS: This study was limited by its retrospective study design. CONCLUSIONS: Lavage cytology positivity is an independent prognostic and regulatory factor of stage IV colorectal cancer. See Video Abstract at http://links.lww.com/DCR/B770.INCIDENCIA Y VALOR PRONÓSTICO EN LA CITOLOGÍA DEL LAVADO PERITONEAL EN CÁNCER COLORECTALANTECEDENTES:La citología del lavado peritoneal es un método para detectar células cancerosas liberadas dentro de la cavidad abdominal. Se ha utilizado ampliamente, en particular para el cáncer gástrico. Sin embargo, aún no se ha determinado su importancia clínica en el cáncer colorrectal.OBJETIVO:Este estudio tuvo como objetivo investigar la frecuencia de positividad de la citología del lavado y su influencia en el pronóstico de los pacientes con cáncer colorrectal.DISEÑO:Este fue un estudio observacional retrospectivo de una sola institución.DISENTORNO CLÍNICO:El estudio se llevó a cabo en un centro oncológico integral.PACIENTES:Analizamos retrospectivamente 3.135 casos de cáncer colorrectal desde 2007 hasta 2013 en nuestra institución. La citología de lavado peritoneal intraoperatorio se realizó inmediatamente después del inicio de la operación. Los fluidos se centrifugaron durante 5 min a 2.500 rpm, los sedimentos celulares se extendieron sobre portaobjetos de vidrio de microscopio y se realizó la tinción con Papanicolaou.DISPRINCIPALES MEDIDAS DE VALORACIÓN:El primer resultado fueron las tasas de supervivencia general a 5 años. El segundo resultado las tasas de recurrencia a los 5 años.RESULTADOS:Se detectó positividad en la citología de lavado en 19 (2,0%) y 86 (16,9%) casos de cáncer colorrectal en estadio III y IV, respectivamente; sin embargo, no se encontraron casos positivos en el cáncer colorrectal en estadio I y II. La positividad de la citología de lavado fue un factor pronóstico independiente en el cáncer colorrectal en estadio III y IV en el análisis multivariado [cociente de riesgo de mortalidad a 5 años 3,59 (1,69-7,64), en estadio III, 2,23 (1,15-4,31), en estadio IV]. El pronóstico de la tasa de supervivencia a 5 años fue significativamente peor en el grupo con citología de lavado positiva en los estadios III y IV. En cuanto a la recurrencia, los resultados del grupo de lavado con citología positiva en el estadio III fueron similares a los del grupo de lavado con citología positiva / negativa en el estadio IV (73,7%, 70,0% y 75,0%).LIMITACIONES:Este estudio estuvo limitado por su diseño de estudio retrospectivo.CONCLUSIONES:La positividad de la citología de lavado es un factor pronóstico y regulador independiente del cáncer colorrectal en estadio IV. Consulte Video Resumen en http://links.lww.com/DCR/B770. (Traducción- Dr. Ingrid Melo).

Two Distinct Tumorigenic Processes in Endometrial Endometrioid Adenocarcinoma.

Endometrial endometrioid adenocarcinoma (EEA) is conventionally considered to be a single pathologic entity that develops through a hyperplasia-carcinoma sequence under the influence of estrogen. Previously, another EEA subtype was described and proposed to arise directly from normal endometrium. These conventional and de novo subtypes are designated groups 1 and 2, respectively. To identify the molecular mechanisms of these distinct tumorigenic processes, we conducted comprehensive integrated analyses of genomic data with hormonal status for group 1 paired carcinoma and hyperplasia and group 2 carcinoma samples. Although group 1 carcinomas mostly exhibited genomically stable characteristics and the activation of estrogen signaling, group 2 EEAs showed enriched hypermutator and CpG island methylator phenotypes. Pairwise comparisons of hyperplasia and carcinoma, along with time-course analyses of the hyperplasia-carcinoma sequence, revealed the acquisition of driver mutations in the evolutionary process of hyperplasia but not in the transition from hyperplasia to carcinoma. The current study confirms the existence of two different histopathologic programs during EEA development that harbor distinct molecular bases and demonstrates the biological relevance of these differential tumorigenic processes.

Immunogenomic landscape of gynecologic carcinosarcoma.

OBJECTIVE: Carcinosarcoma (CS) of the uterus or ovary is a rare, biphasic tumor comprising epithelial and mesenchymal elements, and exhibits more aggressive clinical features than its carcinoma counterpart. Four molecular subtypes of CS were recently established based on genomic aberration profiles (POLE, MSI, CNH, and CNL) and shown to be associated with multiple clinicopathological parameters, including patient outcomes. However, the role of the immune microenvironment in CS remains unclear. Here, we investigated the influence of the immune cells that infiltrate CS to better understand the immunological status of gynecological CS. METHODS: Tumor immune microenvironmental analyses on CS samples were performed using immune cell profiling with RNA-seq, transcriptomic subtyping with microenvironmental genes, and T-cell receptor repertoire assay. Carcinoma and sarcoma elements from CS samples were also assessed separately. RESULTS: Relying on estimations of tumor-infiltrating cell types from RNA-seq data, POLE and MSI (hypermutator) tumors showed an enrichment of M1 macrophages, plasma cells and CD8+ T cells, whereas CNH and CNL (non-hypermutator) tumors had high levels of M2 macrophages. Further subclassification by immune-related, non-cancer genes identified a fraction of tumors with distinct patient outcomes, particularly those with the CNH genomic aberration subtype. T-cell heterogeneity was independently correlated with prolonged progression-free survival. Differential analysis of carcinoma and sarcoma elements identified many shared mutations but there was little overlap in the T-cell receptor repertoire between the two elements. CONCLUSIONS: Tumor immune microenvironmental analyses could offer potential clinical utility in the stratification of gynecological CS above classification by genomic aberration subtype alone.

Clinical management of the status of atypical endometrial cells using the descriptive reporting format for endometrial cytology.

OBJECTIVE: We aimed to develop and reinforce a clinical management regimen for atypical endometrial cell (ATEC) categories within the descriptive reporting format for endometrial cytology. METHODS: Between January 2013 and December 2014, 215 samples, for which histological examination was performed immediately or within 3 months after cytology, were cytologically diagnosed as ATEC. For these samples, the medical records were retrospectively reviewed to identify risk factors for malignancy. RESULTS: Among 152 samples diagnosed as ATEC, of undetermined significance, 19 (12.5%) were malignant. In the younger group (age <55 years), the χ2 values of body mass index (BMI) ≥25 kg/m2 (5.85), gravidity (5.64) and parity (5.15) were relatively high, suggesting that these were risk factors for malignancy. Of the nulligravida patients, those with BMI ≥25 kg/m2 , 28% were diagnosed with malignant disease. In the older group (≥55 years), endometrial thickening (6.84), atypical genital bleeding (6.43) and BMI ≥25 kg/m2 (3.79) were found to be risk factors for malignancy. Of the patients with endometrial thickening and atypical genital bleeding, 67% were diagnosed with malignant disease. Among 63 samples diagnosed as ATEC, cannot exclude atypical endometrial hyperplasia or more, 35 (55.6%) samples were positive for malignancy. CONCLUSIONS: High-risk patients diagnosed with ATEC, of undetermined significance were identified. Endometrial biopsy should be considered for nulligravida patients aged <55 years with a BMI ≥25 kg/m2 .

Molecular Components of Arabidopsis Intact Vacuoles Clarified with Metabolomic and Proteomic Analyses.

We analyzed the metabolites and proteins contained in pure intact vacuoles isolated from Arabidopsis suspension-cultured cells using capillary electrophoresis-mass spectrometry (CE-MS), Fourier transform-ion cyclotron resonance (FT-ICR)-MS and liquid chromatography (LC)-MS. We identified 21 amino acids and five organic acids as major primary metabolites in the vacuoles with CE-MS. Further, we identified small amounts of 27 substances including well-known vacuolar molecules, but also some unexpected substances (e.g. organic phosphate compounds). Non-target analysis of the vacuolar sample with FT-ICR-MS suggested that there are 1,106 m/z peaks that could predict the 5,090 molecular formulae, and we have annotated 34 compounds in these peaks using the KNapSAck database. By conducting proteomic analysis of vacuolar sap, we found 186 proteins in the same vacuole samples. Since the vacuole is known as a major degradative compartment, many of these were hydrolases, but we also found various oxidoreductases and transferases. The relationships between the proteins and metabolites in the vacuole are discussed.

Maintenance hormonal therapy after treatment with medroxyprogesterone acetate for patients with atypical polypoid adenomyoma.

BACKGROUND: As atypical polypoid adenomyoma (APA) has been reported to be a hormone-related tumor, we aimed to analyze the efficacy and safety of maintenance hormonal therapy after fertility-preserving treatment of these patients with medroxyprogesterone acetate (MPA). METHODS: Data were retrospectively analyzed from patients with APA who were treated with a fertility-preserving regimen including MPA between October 2001 and December 2011. Eighteen patients were treated with MPA and 14 (77.8%) achieved either a complete or a partial response after the planned treatment. Five patients took progestin for maintenance therapy. RESULTS: Eighteen patients were treated for a mean observation period of 96.7 months. While taking the maintenance therapy, no patient had APA relapse. One patient developed well-differentiated endometrioid adenocarcinoma 18 months after she stopped taking maintenance progestin. Eleven patients without maintenance therapy underwent hysterectomy, andnine of them developed well-differentiated endometrial cancer. Through univariate analysis, there was a significant difference in time to hysterectomy between patients with and without maintenance therapy (P = 0.015). Through multivariate analysis, body mass index (BMI), menstrual status before protocol therapy, maintenance treatment, and pregnancy were found to be significantly associated with a lower risk of hysterectomy. No patient had a recurrence of APA after hysterectomy during the observation period (median, 54 months; range, 2-148 months). CONCLUSION: No patient showed progression while receiving hormonal therapy, including initial protocol therapy. Maintenance hormonal therapy after treatment with MPA was highly effective and safe, particularly in patients with BMI ≧24 kg/m2 and irregular menstruation cycle.

Plutonium Partitioning Behavior to Humic Acids from Widely Varying Soils Is Related to Carboxyl-Containing Organic Compounds.

In order to examine the influence of the HA molecular composition on the partitioning of Pu, ten different kinds of humic acids (HAs) of contrasting chemical composition, collected and extracted from different soil types around the world were equilibrated with groundwater at low Pu concentrations (10-14 M). Under mildly acidic conditions (pH ∼ 5.5), 29 ± 24% of the HAs were released as colloidal organic matter (>3 kDa to <0.45 µm), yet this HA fraction accounted for a vast majority of the bound Pu, 76 ± 13% on average. In comparison, the particulate HA fraction bound only 8 ± 4% on average of the added Pu. The truly dissolved Pu fraction was typically <1%. Pu binding was strongly and positively correlated with the concentrations of organic nitrogen in both particulate (>0.45 µm) and colloidal phases in terms of activity percentage and partitioning coefficient values (logKd). Based on molecular characterization of the HAs by solid state 13C nuclear magnetic resonance (NMR) and elemental analysis, Pu binding was correlated to the concentration of carboxylate functionalities and nitrogen groups in the particulate and colloidal phases. The much greater tendency of Pu to bind to colloidal HAs than to particulate HA has implications on whether NOM acts as a Pu source or sink during natural or man-induced episodic flooding.

Long-term outcomes of fertility-sparing treatment of atypical polypoid adenomyoma with medroxyprogesterone acetate.

PURPOSE: Our objective was to analyze the long-term oncologic outcomes of fertility-preserving hormonal treatment with medroxyprogesterone acetate (MPA) in patients with APA. METHODS: In a retrospective chart review, we identified patients with APA who were treated with MPA for fertility preservation at our hospital between 2001 and 2011. Eighteen patients with histologically diagnosed APA were identified. Clinical data including treatment, obstetrical, and oncologic outcomes were recorded. RESULTS: The mean observation period was 77.6 months (median 73.5, range 22-142), and the mean age was 33.6 years. Four patients also developed well-differentiated endometrial carcinoma. After the treatment, 14 patients (77.8 %) achieved either a complete response or partial response. Eight patients experienced recurrence, while four experienced persistent disease. Ten patients (55.6 %) eventually underwent hysterectomy. The median time to hysterectomy was 40.3 months (range 24-68). Nine patients progressed to endometrial cancer, and one experienced persistent APA. Among younger patients (<35 years of age), four out of five patients who were married could have children. Seven patients (38.9 %) showed no evidence of the disease during the observation period (median 60 months, range 22-117 months). No one died because of the disease during the observation period. CONCLUSIONS: MPA yields a high response rate in APA, and if only younger patients are considered, a favorable pregnancy rate can be obtained. However, because recurrence rate is high, long-term follow-up under supervision of a trained gynecologic oncologist is required. To confirm MPA's utility, multi-center collaboration would be warranted.

Successful Surveillance Using Endometrial Cytology in a Woman With Lynch Syndrome.

Lynch syndrome (LS) results from pathogenic variants in mismatch repair genes and is the most common hereditary cancer syndrome. Some guidelines or studies recommend restricting screening according to endometrial cancer (EC) using endometrial biopsy. The pooled sensitivity and specificity of endometrial cytology for detecting endometrial atypical hyperplasia or cancer have been reported to be as high as the pooled sensitivity and specificity of endometrial biopsy. We conduct transvaginal ultrasound and endometrial cytology in women with LS every six months as surveillance for gynecological malignancy. Through this surveillance program, we can detect early-stage EC in women with LS. Here, we report the case of a patient with stage IA EC detected by endometrial cytology and treated completely. The patient was a 47-year-old woman under surveillance for gynecological malignancy. She was diagnosed as having LS with a germline pathogenic variant in MSH6 after surgery for rectal cancer. Thereafter, gynecological surveillance was started. She had regular menstruation and never experienced atypical genital bleeding. However, her cytopathological findings indicated grade 1 endometrial carcinoma. Endometrial biopsy was performed and endometrial carcinoma was confirmed pathologically. A laparoscopic modified radical hysterectomy with bilateral salpingo-oophorectomy was performed. The resected specimen was reviewed pathologically, and the tumor was finally diagnosed as grade 1 endometrioid carcinoma confined to the endometrium without lymphovascular space invasion. She has remained asymptomatic and free of cancer for five years without any adjuvant therapy. We achieved successful surveillance using endometrial cytology. Endometrial cytology could replace endometrial biopsy as a screening tool for EC.

Usefulness of intraoperative imprint cytology in ovarian germ cell tumors.

OBJECTIVE: This study retrospectively investigated the usefulness of intraoperative diagnosis based on imprint cytology and frozen sections for ovarian germ cell tumor. STUDY DESIGN: Intraoperative studies were reviewed for 23 cases with ovarian germ cell tumor treatment for which both frozen sections and imprint cytology were available. Final histopathologic diagnoses were compared with those based on intraoperative examinations. RESULTS: Underlying pathologies included dysgerminoma (n = 6), yolk sac tumor (n = 1), non-gestational choriocarcinoma (n = 1), mature cystic teratoma with malignant transformation (n = 1), immature teratoma (n = 11), and mixed germ cell tumor (n = 3). Discrepancies between intraoperative imprint cytology and definitive histologic diagnosis were seen in 6 of the 23 cases. Accuracy was 54.5% (6/11) for immature teratoma and 91.7% (11/12) for other tumors. Cytologic examination facilitated accurate diagnosis in both of our cases, and intraoperative diagnosis by frozen section proved inaccurate. CONCLUSION: These results demonstrate that intraoperative assessment based on imprint cytology for immature teratoma has a relatively lower sensitivity, but an acceptable sensitivity for other germ cell tumors. Diagnostic approaches combining frozen sections and imprint cytology are advisable to improve the yield for intraoperative diagnosis.

Cardio-ankle vascular index relates to left ventricular ejection fraction in patients with heart failure. A retrospective study.

The cardio-ankle vascular index (CAVI) has been proposed as a new noninvasive marker of arterial stiffness independent of blood pressure. Arterial stiffness is closely related to afterload, and elevated afterload aggravates heart failure. We hypothesized that CAVI is a potential marker of afterload in patients with heart failure. Thirty patients who were admitted because of acute heart failure were identified retrospectively from a review of clinical records. Plasma brain natriuretic peptide (BNP) levels, CAVI, cardiothoracic ratio (CTR), and echocardiographic parameters obtained during acute and chronic phases of heart failure were analyzed. Left ventricular ejection fraction (LVEF) increased significantly and CTR, BNP and CAVI decreased significantly after treatment of heart failure. A significant negative correlation was observed between the change in CAVI and change in LVEF in all subjects (r = -0.3272, P < 0.05). To examine the relationship between CAVI and LVEF, we divided the patients into two subgroups (∆CAVI < -0.5; CAVI decrease group, ∆CAVI ≥ -0.5; CAVI non-decrease group). CAVI was significantly improved after heart failure treatment only in the CAVI decrease group. LVEF decreased significantly in both groups, but the P value was smaller in the CAVI decrease group than in the CAVI non-decrease group. The change in LVEF correlated significantly with the change in CAVI in the CAVI decrease group (r = -0.4201, P < 0.05), whereas no significant correlation was found in the CAVI non-decrease group. CAVI correlates inversely with LVEF after heart failure treatment. Our results suggest that CAVI might partially reflect the afterload in patients with heart failure.

Physiological ER stress caused by amylase production induces regulated Ire1-dependent mRNA decay in Aspergillus oryzae.

Regulated Ire1-dependent decay (RIDD) is a feedback mechanism in which the endoribonuclease Ire1 cleaves endoplasmic reticulum (ER)-localized mRNAs encoding secretory and membrane proteins in eukaryotic cells under ER stress. RIDD is artificially induced by chemicals that generate ER stress; however, its importance under physiological conditions remains unclear. Here, we demonstrate the occurrence of RIDD in filamentous fungus using Aspergillus oryzae as a model, which secretes copious amounts of amylases. α-Amylase mRNA was rapidly degraded by IreA, an Ire1 ortholog, depending on its ER-associated translation when mycelia were treated with dithiothreitol, an ER-stress inducer. The mRNA encoding maltose permease MalP, a prerequisite for the induction of amylolytic genes, was also identified as an RIDD target. Importantly, RIDD of malP mRNA is triggered by inducing amylase production without any artificial ER stress inducer. Our data provide the evidence that RIDD occurs in eukaryotic microorganisms under physiological ER stress.

Unexpected tumor progression after conization for carcinoma in situ of the uterine cervix.

AIM: To determine the safety and usefulness of conization with an electrosurgical loop (the loop electrosurgical excision procedure [LEEP]) in young women with carcinoma in situ (CIS) of the uterine cervix. METHODS: A retrospective medical chart review of five patients with CIS initially treated with LEEP conization between 2002 and 2010 and who later experienced recurrence in the form of invasive or advanced disease was conducted. RESULTS: The median patient age at initial LEEP conization was 41years (33-56years). The margin status in conization specimens was positive in three of the five patients. The median time to detection of tumor progression was 50months (17-58months). Magnetic resonance imaging was effective in detecting tumor recurrence in all cases. In four patients, hysterectomy was performed to treat the recurrence; these four patients are currently alive and disease-free. One patient with cervical lymph nodes and bone metastases was treated with chemotherapy alone; however, the patient died. In surgical specimens, tumor progression was observed extending toward the endometrium in all five patients and toward the vagina in two patients. CONCLUSION: This study indicates that patients with CIS occasionally show unexpected tumor progression after conization and the progression could be life-threatening. Recurrent disease often shows tumor progression toward the endometrium or vagina, leading to difficulties in its detection at periodic pelvic examinations.

Machine learning-based gene alteration prediction model for primary lung cancer using cytologic images.

BACKGROUND: Understanding the gene alteration status of primary lung cancers is important for determining treatment strategies, but gene testing is both time-consuming and costly, limiting its application in clinical practice. Here, potential therapeutic targets were selected by predicting gene alterations in cytologic specimens before conventional gene testing. METHODS: This was a retrospective study to develop a cytologic image-based gene alteration prediction model for primary lung cancer. Photomicroscopic images of cytology samples were collected and image patches were generated for analyses. Cancer-positive (n = 106) and cancer-negative (n = 32) samples were used to develop a neural network model for selecting cancer-positive images. Cancer-positive cases were randomly assigned to training (n = 77) and validation (n = 26) data sets. Another neural network model was developed to classify cancer images of the training data set into 4 groups: anaplastic lymphoma kinase (ALK)-fusion, epidermal growth factor receptor (EGFR), or Kirsten rat sarcoma viral oncogene homologue (KRAS) mutated groups, and other (None group), and images of the validation data set were classified. A decision algorithm to predict gene alteration for cases with 3 probability ranks was developed. RESULTS: The accuracy and precision for selecting cancer-positive patches were 0.945 and 0.991, respectively. Predictive accuracy for the EGFR and KRAS groups in the validation data set was ~0.95, whereas that for the ALK and None groups was ~0.75 and ~ 0.80, respectively. Gene status was correctly predicted in the probability rank A cases. The model extracted characteristic conventional cytologic findings in images and a novel specific feature was discovered for the EGFR group. CONCLUSIONS: A gene alteration prediction model for lung cancers by machine learning based on cytologic images was successfully developed.

Clinical Management of Atypical Endometrial Cells of Undetermined Significance Followed by Negative Cytology.

INTRODUCTION: In Japan, endometrial cytology is widely performed to evaluate the status of the endometrium in women with suspected endometrial cancer. A new classification system for endometrial cytology has recently been used: the Yokohama system, based on a descriptive reporting format. This study aimed to clarify the triage for patients with atypical endometrial cells of undetermined significance (ATEC-US) when followed by negative endometrial cytology. METHODS: We enrolled patients diagnosed with ATEC-US at the Cancer Institute Hospital between January 2016 and December 2017, based on the following inclusion criteria: (1) ATEC-US diagnosed by office endometrial cytology, with or without office endometrial biopsy; (2) follow-up endometrial cytology was performed 3-6 months after initial sampling, with a negative result for malignancy; and (3) no prior history of conservative treatment with progestin for endometrial cancer or atypical endometrial hyperplasia (ATEC-A). Among eligible patients, we analyzed those later diagnosed by endometrial biopsy with ATEC-A or carcinoma. RESULTS: Among 187 patients, 65 met the inclusion criteria. Forty-two patients (64.6%) were observed for more than 24 months. Two patients (3.1%) developed ATEC-A during a median observation time of 26.5 months; the times to diagnosis were 32 months and 22 months. DISCUSSION/CONCLUSION: No patient developed ATEC-A or worse within 1 year. For patients with ATEC-US, if negative cytology is obtained at the next examination, a close follow-up is not necessary.

Prognosis and adjuvant chemotherapy for patients with positive peritoneal cytology in stage IA endometrial cancer.

This study evaluated the influence of positive peritoneal cytology (PPC) on the prognosis of patients with stage IA endometrial cancer, and the usefulness of adjuvant chemotherapy in their treatment. We retrospectively analyzed the data of patients with stage IA endometrial cancer admitted in our hospital between 2005 and 2015. Among 989 patients who underwent peritoneal cytology, 135 (13.7%) had PPC. Multivariate analysis extracted several independent risk factors for recurrence in stage IA patients, including those with PPC. Adjuvant chemotherapy did not cause a significant difference in the 5-year relapse-free survival rate in patients with PPC (p = 0.78). Similarly, the 5-year recurrence-free survival rate with or without chemotherapy was not different among type II cancer patients (p = 0.11). However, the baseline risk of 5-year relapse-free survival without chemotherapy in patients with PPC and type II was very low (66.7%). While PPC was an independent risk factor for recurrence in stage IA endometrial cancer, adjuvant chemotherapy did not influence the survival rate in patients with PPC. While it is controversial whether adjuvant chemotherapy should be administered in stage IA uterine cancer with only PPC as a prognostic factor, it should be considered for early-stage patients who have multiple risk factors for recurrence.

Parametrial involvement in FIGO stage IB1 cervical carcinoma diagnostic impact of tumor diameter in preoperative magnetic resonance imaging.

BACKGROUND: In the surgical treatment for early-stage cervical carcinoma, it is important to identify preoperatively a low-risk group of patients as candidates for less radical surgery to avoid the morbidity associated with radical hysterectomy. The aim of this study was to evaluate the correlation between tumor diameter measured preoperatively using magnetic resonance imaging (MRI) and pathological prognostic factors in International Federation of Gynecology and Obstetrics (FIGO) stage IB1 cervical carcinoma. METHODS: A total of 125 patients with FIGO stage IB1 cervical cancer were included in this study. Clinical records, pathology reports, and MRI findings were retrospectively reviewed. RESULTS: Histological diagnosis was squamous cell carcinoma in 57 patients and non squamous cell carcinoma in 68 patients. All patients underwent preoperative evaluation by MRI within a median period of 13.5 days before surgery. The tumor diameter measured by MRI ranged from zero (no tumor detected) to 42 mm, with a median of 23 mm.Pathological prognostic factors included parametrial involvement, lymph node metastasis,deep stromal invasion, and lymphovascular space invasion. All these factors were found less frequently in patients with a smaller tumor diameter. Most notably, parametrial involvement was seen in none of the patients with tumors 20 mm or less and was detected only in patients with tumors greater than 20 mm (P = 0.01). CONCLUSIONS: In the FIGO stage IB1 cervical carcinoma, the tumor diameter measured preoperatively by MRI correlates well with other pathological prognostic factors, especially with parametrial involvement. This finding suggests that the tumor diameter measured in preoperative MRI may serve as a strong predictor of parametrial involvement in FIGO stage IB1 cervical carcinoma, which can be used to select a candidate population for less radical surgery without the need for a cone biopsy before hysterectomy.

Stage IA ovarian cancers: comparison of sonographic findings and histopathologic types between patients with normal and elevated serum cancer antigen 125 levels.

OBJECTIVES: The purpose of this study was to compare sonographic findings and histopathologic types of stage IA ovarian cancers between groups with normal and elevated cancer antigen 125 (CA-125) levels. METHODS: Between 2000 and 2009, 146 stage IA ovarian cancers were treated surgically (85 invasive and 61 borderline, 73 self-referred with tumor-related symptoms, 20 self-referred with nonspecific symptoms, 52 identified through screening, and 1 other). Of these, 87 cases (60%) had normal serum CA-125 levels (<35 U/mL). Their pre-operative sonographic findings and histopathologic types were compared to those of cases with elevated CA-125 levels. RESULTS: Statistically significant differences were found between the proportions of patients with elevated CA-125 levels in groups having tumors with maximal diameters of less than 20 cm and at least 20 cm (P = .03) and groups having tumors with less than 50% and 50% to 80% solid components (P = .02). In the group with normal CA-125 levels, we found predominantly mucinous adenocarcinoma in multilocular cysts with less than 50% solid components (25 cases), and clear cell adenocarcinoma in unilocular cysts with less than 50% solid components (12 cases), whereas in the group with elevated CA-125 levels, mucinous adenocarcinoma in multilocular cysts with less than 50% solid components (19 cases) and endometrioid adenocarcinoma in solid tumors (≥80% solid components) were predominant (5 cases). CONCLUSIONS: Stage IA ovarian cancers with normal CA-125 levels tend to be smaller, have less solid components, and have a slightly different distribution of histopathologic types than cancers with elevated CA-125 levels.