Identification of target cells of human papillomavirus 18 using squamocolumnar junction organoids.

Human papillomavirus 18 (HPV18) is a highly malignant HPV genotype among high-risk HPVs, characterized by the difficulty of detecting it in precancerous lesions and its high prevalence in adenocarcinomas. The cellular targets and molecular mechanisms underlying its infection remain unclear. In this study, we aimed to identify the cells targeted by HPV18 and elucidate the molecular mechanisms underlying HPV18 replication. Initially, we established a lentiviral vector (HPV18LCR-GFP vector) containing the HPV18 long control region promoter located upstream of EGFP. Subsequently, HPV18LCR-GFP vectors were transduced into patient-derived squamocolumnar junction organoids, and the presence of GFP-positive cells was evaluated. Single-cell RNA sequencing of GFP-positive and GFP-negative cells was conducted. Differentially expressed gene analysis revealed that 169 and 484 genes were significantly upregulated in GFP-positive and GFP-negative cells, respectively. Pathway analysis showed that pathways associated with cell cycle and viral carcinogenesis were upregulated in GFP-positive cells, whereas keratinization and mitophagy/autophagy-related pathways were upregulated in GFP-negative cells. siRNA-mediated luciferase reporter assay and HPV18 genome replication assay validated that, among the upregulated genes, ADNP, FHL2, and NPM3 were significantly associated with the activation of the HPV18 early promoter and maintenance of the HPV18 genome. Among them, NPM3 showed substantially higher expression in HPV-related cervical adenocarcinomas than in squamous cell carcinomas, and NPM3 knockdown of HPV18-infected cells downregulated stem cell-related genes. Our new experimental model allows us to identify novel genes involved in HPV18 early promoter activities. These molecules might serve as therapeutic targets in HPV18-infected cervical lesions.

Impact of human papillomavirus types on uterine cervical neoplasia.

Human papillomavirus (HPV) is a major cause of cervical cancer. As the natural history of HPV-associated cervical lesions is HPV genotype-dependent, it is important to understand the characteristics of these genotypes and to manage them accordingly. Among high-risk HPVs, HPV16 and 18 are particularly aggressive, together accounting for 70% of HPV genotypes detected in cervical cancer. Other than HPV16 and 18, HPV31, 33, 35, 45, 52, and 58 are also at a high risk of progression to cervical intraepithelial neoplasia (CIN)3 or higher. Recent studies have shown that the natural history of HPV16, 18, 52, and 58, which are frequently detected in Japan, depends on the HPV genotype. For example, HPV16 tends to progress in a stepwise fashion from CIN1 to CIN3, while HPV52 and 58 are more likely to persist in the CIN1 to CIN2 state. Among the high-risk HPVs, HPV18 has some peculiar characteristics different from those of other high-risk HPV types; the detection rate in precancerous lesions is much lower than those of other high-risk HPVs, and it is frequently detected in highly malignant adenocarcinoma and small cell carcinoma. Recent findings demonstrate that HPV18 may be characterized by latent infection and carcinogenesis in stem cell-like cells. In this context, this review outlines the natural history of HPV-infected cervical lesions and the characteristics of each HPV genotype.

Risk stratification of invasive cervical cancer diagnosed after cervical conization.

BACKGROUND: Cervical intraepithelial neoplasia (CIN) diagnosis is based on colposcopy-aided histological examination. However, its accuracy in CIN diagnosis is limited. Some invasive cervical cancers (ICCs) are diagnosed after cervical conization. Therefore, risk stratification of undetected ICC is particularly important for the management of patients with CIN. This study aimed to identify the risk factors for undetected ICC. We especially focused on the association of human papillomavirus (HPV) genotypes. METHODS: We retrospectively reviewed the clinicopathological characteristics (including age, parity, and preoperative diagnosis) and HPV genotypes of 348 patients diagnosed with CIN or adenocarcinoma in situ (AIS) who underwent cervical conization at our hospital between 2008 and 2016. The relationship between preoperative factors, including HPV genotypes and post-conization ICC, was evaluated. RESULTS: Among the 348 patients, 322, 7, and 19 had preoperative CIN3, CIN2, and AIS, respectively; 181 were nulliparous. The median patient age was 41 (23-83) years. HPV genotyping was performed on 237 patients. Overall, post-conization ICC was detected in 16 patients (4.6%). Multivariate analysis showed that nulliparity and HPV16 positivity were the independent risk factors for post-conization ICC (OR: 6.01, P = 0.0302; OR: 5.26, P = 0.0347, respectively). The combination of HPV16 status and parity improved diagnostic accuracy. Seven of 53 HPV16-positive cases (13%) without childbirth history were diagnosed with post-conization ICC. In contrast, none of the HPV16-negative cases with childbirth history was diagnosed with post-conization ICC. CONCLUSION: HPV16 positivity and nulliparity were identified as risk factors for undetected ICC. Careful treatment selection and preoperative scrupulous examination are especially important in these cases.

Efficacy of regional cooling + oral dexamethasone for primary prevention of hand-foot syndrome associated with pegylated liposomal doxorubicin.

PURPOSE: Pegylated liposomal doxorubicin (PLD)-induced hand-foot syndrome (HFS) frequently lowers the quality of life of ovarian cancer patients. Wrist and ankle cooling, having a limited preventive effect, has been the commonest supportive HFS care. In this study, we retrospectively assessed the primary preventive effect of a combination of regional cooling and oral dexamethasone therapy (cooling + oral Dex) on HFS. METHODS: This study is a single-arm retrospective, observational study. Recurrent ovarian cancer patients were administered PLD ± bevacizumab. We retrospectively examined the efficacy of hands and feet cooling (from the start of PLD to the end) + oral Dex (day 1-5: 8 mg/day, day 6, 7: 4 mg/day) for primary HFS prevention. RESULTS: This study included 74 patients. The initial dose of PLD was 50 mg/m2 and 40 mg/m2 for 32 (43.2%) and 42 (56.8%) patients, respectively. HFS of Grade ≥ 2 and Grade ≥ 3 developed in five (6.8%) and one (1.4%) patient(s), respectively. The incidence of ≥ Grade 2 and ≥ Grade 3 HFS was much lower than those reported in previous studies. Dose reduction was required in 13 patients (17.6%) mainly because of neutropenia or mucositis; there was no HFS-induced dose reduction. Meanwhile, PLD therapy was discontinued mainly because of interstitial pneumonia (4 patients) and HFS (one patient). CONCLUSIONS: We demonstrated the efficacy of regional cooling and oral Dex for primary prevention of PLD-induced HFS. Although future prospective studies are needed to confirm its efficacy, this combination therapy can be considered for primary prevention of HFS in ovarian cancer patients on PLD.

Carcinogenesis and management of human papillomavirus-associated cervical cancer.

Approximately 95% of cervical cancer are caused by human papillomavirus (HPV) infection. Although it is estimated that HPV-associated cervical cancer will decrease with the widespread use of HPV vaccine, it may take time for HPV-associated cervical cancer to be eliminated. For the appropriate management of HPV-associated cervical cancer, it is important to understand the detailed mechanisms of cervical cancer development. First, the cellular origin of most cervical cancers is thought to be cells in the squamocolumnar junction (SCJ) of the uterine cervix. Therefore, it is important to understand the characteristics of SCJ for cervical cancer screening and treatment. Second, cervical cancer is caused by high risk HPV (HR-HPV) infection, however, the manner of progression to cervical cancer differs depending on the type of HR-HPV: HPV16 is characterized by a stepwise carcinogenesis, HPV18 is difficult to detect in precancerous lesions, and HPV52, 58 tends to remain in the state of cervical intraepithelial neoplasia (CIN). Third, in addition to the type of HPV, the involvement of the human immune response is also important in the progression and regression of cervical cancer. In this review, we demonstrate the carcinogenesis mechanism of HPV-associated cervical cancer, management of CIN, and the current treatment of CIN and cervical cancer.

Heterogeneous effects of cytotoxic chemotherapies for platinum-resistant ovarian cancer.

BACKGROUND: Single-agent chemotherapy with or without bevacizumab (Bev) is a standard therapy for platinum-resistant ovarian cancer (PR-OC). However, there is a lack of literature on chemotherapy agent selection in heterogenous PR-OC. Therefore, we aimed to clarify the heterogeneous treatment effects of each chemotherapy agent. METHODS: Patients who underwent single-drug chemotherapy agents or Bev combination therapy for PR-OC between January 2009 and June 2022 were included in this study. We assessed the impact of each chemotherapy agent on the time to treatment failure (TTF) according to histological type, platinum-free interval (PFI), and Bev usage. RESULTS: A total of 158 patients received 343 different chemotherapy regimens. In patients with clear cell carcinoma/mucinous carcinoma (CC/MC), gemcitabine (GEM) had the strongest effect with a median TTF of 5.3 months, whilst nedaplatin (NDP) had the lowest effect with a median TTF of 1.4 months. In contrast, in the non-CC/MC group, irinotecan (CPT-11) and NDP had a better TTF than GEM and pegylated liposomal doxorubicin (PLD). There were notable differences in the treatment efficacy of NDP according to PFI. Specifically, NDP prolonged the TTF in patients with a PFI ≥ 3 months. Compared with GEM alone, GEM + Bev tended to prolong the TTF more effectively; however, an additive effect was not observed with PLD + Bev. CONCLUSIONS: This study demonstrated that the effect of chemotherapy agents differed according to the tumor and background characteristics of the patient. Our findings will improve selection of effective therapies for patients with PR-OC by considering their background characteristics.

A case of refractory pelvic squamous cell carcinoma of unknown primary that responded to nivolumab.

Cancer of unknown primary (CUP) is a heterogeneous group of metastatic tumors with a usually unfavorable prognosis. A 33-year-old female was diagnosed with pelvic squamous cell carcinoma of unknown primary. The tumor was p16-positive, suggesting that it was human papillomavirus (HPV)-related. The tumor progressed for 4 months after concurrent chemoradiotherapy (initial treatment) and was refractory to paclitaxel plus carboplatin (second-line therapy). Liquid-based cancer genomic profiling identified five pathogenic variants, including Neurofibromin1 (NF1) (p.T1690Mfs*5); however, due to the lack of domestic clinical trials, the patient could not receive genome-based molecular-target therapies. Simultaneously, nivolumab was administered to the patient post its approval in Japan for CUP. The tumor responded to nivolumab, accompanied by decreased levels of tumor markers. NF1 mutations and HPV-related carcinogenesis may be associated with a favorable response to nivolumab treatment. It may therefore serve as a potential treatment against cancers of unknown primaries.

Prognosis of patients with endometrial cancer or atypical endometrial hyperplasia after complete remission with fertility-sparing therapy.

PURPOSE: Although many patients with endometrial cancer (EC) or atypical endometrial hyperplasia (AEH) achieve complete remission (CR) after high-dose medroxyprogesterone acetate (MPA) treatment, no consensus has been reached on management after CR. Currently, patients receive estrogen-progestin maintenance therapy, but no recommendations exist regarding the duration of maintenance therapy or whether hysterectomy should be considered. This study aimed to provide insights into the management of EC/AEH after achieving CR. METHODS: We retrospectively investigated the prognosis of 50 patients with EC or AEH who achieved CR after MPA therapy. We assessed the association between disease recurrence and clinicopathological features and the pre- and post-operative histological diagnoses of patients who underwent hysterectomy. RESULTS: The median follow-up duration was 34 months (range: 1-179 months). Recurrence was observed in 17 patients. Among the clinical characteristics investigated, only the primary disease was significantly associated with disease recurrence; patients with EC had a higher risk of recurrence than those with AEH (p = 0.037). During the observation period, 27 patients attempted pregnancy, and 14 pregnancies resulted in delivery. Patients who gave birth had significantly longer relapse-free survivals than those who did not (p = 0.031). Further, 16 patients underwent hysterectomies, and AEH was detected postoperatively in 4 of 11 patients (36.4%) with no preoperative abnormalities. CONCLUSIONS: We identified several clinical features of patients with EC and AEH after CR. Given the high probability of endometrial abnormalities detected postoperatively, hysterectomy may be considered for patients who no longer want children.

Regional differences in human papillomavirus type 52 prevalence among Japanese women with cervical intraepithelial neoplasia†.

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.

Endometrial cancer with concomitant endometriosis is highly associated with ovarian endometrioid carcinoma: a retrospective cohort study.

BACKGROUND: Endometriosis is assumed to be involved in ovarian cancer development, which is called endometriosis-associated ovarian cancer (EAOC). Uterine endometrial cells may be the cell of origin of EAOC. Accumulated carcinogenic changes in the uterine endometrial cells may increase the risk of developing EAOC. To further understand the pathogenesis of EAOCs, we focused on the clinicopathological characteristics of EAOCs in endometrial cancer patients with concomitant endometriosis. METHODS: We retrospectively reviewed 376 patients who were surgically treated for stage I-III endometrial cancer. Clinicopathological characteristics were compared between patients with and without endometriosis. Furthermore, the incidence of simultaneous endometrial and ovarian cancer (SEOC) and the histological characteristics of SEOC were compared between the two groups. RESULTS: Among 376 patients with endometrial cancer, 51 had concomitant endometriosis. Patients with endometriosis were significantly younger and more frequently had endometrioid G1/G2 tumors than those without endometriosis. The incidence of SEOCs was significantly higher in endometrial cancer patients with endometriosis than those without it (p < 0.0001); notably, 12 of 51 endometrial cancer patients with endometriosis (24%) had SEOCs. All of the ovarian cancers in endometrial cancer patients with endometriosis were endometrioid carcinomas. Moreover, even in those without endometriosis, endometrioid carcinoma was the most common histological type of SEOC. CONCLUSION: We revealed that endometrial cancer patients with endometriosis had a high probability of SEOC and that endometrioid carcinoma was the most common histological subtype of SEOC regardless of the presence of endometriosis. For patients with endometrial cancer and endometriosis, careful examination of ovarian endometriotic lesions may be important to detect EAOCs.

Transiently elevated D-dimer levels post-concentrated ascites reinfusion therapy cannot be used to predict deep vein thrombosis-pulmonary embolism.

AIM: Cell-free and concentrated ascites reinfusion therapy (CART) is useful for treating malignant ascites. We have previously experienced cases with no DVT-PE despite a marked elevation in D-dimer post-CART. In this study, we assessed the changes in the D-dimer levels in patients who received CART and investigated the association between elevated D-dimer levels and occurrence of DVT-PE. METHODS: We performed an observational retrospective analysis of patients with gynecological malignancies treated with CART between March 2018 and April 2021. The selected patients had their D-dimer levels measured before and post-CART. The presence or absence of clinical DVT-PE findings was then examined, and contrast-enhanced computed tomography was performed using a DVT protocol in some cases. RESULTS: Eleven patients received 17 CART procedures in this study. Patients of 16 procedures (94.1%) showed a significant elevation in D-dimer levels on day 1 post-CART. Changes in D-dimer levels were monitored in these patients of 16 procedures. In all 16 cases, the D-dimer levels decreased after day 2 post-CART. Only one patient, who presented with respiratory failure, out of the patients of 16 procedures (6.2%) with elevated D-dimer levels on day 1 had PE. CONCLUSIONS: D-dimer elevation after CART is likely to be transient and a false-positive. None of the patients in this study had PE if they were asymptomatic after CART, there is no need to strongly suspect PE only by D-dimer elevation. In conclusion, D-dimer measurement immediately post-CART is not helpful in predicting the diagnosis of DVT-PE.

A low preoperative albumin-to-globulin ratio is a negative prognostic factor in patients with surgically treated cervical cancer.

BACKGROUND: The albumin-to-globulin ratio reflects both the nutrition and inflammation and predicts prognosis in patients with various malignancies. However, in cervical cancer patients who undergo surgery, its significance has yet to be established. METHODS: A total of 247 cervical cancer patients who received surgical treatment at our institution between 2005 and 2017 were enrolled in this study. Preoperative data, such as the levels of serum albumin and serum globulin as well as the albumin-to-globulin ratio along with the other clinicopathological characteristics were retrospectively assessed, and their association with the overall survival was analyzed. RESULTS: Overall, 49 cases of recurrence and 26 deaths were observed during the median follow-up time of 58.6 months. A low albumin-to-globulin ratio (< 1.345) as well as low albumin (< 3.25 g/dL) and high globulin levels (≥ 3.25 g/dL) were significantly associated with poor prognosis. According to the multivariate analysis, a low albumin-to-globulin ratio was an independent prognostic factor for overall survival (HR = 2.59, 95% CI 1.12-5.96, P = 0.026); however, low albumin or high globulin levels was not associated with the overall survival. Among the clinicopathological characteristics, older age, diabetes mellitus, hypertension, larger tumor size, and parametrial invasion were associated with a low albumin-to-globulin ratio. CONCLUSION: A low albumin-to-globulin ratio was associated with a poor prognosis in patients with surgically treated invasive cervical cancer. Therefore, the albumin-to-globulin ratio may serve as a prognostic marker, which predicts a worse prognosis.

History of whole pelvis plus para-aortic radiation is a risk factor associated with febrile neutropenia during chemotherapy for recurrent cervical cancer.

BACKGROUND: Radiation-based therapy is widely used for advanced cervical cancer. Prior radiation-based therapy is a potential risk factor for febrile neutropenia (FN). However, the effect of irradiation field size on the incidence of FN during recurrent cervical cancer treatment is unclear. This study aimed to investigate the relationship between prior irradiation field size and FN development during recurrent chemotherapy. METHODS: This retrospective, observational study included cervical cancer patients who received recurrent chemotherapy between November 2006 and June 2020. The patients were classified into two groups based on the area of irradiation fields. The first group included patients with a history of whole pelvis (WP) irradiation (WP group). The second group had patients who underwent WP plus para-aortic lymph node (PAN) irradiation (WP + PAN group). The incidences of hematological toxicities and FN during the recurrent chemoradiotherapy were compared between the two groups. RESULTS: The FN incidence was significantly higher in the WP + PAN group than in the WP group (32.1% vs. 0%, P < 0.001). The incidence of Grade 4 neutropenia was not significantly different between the WP + PAN and WP groups. The nadir absolute neutrophil counts were significantly lower and the dose reduction or discontinuation rate of chemotherapy was significantly higher in the WP + PAN group than in the WP group. CONCLUSION: History of WP plus PAN radiation is a risk factor for developing FN during recurrent cervical cancer chemotherapy.

Application of artificial intelligence in gynecologic malignancies: A review.

With the development of machine learning and deep learning models, artificial intelligence is now being applied to the field of medicine. In oncology, the use of artificial intelligence for the diagnostic evaluation of medical images such as radiographic images, omics analysis using genome data, and clinical information has been increasing in recent years. There have been increasing numbers of reports on the use of artificial intelligence in the field of gynecologic malignancies, and we introduce and review these studies. For cervical and endometrial cancers, the evaluation of medical images, such as colposcopy, hysteroscopy, and magnetic resonance images, using artificial intelligence is frequently reported. In ovarian cancer, many reports combine the assessment of medical images with the multi-omics analysis of clinical and genomic data using artificial intelligence. However, few study results can be implemented in clinical practice, and further research is needed in the future.

Differential expression of human papillomavirus 16-, 18-, 52-, and 58-derived transcripts in cervical intraepithelial neoplasia.

BACKGROUND: Human papillomavirus (HPV) infection is a primary cause of cervical cancer. Although epidemiologic study revealed that carcinogenic risk differs according to HPV genotypes, the expression patterns of HPV-derived transcripts and their dependence on HPV genotypes have not yet been fully elucidated. METHODS: In this study, 382 patients with abnormal cervical cytology were enrolled to assess the associations between HPV-derived transcripts and cervical intraepithelial neoplasia (CIN) grades and/or HPV genotypes. Specifically, four HPV-derived transcripts, namely, oncogenes E6 and E6*, E1^E4, and viral capsid protein L1 in four major HPV genotypes-HPV 16, 18, 52, and 58-were investigated. RESULTS: The detection rate of E6/E6* increased with CIN progression, whereas there was no significant change in the detection rate of E1^E4 or L1 among CIN grades. In addition, we found that L1 gene expression was HPV type-dependent. Almost all HPV 52-positive specimens, approximately 50% of HPV 58-positive specimens, around 33% of HPV 16-positive specimens, and only one HPV18-positive specimen expressed L1. CONCLUSIONS: We demonstrated that HPV-derived transcripts are HPV genotype-dependent. Especially, expression patterns of L1 gene expression might reflect HPV genotype-dependent patterns of carcinogenesis.

Desensitization strategy for hypersensitivity reactions to carboplatin in five patients with gynecological cancer.

AIM: Carboplatin is a key drug for gynecologic cancers. However, hypersensitivity reactions (HSR) are major adverse effects that might necessitate carboplatin discontinuation. Desensitization is an effective method in patients who developed initial HSR and further required carboplatin treatment. Here, we aimed to evaluate our experience with the use of the carboplatin desensitization protocol in five patients at the University of Tokyo Hospital. METHODS: We established a four-step, 5-h desensitization protocol for our hospital. Observational and retrospective analyses were performed. Additionally, we have shared the patients' clinical information with the emergency department to ensure the safety of this protocol. RESULTS: Five patients with recurrent gynecological cancer were treated using this protocol. Four of the five patients were treated effectively and 28 of 29 desensitization protocols were completed successfully. In one patient, we switched to olaparib successfully after two courses of our protocol. One patient who developed grade 4 HSR during initial carboplatin administration developed grade 2 HSR and we discontinued the protocol. CONCLUSION: The carboplatin desensitization protocol is very efficient. The outcome of our protocol was on a par with other protocols. To the best of our knowledge, this is the first study to indicate that switching to olaparib can be considered a suitable option in patients who develop HSR to carboplatin.

Blood Vessel Invasion Is a Strong Predictor of Postoperative Recurrence in Endometrial Cancer.

OBJECTIVES: Although lymphovascular space invasion is a prognostic factor for the recurrence of resectable endometrial cancer, the differential impacts of lymphatic vessel invasion (LVI) and blood vessel invasion (BVI) on the recurrence of endometrial cancer are poorly described. We investigated the prognostic significance of LVI and BVI on the recurrence of endometrial cancer and their association with patterns of recurrence. METHODS: We retrospectively reviewed 376 patients with stage I to III endometrial cancer who underwent surgery with curative intent at our institution between 2007 and 2015. The associations of the presence of lymphovascular space invasion or LVI and BVI with recurrence-free survival and patterns of recurrence were evaluated. RESULTS: Lymphovascular space invasion positivity was an independent prognostic factor for recurrence-free survival (hazards ratio [HR], 3.070; 95% confidence interval [CI], 1.404-6.824; P = 0.0048). However, when categorized by LVI versus BVI, the latter was a strong independent prognostic factor (HR, 2.697; CI, 1.288-5.798; P = 0.0081), whereas the former was not (HR, 1.740; CI, 0.795-3.721; P = 0.1637). Hematogenous metastasis was the most prevalent form of recurrence in endometrial cancer (24 [50%] of all 48 recurrent cases). Notably, 17 (19.5%) of 87 patients with BVI developed hematogenous metastases, compared with 7 (2.4%) of 289 without BVI (χ test, P < 0.0001). CONCLUSIONS: Blood vessel invasion rather than LVI was a strong predictor of postoperative recurrence in stage I to III endometrial cancer, probably due to its predisposition to hematogenous metastases.

Radical hysterectomy with or without para-aortic lymphadenectomy for patients with stage IB2, IIA2, and IIB cervical cancer: outcomes for a series of 308 patients.

BACKGROUND: Although many studies have already shown that lymph node metastasis is one of the major prognostic factors for cervical cancer, the therapeutic significance of para-aortic lymphadenectomy for the surgical treatment of cervical cancer remains controversial. METHODS: A total of 308 patients diagnosed with stage IB2, IIA2, or IIB cervical cancer and treated with radical hysterectomy were retrospectively investigated to assess the incidence of para-aortic lymph node metastasis and the clinicopathological factors linked to cervical cancer prognosis. RESULTS: Para-aortic lymph node metastases were pathologically confirmed in 13 of the 136 patients (9.6 %) who underwent para-aortic lymphadenectomy. The incidence of para-aortic lymph node metastasis was significantly higher in the patients who had common iliac lymph node metastases (odds ratio 31.5, p < 0.001) according to logistic regression analysis. Common iliac lymph node metastasis was related to risk of recurrence (hazard ratio 2.43, p = 0.003) and death (hazard ratio 2.62, p = 0.007) in Cox regression analysis. Kaplan-Meier analysis and Cox regression analysis showed that para-aortic lymphadenectomy did not have a positive impact on survival in 308 patients or 140 pN1 patients, but para-aortic lymphadenectomy was related to better overall survival with a marginal trend toward significance (p = 0.053) in 30 patients with common iliac lymph node metastasis. CONCLUSIONS: Indication for para-aortic lymphadenectomy in the surgical treatment of stage IB2, IIA2, or IIB cervical cancer needs to be individualized. Patients with common iliac lymph node metastasis are possible candidates, and a prospective study is needed to clarify this issue.

Rare case of endometrioid adenocarcinoma arising from cystic adenomyosis.

Few reports on malignant transformation of adenomyosis are available, and endometrioid adenocarcinoma arising from cystic adenomyosis is further rarely reported. We report a case of a 67-year-old asymptomatic woman who was referred to our hospital for evaluation of a cystic lesion in the pelvis, which had been diagnosed as cystic degeneration of leiomyoma for 3 years. Magnetic resonance imaging revealed a cystic mass measuring 11 cm in diameter, which was contiguous with uterine myometrium. The lesion contained solid areas enhanced on gadolinium-enhanced T1 -weighted imaging. Transabdominal simple total hysterectomy with bilateral salpingo-oophorectomy was performed. Pathological examination revealed endometrioid adenocarcinoma arising from cystic adenomyosis. The patient underwent six courses of adjuvant combination chemotherapy with paclitaxel and carboplatin. No metastasis or recurrence has been demonstrated for 16 months following surgery. Our case demonstrates that cystic adenomyoma possesses the risk of malignant transformation, indicating the importance of long-term follow-up with imaging examination.

Allelic loss of HLA class I facilitates evasion from immune surveillance in cervical intraepithelial neoplasia.

Loss of heterozygosity (LOH) has been reported to occur in HLA regions in cervical intraepithelial neoplasia (CIN) and cervical cancer. However, the details of how this is related to the progression of CIN have been unclear. In this study, we examined the human papillomavirus (HPV) antigen-presenting capacity of people with CIN and the significance of LOH of HLA class I in the progression of CIN. It was shown that differences in antigen-presenting capacity among each case depended on HLA types, not HPV genotypes. Focusing on the HLA type, there was a positive correlation between antigen-presenting capacity against HPV and the frequency of allelic loss. Furthermore, the lost HLA-B alleles had a higher HPV antigen-presenting capacity than intact alleles. In addition, frequency of LOH of HLA class I was significantly higher in advanced CIN (CIN2-3) than in cervicitis or early-stage CIN (CIN1): around half of CIN2-3 had LOH of any HLA class I. Moreover, the antigen-presenting capacity against E5, which is the HPV proteins that facilitate viral escape from this immune surveillance by suppressing HLA class I expression, had the most significant impact on the LOH in HLA-B. This study suggests that HPV evades immune surveillance mechanisms when host cells lose the capacity for antigen presentation by HLA class I molecules, resulting in long-term infection and progression to advanced lesions.