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Recent studies reveal that biosynthesis of iron-sulfur clusters (Fe-Ss) is essential for cell proliferation, including that of cancer cells. Nonetheless, it remains unclear how Fe-S biosynthesis functions in cell proliferation/survival. Here, we report that proper Fe-S biosynthesis is essential to prevent cellular senescence, apoptosis or ferroptosis, depending on cell context. To assess these outcomes in cancer, we developed an ovarian cancer line with conditional KO of FDX2, a component of the core Fe-S assembly complex. FDX2 loss induced global down-regulation of Fe-S-containing proteins and Fe2+ overload, resulting in DNA damage and p53 pathway activation, and driving the senescence program. p53-deficiency augmented DNA damage responses upon FDX2 loss, resulting in apoptosis rather than senescence. FDX2 loss also sensitized cells to ferroptosis, as evidenced by compromised redox homeostasis of membrane phospholipids (PLs). Our results suggest that p53 status and PL homeostatic activity are critical determinants of diverse biological outcomes of Fe-S deficiency in cancer cells.
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Four subtypes of ovarian high-grade serous carcinoma (HGSC) have previously been identified, each with different prognoses and drug sensitivities. However, the accuracy of classification depended on the assessor's experience. This study aimed to develop a universal algorithm for HGSC-subtype classification using deep learning techniques. An artificial intelligence (AI)-based classification algorithm, which replicates the consensus diagnosis of pathologists, was formulated to analyze the morphological patterns and tumor-infiltrating lymphocyte counts for each tile extracted from whole slide images of ovarian HGSC available in The Cancer Genome Atlas (TCGA) data set. The accuracy of the algorithm was determined using the validation set from the Japanese Gynecologic Oncology Group 3022A1 (JGOG3022A1) and Kindai and Kyoto University (Kindai/Kyoto) cohorts. The algorithm classified the four HGSC-subtypes with mean accuracies of 0.933, 0.910, and 0.862 for the TCGA, JGOG3022A1, and Kindai/Kyoto cohorts, respectively. To compare mesenchymal transition (MT) with non-MT groups, overall survival analysis was performed in the TCGA data set. The AI-based prediction of HGSC-subtype classification in TCGA cases showed that the MT group had a worse prognosis than the non-MT group (P = 0.017). Furthermore, Cox proportional hazard regression analysis identified AI-based MT subtype classification prediction as a contributing factor along with residual disease after surgery, stage, and age. In conclusion, a robust AI-based HGSC-subtype classification algorithm was established using virtual slides of ovarian HGSC.
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A Japanese clinical trial (JGOG3016) showed that dose-dense weekly paclitaxel in combination with carboplatin extensively prolonged overall survival (OS) in patients with advanced ovarian cancer. However, in other clinical trials, dose-dense paclitaxel regimens were not superior to triweekly paclitaxel regimens. In this study, causal tree analysis was applied to explore subpopulations with different treatment effects of dose-dense paclitaxel in a data-driven approach. The 587 participants with stage II-IV ovarian cancer in the JGOG3016 trial were used for model development. The primary endpoint was treatment effect in terms of 3-year OS in patients receiving dose-dense vs. conventional paclitaxel therapies. In patients <50 years, the 3-year OS was similar in both groups; however, it was higher in the dose-dense group in patients ≥50 years. Dose-dense paclitaxel showed strong positive treatment effects in patients ≥50 years with stage II/III disease, BMI <23 kg/m2, non-CC/MC, and residual tumor ≥1 cm. In contrast, although there was no significant difference in OS; the 3-year OS rate was 23% lower in dose-dense paclitaxel than conventional paclitaxel in patients ≥60 years with stage IV cancer. Patients in this group had a particularly lower performance status than other groups. Our causal tree analysis suggested that poor prognosis groups represented by residual tumor tissue ≥1 cm benefit from dose-dense paclitaxel, whereas elderly patients with advanced disease and low-performance status are negatively impacted by dose-dense paclitaxel. These subpopulations will be of interest to future validation studies. Personalized treatments based on clinical features are expected to improve advanced ovarian cancer prognosis.
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Protocolos de Quimioterapia Combinada Antineoplásica , Carboplatino , Neoplasias Ováricas , Paclitaxel , Humanos , Femenino , Paclitaxel/administración & dosificación , Carboplatino/administración & dosificación , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Neoplasias Ováricas/mortalidad , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Persona de Mediana Edad , Anciano , Adulto , Estadificación de Neoplasias , Resultado del Tratamiento , Heterogeneidad del Efecto del TratamientoRESUMEN
OBJECTIVE: To examine the efficacy and safety of minimally invasive surgery (MIS) and conventional abdominal surgery for epithelial ovarian cancer (EOC), stratified by treatment type. METHODS: A systematic review and meta-analysis were conducted by an Expert Panel of the Japan Society of Gynecologic Oncology Ovarian Cancer Committee. Several academic databases, including PubMed/MEDLINE, Cochrane Database, and Ichushi were searched by the Japan Medical Library Association on November 11, 2023, using the keywords "epithelial ovarian cancer", "minimally invasive surgery", "laparoscopic", and "robot-assisted". Articles describing MIS treatment for EOC compared with conventional abdominal surgery were independently assessed by two authors. The primary outcomes were survival and perioperative adverse events. RESULTS: After screening 1114 studies, 35 articles were identified, including primary staging surgery (PSS) for early-stage EOC EOC (n = 20) and neoadjuvant chemotherapy following interval debulking surgery (NACT-IDS; n = 10) and upfront primary debulking surgery (PDS; n = 5) for advanced-stage EOC. These studies included 29,888 patients (7661 undergoing MIS and 22,227 undergoing abdominal surgery). Patients receiving MIS and abdominal surgery had similar overall survival (PSS: odds ratio [OR] 1.02, 95% confidence interval [CI] 0.75-1.37; NACT-IDS: OR 0.93, 95%CI 0.25-3.44 and PDS: OR 0.66, 95%CI 0.36-1.22, all P > 0.05). MIS showed perioperative complication rates comparable to those of abdominal surgery (intraoperative and postoperative, all treatment types P ≥ 0.05). However, the rate of lymph node dissection in early-stage EOC (PSS: OR 0.49, 95%CI0.26-0.91) and multivisceral resections in advanced-stage EOC (NACT-IDS: OR 0.27 95%CI 0.16-0.44 and PDS: OR 0.27, 95%CI 0.16-0.44) was lower in MIS than in abdominal surgery (all P < 0.05). CONCLUSION: MIS did not negatively impact the survival and perioperative complications of patients with EOC compared to abdominal surgery. While MIS is a viable option, varied case selection and surgical procedures suggest potential bias, requiring further validation studies.
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OBJECTIVE: The objective of this study was to assess the oncologic outcome of surgically-treated patients with early-stage, intermediate-risk cervical cancer according to postoperative therapy modality. METHODS: This retrospective cohort study queried the Japanese Gynecologic Oncology Group's nationwide surgical data platform. The study population was 1084 patients with stage IB cervical cancer who underwent primary radical hysterectomy and lymphadenectomy from 2004 to 2008. Histology type-incorporated intermediate-risk factor patterns were clustered into three groups based on recurrence risk. Oncologic outcomes were assessed per postoperative therapy: external beam radiotherapy alone, concurrent chemo-radiotherapy, chemotherapy alone, and no treatment. RESULTS: Histology-incorporated intermediate-risk groups included: no lympho-vascular space invasion in any histology, or squamous cell carcinoma with lympho-vascular space invasion but no deep stromal invasion (n=559, 51.6%, group 1); squamous cell carcinoma with both lympho-vascular space invasion and deep cervical stromal invasion (n=281, 25.9%; group 2); and non-squamous histology with lympho-vascular space invasion (n=244, 22.5%; group 3). The 5-year disease-free survival rates were 93.3%, 89.3%, and 82.5% for group 1,-2, and -3, respectively (p<0.001), with group 3 exhibiting an almost three-fold increased recurrence risk compared with group 1 (adjusted-hazard ratio (aHR) 2.70, 95% confidence interval (CI) 1.70-4.32), followed by group 2 (aHR 1.67, 95% CI 1.01 to 2.75). Disease-free survival was similar across the postoperative therapy groups: 5 year rates for external beam radiotherapy alone, concurrent chemo-radiotherapy, chemotherapy alone, and no postoperative treatment, 94.8%, 87.2%, 93.6%, and 94.2% for group 1 (p=0.294); 85.0%, 93.3%, 87.3%, and 90.5% for group 2 (p=0.578); and 85.4%, 83.1%, 80.5%, and 83.3% for group 3 (p=0.876). The aHR for disease-free survival comparing no postoperative treatment to external beam radiotherapy alone was 1.10 (95% CI 0.37 to 3.28), 0.71 (95% CI 0.29 to 1.79), and 1.21 (95% CI 0.42 to 3.51) for group 1, group 2, and group 3, respectively. The observed exposure-outcome associations were similar for cause-specific survival (all, p>0.05). CONCLUSION: In this retrospective investigation in Japan, active surveillance without postoperative therapy following radical hysterectomy and lymphadenectomy was not associated with oncologic outcome in early-stage, intermediate-risk cervical cancer.
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BACKGROUND: Platinum/taxane (TC) chemotherapy with debulking surgery stays the mainstay of the treatment in ovarian cancer patients with peritoneal metastasis, and recently its novel modality, intraperitoneal carboplatin with dose-dense paclitaxel (ddTCip), was shown to have greater therapeutic impact. Nevertheless, the response varies among patients and consequent recurrence, or relapse often occurs. Discovery of therapeutic response predictor to ddTCip and/or TC therapy is eagerly awaited to improve the treatment outcome. METHODS: Using datasets in 76 participants in our ddTCip study and published databases on patients received TC therapy, we first validated a total of 75 previously suggested markers, sought out more active biomarkers through the association analyses of genome-wide transcriptome and genotyping data with progression-free survival (PFS) and adverse events, and then developed multiplex statistical prediction models for PFS and toxicity by mainly using multiple regression analysis and the classification and regression tree (CART) algorithm. RESULTS: The association analyses revealed that SPINK1 could be a possible biomarker of ddTCip efficacy, while ABCB1 rs1045642 and ERCC1 rs11615 would be a predictor of hematologic toxicity and peripheral neuropathy, respectively. Multiple regression analyses and CART algorithm finally provided a potent efficacy prediction model using 5 gene expression data and robust multiplex toxicity prediction models-CART models using a total of 4 genotype combinations and multiple regression models using 15 polymorphisms on 12 genes. CONCLUSION: Biomarkers and multiplex models composed here could work well in the response prediction of ddTCip and/or TC therapy, which might contribute to realize optimal selection of the key therapy.
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BACKGROUND: We previously demonstrated the applicability of the concept of "platinum sensitivity" in recurrent endometrial cancer. Although immune checkpoint inhibitors have been widely incorporated into endometrial cancer treatment, the debate continues regarding treatment options in patients with recurrent endometrial cancer who have previously received platinum-based chemotherapy. In this study, we assessed the duration of response to secondary platinum-based treatment using pooled data from the SGSG-012/GOTIC-004/Intergroup study. METHODS: Among the 279 participants in the SGSG-012/GOTIC-004/Intergroup study wherein platinum-based chemotherapy was re-administered for managing recurrent endometrial cancer between January 2005 and December 2009, 130 (47%) responded to chemotherapy. We compared the relationship between platinum-free interval and duration of secondary platinum-based treatment using pooled data. RESULTS: In 40 patients (31%), the duration of response to secondary platinum-based treatment exceeded the platinum-free interval. The duration of response to secondary platinum-based treatment exceeded 12 months in 51 patients (39%) [platinum-free interval: < 12 months, 14/48 (29%); 12-23 months, 18/43 (42%); 24-35 months, 8/19 (42%); ≥ 36 months, 11/20 (55%)]. In particular, in eight patients (6%), the duration of response to secondary platinum-based treatment exceeded 36 months [platinum-free interval: < 12 months, 3/48 (6%); 12-23 months, 0/19 (0%); 24-35 months, 2/19 (11%); ≥ 36 months, 3/20 (15%)]. CONCLUSIONS: Re-administration of platinum-based chemotherapy for recurrent endometrial cancer may result in a long-term response exceeding the platinum-free interval in some patients. Even in the current situation, where immune checkpoint inhibitors have been introduced, re-administration of platinum-based chemotherapy is worth considering.
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A multi-kinase inhibitor, lenvatinib, plus an immune checkpoint inhibitor, pembrolizumab, became a viable therapeutic option for advanced or recurrent endometrial cancer in Japan by the end of 2021. The Japanese population has a relatively unique genetic background. Hence, the safety profile and effectiveness of lenvatinib plus pembrolizumab may differ between the Japanese and other populations. This single-center, retrospective study aimed to evaluate the treatment efficacy of lenvatinib plus pembrolizumab and the safety profile of the associated adverse events. The clinical records of 15 patients, who received lenvatinib plus pembrolizumab for advanced or recurrent endometrial cancer at the Tohoku University Hospital, were reviewed. Best overall response and disease control rates were 40.0% and 73.3%, respectively. Treatment was discontinued owing to disease progression and adverse events in six patients, respectively. As of the end of July 2023, treatment was ongoing in the remaining three patients. The median treatment and progression-free survival durations were 118 and 258 days, respectively. Relative dose intensity of lenvatinib was not positively associated with progression-free survival, neither during the first 4 weeks after treatment initiation nor during the entire treatment period. All patients experienced one or more adverse events, the most common of which were hypothyroidism (90%) and hypertension (83.3%). Among the 15 patients, 13 required lenvatinib dose reduction owing to adverse events. One patient developed grade 4 interstitial pneumonia requiring intensive care. Our results validate the short-term efficacy of lenvatinib plus pembrolizumab, and indicate that dose optimization of lenvatinib could be individualized without impairing efficacy.
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Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Endometriales , Quinolinas , Femenino , Humanos , Estudios Retrospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Compuestos de Fenilurea/efectos adversos , Neoplasias Endometriales/tratamiento farmacológicoRESUMEN
The aim of this study was to determine the impact of nerve preservation confirmed by intraoperative electrical stimulation (IES) on subjective symptoms of urinary and sexual function in uterine cervical cancer patients who underwent radical hysterectomies. This study included 85 patients who underwent type C radical hysterectomy with IES. Pelvic splanchnic nerve preservation with IES after hysterectomy (nerve-stimulation positive group) was confirmed in 61 women and 24 women did not have nerve preservation (negative group). Urinary function was assessed with the Overactive Bladder Symptom Score (OABSS), International Prostate Symptom Score (IPSS), and International Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF) questionnaires. Sexual function was surveyed using the Female Sexual Function Index (FSFI). Longitudinal changes in those scores according to response to nerve-stimulation were evaluated using a generalized estimating equation. IPSS quality of life (QOL) scores were significantly better in the nerve-stimulation positive group compared with the scores in the negative group until 12 months after surgery, whereas OABSS, IPSS total, IPSS voiding, and ICIQ-SF scores evaluating urinary symptoms were not significantly different between the two groups. FSFI scores were better in the nerve-stimulation positive group 36 months after surgery compared with the scores in the negative group. In this study, we assessed self-reported urinary and sexual symptoms after nerve-sparing radical hysterectomy (NSRH) with IES in the long term. We demonstrated that nerve-sparing significantly reduced distress associated with QOL until 1 year, improved urinary storage symptoms at 2 years, and sexual symptoms 3 years after surgery.
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Histerectomía , Autoinforme , Humanos , Histerectomía/efectos adversos , Femenino , Estudios Prospectivos , Persona de Mediana Edad , Calidad de Vida , Adulto , Factores de Tiempo , Tratamientos Conservadores del Órgano/métodos , Micción/fisiología , Neoplasias del Cuello Uterino/cirugía , Encuestas y Cuestionarios , AncianoRESUMEN
The association between germline BRCA1 and BRCA2 pathogenic variants (mutations: gBRCAm) and ovarian cancer risk is well established. Germline testing alone cannot detect somatic BRCA1/2 pathogenic variants (sBRCAm), which is calculated based on the proportion of tumor BRCAm (tBRCAm) from tumor samples and gBRCAm. Homologous recombination deficiency (HRD) results mainly from genetic/epigenetic alterations in homologous recombination repair-related genes and can be evaluated by genomic instability status. In Japan, the prevalence of tBRCAm, sBRCAm, and HRD remains unclear. This multicenter, cross-sectional, observational study, CHaRacterIzing the croSs-secTional approach to invEstigate the prevaLence of tissue BRCA1/2 mutations in newLy diagnosEd advanced ovarian cancer patients (CHRISTELLE), evaluated the prevalence of tBRCAm, sBRCAm, and HRD in tumor specimens from newly diagnosed patients with ovarian cancer who underwent gBRCA testing. Of the 205 patients analyzed, 26.8% had a tBRCAm, including tBRCA1m (17.6%) and tBRCA2m (9.3%). The overall prevalence of tBRCAm, gBRCAm, sBRCAm, and HRD-positive status was 26.8%, 21.5%, 6.3%, and 60.0%, respectively. The calculated sBRCAm/tBRCAm ratio was 23.6% (13/55), and the prevalence of gBRCA variant of uncertain significance was 3.9%. These results suggest gBRCA testing alone cannot clearly identify the best course of treatment, highlighting the importance of sBRCA testing in Japan. The present results also suggest that testing for tBRCA and HRD should be encouraged in advanced ovarian cancer patients to drive precision medicine.
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Pueblos del Este de Asia , Neoplasias Ováricas , Humanos , Femenino , Carcinoma Epitelial de Ovario/genética , Neoplasias Ováricas/patología , Proteína BRCA1/genética , Genes BRCA2 , Mutación , Mutación de Línea GerminalRESUMEN
The Cancer Genome Atlas (TCGA) network has clarified that ~50% of high-grade serous ovarian cancers show homologous recombination deficiency (HRD). However, the frequency of HRD in Japanese patients with ovarian cancer remains unclear. We aimed to identify the frequency of HR-associated gene mutations in Japanese patients with ovarian cancer. The JGOG3025 study is a multicenter collaborative prospective observational study involving 65 study sites throughout Japan. We recruited 996 patients who were clinically diagnosed with ovarian cancer before surgery from March 2017 to March 2019, and 701 patients were eligible according to the criteria. We used frozen tumor tissues to extract DNA and performed next-generation sequencing for 51 targeted genes (including 29 HR-associated genes) in 701 ovarian cancers (298 high-grade serous cases, 189 clear cell cases, 135 endometrioid cases, 12 mucinous cases, 3 low-grade serous cases, and 64 others). HRD was defined as positive when at least one HR-associated gene was mutated. The frequencies of HRD and tumor BRCA1/2 mutations were 45.2% (317/701) and 18.5% (130/701), respectively, in the full analysis set. Next, we performed multivariate Cox proportional hazards regression analysis for progression-free survival (PFS) and overall survival (OS). Advanced-stage ovarian cancer patients with HRD had adjusted hazard ratios of 0.72 (95% CI, 0.55-0.94) and 0.57 (95% CI, 0.38-0.86) for PFS and OS, respectively, compared with those without HRD (p = 0.016 and 0.007). Our study demonstrated that mutations in HR-associated genes were associated with prognosis. Further studies are needed to investigate the prognostic impact of each HR-associated gene in ovarian cancer.
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Proteína BRCA1 , Neoplasias Ováricas , Femenino , Humanos , Proteína BRCA1/genética , Proteína BRCA2/genética , Recombinación Homóloga/genética , Neoplasias Ováricas/patologíaRESUMEN
BACKGROUND: This study aimed to evaluate the homologous recombination repair pathway deficiency (HRD) in ovarian high-grade serous carcinoma (HGSC). METHODS: In the ovarian cancer data from The Cancer Genome Atlas, we identified genes differentially expressed between tumours with and without HRD genomic scars and named these genes "HRDness signature". We performed SNP array, RNA sequencing, and methylation array analyses on 274 HGSC tumours for which targeted sequencing of 51 genes and clinical data were available to generate JGOG3025-TR2 dataset. The HRDness signature was tested on external datasets, including the JGOG3025-TR2 cohort, by computational scoring and machine-learning prediction. RESULTS: High scores and positive predictions of the HRDness signature were significantly associated with BRCA alterations, genomic scar scores, and better survival. On the other hand, among cases with high scores and/or positive predictions, those with BRCA1 methylation showed poorer survival. In the JGOG3025-TR2 cohort, HRD status was significantly associated with the use of olaparib after relapse and progression-free survival after its initiation. CONCLUSIONS: The HRDness gene expression signature is associated with a good prognosis, while BRCA1 methylation is associated with a poor prognosis. The newly generated JGOG3025-TR2 dataset will be useful in future HGSC studies.
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Carcinoma , Cistadenocarcinoma Seroso , Neoplasias Ováricas , Femenino , Humanos , Pronóstico , Mutación , Transcriptoma , Proteína BRCA2/genética , Recurrencia Local de Neoplasia/patología , Neoplasias Ováricas/genética , Cistadenocarcinoma Seroso/genéticaRESUMEN
Cancer treatment is increasingly evolving toward personalized medicine, which sequences numerous cancer-related genes and identifies therapeutic targets. On the other hand, patients with germline pathogenic variants (GPV) have been identified as secondary findings (SF) and oncologists have been urged to handle them. All SF disclosure considerations for patients are addressed and decided at the molecular tumor boards (MTB) in the facility. In this study, we retrospectively summarized the results of all cases in which comprehensive genomic profiling (CGP) test was conducted at our hospital, and discussed the possibility of presumed germline pathogenic variants (PGPV) at MTB. MTB recommended confirmatory testing for 64 patients. Informed consent was obtained from attending physicians for 53 of them, 30 patients requested testing, and 17 patients tested positive for a confirmatory test. Together with already known variants, 4.5 % of the total confirmed in this cohort. Variants verified in this study were BRCA1 (n = 12), BRCA2 (n = 6), MSH2 (n = 2), MSH6 (n = 2), WT1 (n = 2), TP53, MEN1, CHEK2, MLH1, TSC2, PTEN, RB1, and SMARCB1. There was no difference in the tumor's VAF between confirmed positive and negative cases for variants determined as PGPV by MTB. Current results demonstrate the actual number of cases until confirmatory germline test for patients with PGPV from tumor-only CGP test through the discussion at the MTB. The practical results at this single facility will serve as a guide for the management of the selection and distribution of SF in the genome analysis.
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Mutación de Línea Germinal , Neoplasias , Humanos , Estudios Retrospectivos , Mutación de Línea Germinal/genética , Neoplasias/diagnóstico , Neoplasias/genética , Genes BRCA2 , GenómicaRESUMEN
Advantages of lymphadenectomy for early stage endometrial cancer remain controversial. Lymphadenectomy had been routinely omitted for patients aged ≥ 70 years at our institute if lymph node metastasis was unsuspected due to an increased risk of peri- and postsurgical complications. Since 2013, with the introduction of minimally invasive surgery and considering the heterogeneous medical conditions, we started performing lymphadenectomy in patients who were considered well-tolerated. We retrospectively investigated our clinical database to assess the effect of lymphadenectomy in older patients with early stage endometrial carcinoma. Patients aged ≥ 70 years, preoperatively diagnosed with stage I endometrial carcinoma, and who underwent lymphadenectomy between 2013 and 2021 at Tohoku University Hospital were included in the lymphadenectomy group (n = 33), whereas patients who underwent surgery without lymphadenectomy before the end of 2012 were included in the no-lymphadenectomy group (n = 49). Clinical parameters and patient outcomes, such as disease-free survival (DFS) and disease-specific survival (DSS), were compared. The median age was significantly higher and fewer patients received adjuvant chemotherapy in the no-lymphadenectomy group. Neither DSS nor DFS differed significantly between the two groups. Five-year-DFS rates were 77.2% and 82.5% and 5-year-DSS rates were 89.7% and 97.8% for the lymphadenectomy and no-lymphadenectomy groups, respectively. No significant differences were observed in the subsequent survival analysis by substage, histological subtype, or risk of recurrence. Our results suggest that the indications for lymphadenectomy in older patients should be individually optimized according to the risk of recurrence and postoperative complications.
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AIM: Uterine cervical cancer (UCC) is the fourth most common cancer in women, responsible for more than 300 000 deaths worldwide. Its early detection, by cervical cytology, and prevention, by vaccinating against human papilloma virus, greatly contribute to reducing cervical cancer mortality in women. However, penetration of the effective prevention of UCC in Japan remains low. Plasma metabolome analysis is widely used for biomarker discovery and the identification of cancer-specific metabolic pathways. Here, we aimed to identify predictive biomarkers for the diagnosis and radiation sensitivity of UCC using wide-targeted plasma metabolomics. METHODS: We analyzed 628 metabolites in plasma samples obtained from 45 patients with UCC using ultra-high-performance liquid chromatography with tandem mass spectrometry. RESULTS: The levels of 47 metabolites were significantly increased and those of 75 metabolites were significantly decreased in patients with UCC relative to healthy controls. Increased levels of arginine and ceramides, and decreased levels of tryptophan, ornithine, glycosylceramides, lysophosphatidylcholine, and phosphatidylcholine were characteristic of patients with UCC. Comparison of metabolite profiles in groups susceptible and non-susceptible to radiation therapy, a treatment for UCC, revealed marked variations in polyunsaturated fatty acid, nucleic acid, and arginine metabolism in the group not susceptible to treatment. CONCLUSIONS: Our findings suggest that the metabolite profile of patients with UCC may be an important indicator for distinguishing these patients from healthy cohorts, and may also be useful for predicting sensitivity to radiotherapy.
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Neoplasias del Cuello Uterino , Humanos , Femenino , Neoplasias del Cuello Uterino/diagnóstico , Metabolómica/métodos , Biomarcadores , Metaboloma , Tolerancia a Radiación , Arginina/metabolismoRESUMEN
OBJECTIVE: Sentinel lymph node (SLN) biopsy has been incorporated into surgical care for many malignancies; however, the utility has not been examined in ovarian cancer. This study examined population-level trends, characteristics, and outcomes related to SLN biopsy in early stage ovarian cancer. METHODS: This is a retrospective cohort study querying the National Cancer Institute's Surveillance, Epidemiology, and End Result Program from 2003-2018. The study population consisted of 11,512 women with stage I ovarian cancer who had adnexectomy-based surgical staging including lymph node evaluation. Exposure allocation was based on SLN biopsy use. Main outcomes measured were (i) trends and characteristics associated with SLN biopsy use, assessed by multivariable logistic regression model, and (ii) overall survival assessed with inverse provability of treatment weighting propensity score. RESULTS: SLN biopsy was performed in less than 1% of study population. In a multivariable analysis, recent surgery (2011-2018 versus 2003-2010, odds ratio [OR] 1.64, 95% confidence interval [CI] 1.03-2.59), smaller tumor size (< 10 versus ≥ 10 cm, OR 3.07, 95% CI 1.20-7.84), and East registry area (OR 2.74, 95% CI 1.73-4.36) remained independent characteristics for SLN biopsy use. In a propensity score weighted model, 5-year overall survival rate was 90.5% for the SLN biopsy-incorporated group and 88.6% for the lymphadenectomy group (hazard ratio 0.96, 95% CI 0.53-1.73). CONCLUSION: SLN biopsy was rarely performed for early ovarian cancer surgery during the study period with insufficient evidence to interpret the survival effect. SLN biopsy in early ovarian cancer appears to be in early development phase, warranting further study and careful evaluation to assess feasibility and oncologic outcome.
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Neoplasias Ováricas , Ganglio Linfático Centinela , Femenino , Humanos , Biopsia del Ganglio Linfático Centinela , Estudios Retrospectivos , Metástasis Linfática/patología , Estadificación de Neoplasias , Ganglios Linfáticos/cirugía , Ganglios Linfáticos/patología , Escisión del Ganglio Linfático , Neoplasias Ováricas/cirugía , Neoplasias Ováricas/patología , Ganglio Linfático Centinela/patologíaRESUMEN
This study evaluated the feasibility and efficacy of three postoperative adjuvant chemotherapy regimens for endometrial cancer. Endometrioid cancer patients with intermediate-risk stage I and II or high-risk stage III and IV disease were randomly assigned to receive six cycles of either paclitaxel-epirubicin-carboplatin (TEC), paclitaxel-anthracycline (doxorubicin)-carboplatin (TAC), or dose-dense paclitaxel-carboplatin (ddTC). The primary end-point was the completion rate (CRate) of six cycles of treatment. The secondary end-points were progression-free survival (PFS) and overall survival (OS). One hundred and one patients were treated as follows: 33 received TEC, 33 TAC, and 35 ddTC. The CRates for TEC, TAC, and ddTC were 94%, 64%, and 69%, respectively (P = .005). The TEC CRate was significantly higher than for the other two groups. However, the PFS and OS outcomes were not statistically different between the three groups. The 2-year survival rates were 94%, 97%, and 97% for TEC, TAC, and ddTC, respectively. When compared to the current standard treatments for endometrial cancer, TEC is a promising candidate for a phase III trial based on its significantly superior CRate and equivalent PFS and OS. This study is registered with UMIN Clinical Trials Registry (UMIN000008911).
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Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Endometriales , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carboplatino/efectos adversos , Quimioterapia Adyuvante , Neoplasias Endometriales/tratamiento farmacológico , Femenino , Humanos , Estadificación de Neoplasias , Paclitaxel/uso terapéuticoRESUMEN
OBJECTIVE: The mainstay of treatment for uterine endometrial cancer is surgery, and recurrent-risk cases require multidisciplinary treatment, including surgery, chemotherapy and radiation therapy. METHODS: The standard surgery for uterine endometrial cancer is hysterectomy and bilateral salpingooophorectomy, with additional retroperitoneal lymph node dissection and omentectomy, depending on the case. The appropriate treatment is determined based on the risk classification, such as the depth of invasion into the myometrium, diagnosis of histological type and grade, and risk assessment of lymph node metastasis. RESULTS: Recently, minimally invasive surgery has been widely used not only in low-risk patients but also in intermediate- and high-risk patients. In low-risk patients, the possibility of ovarian preservation is discussed from a healthcare perspective for young women. Determining the need for retroperitoneal lymph node dissection based on sentinel lymph node evaluation may contribute in minimizing the incidence of post-operative lymphedema while ensuring accurate diagnosis of lymph node metastasis. Recently, many studies using sentinel lymph nodes have been reported for patients with uterine endometrial cancer, and the feasibility of sentinel lymph node mapping surgery has been proven. Unfortunately, sentinel lymph node biopsy and sentinel lymph node mapping surgery have not been widely adopted in surgery for uterine cancer in Japan. In addition, the search for biomarkers, such as RNA sequencing using The Cancer Genome Atlas, metabolic profile and lipidomic profile for early detection and prognostic evaluation, has been actively pursued. CONCLUSIONS: Gynecologic oncologists expect to be able to provide uterine endometrial cancer patients with appropriate treatment that preserves their quality of life without compromising oncologic outcomes in the near future.
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Neoplasias Endometriales , Calidad de Vida , Neoplasias Endometriales/patología , Neoplasias Endometriales/cirugía , Femenino , Humanos , Japón , Escisión del Ganglio Linfático , Ganglios Linfáticos/patología , Metástasis Linfática/patología , Biopsia del Ganglio Linfático CentinelaRESUMEN
OBJECTIVE: This retrospective analysis of a real-world database of open radical hysterectomy in Japan aimed to reveal the clinicopathological findings and clinical outcomes of low-risk patients with stage IB-IIA cervical cancer. METHODS: A total of 1143 stage IB1, IB2 and IIA1 (reclassified by FIGO 2018 staging system) patients with cervical cancer who underwent radical hysterectomy between January 2004 and December 2008 from the Japanese Gynecologic Oncology Group database were analyzed. Low-risk patients were defined as those without a tumor size exceeding 4 cm, parametrial tumor involvement, deep (outer half) stromal invasion, lymphovascular space invasion or lymph nodal metastasis. RESULTS: 61.2% (772/1262) patients with stage IB1, 32.1% (229/932) with stage IB2 and 16.9% (72/294) of stage IIA1 were classified into the low-risk group. The 5-year overall survival and disease-free survival rates were 98.4 and 93.7%, respectively. Histological classification did not affect the survival rates, but stage IIA cases had significantly lower overall survival and disease-free survival (83.5 and 93.8%, respectively) than stage IB cases. The independent prognostic factors for disease-free survival were older age (â§50), histology, clinical stage and clinical stage as independent prognostic factors for overall survival. Regarding recurrence, older age, non-SCC and stage IIA1 were independent risk factors for local recurrence, but stage IIA1 was the only independent risk factor for distant metastasis. CONCLUSION: We found that stage IIA1 was the strongest risk factor for survival and recurrence of low-risk uterine cervical cancer (FIGO, 2018). In low-risk cases, stage IIA1 should be considered separately from stage IB.
Asunto(s)
Neoplasias del Cuello Uterino , Humanos , Femenino , Neoplasias del Cuello Uterino/patología , Estudios Retrospectivos , Pronóstico , Estadificación de Neoplasias , Histerectomía , Factores de RiesgoRESUMEN
Although geographical differences in the distribution of human papillomavirus genotypes have been observed worldwide, no studies have reported on national differences in the prevalence of human papillomavirus types in Japan. Here, we report a cross-sectional study to explore regional differences in the prevalence of human papillomavirus types among Japanese women with cervical intraepithelial neoplasia or invasive cervical cancer. Using human papillomavirus genotyping data from the nationwide prospective study on human papillomavirus vaccine effectiveness, we compared the frequency of detection of 15 high-risk and two low-risk human papillomavirus types in each disease category between the women who visited hospitals located in eastern Japan and those who visited hospitals located in western Japan. The risk of cervical intraepithelial neoplasia progression was assessed by calculating a prevalence ratio of each human papillomavirus type for cervical intraepithelial neoplasia grade 2/3 versus grade 1. Among the human papillomavirus types studied, human papillomavirus 52 was detected significantly more frequently in western hospitals than in eastern hospitals in cervical intraepithelial neoplasia grade 1 patients, but was less frequent in cervical intraepithelial neoplasia grade 2/3. The prevalence of particular human papillomavirus types was not significantly different between patients in hospitals in eastern Japan and those in hospitals in western Japan for invasive cervical cancer. In both eastern and western hospitals, a higher risk of cervical intraepithelial neoplasia progression was observed in patients infected with human papillomavirus 16, 31 or 58. In contrast, there was a significantly higher prevalence of human papillomavirus 52 infection in women with cervical intraepithelial neoplasia grade 2/3 than in those with cervical intraepithelial neoplasia grade 1 in eastern hospitals (prevalence ratio, 1.93; 95% confidence interval, 1.48-2.58), but not in western hospitals (prevalence ratio, 1.03; 95% confidence interval, 0.83-1.30). Regional differences of human papillomavirus 52 prevalence in cervical intraepithelial neoplasia lesions may exist and emphasize the importance of continuous monitoring of human papillomavirus type prevalence throughout the country in order to accurately assess the efficacy of human papillomavirus vaccines.