Therapeutic effects of surgical debulking of metastatic lymph nodes in cervical cancer IIICr: a trial protocol for a phase III, multicenter, randomized controlled study (KGOG1047/DEBULK trial).

BACKGROUND: Bulky or multiple lymph node (LN) metastases are associated with poor prognosis in cervical cancer, and the size or number of LN metastases is not yet reflected in the staging system and therapeutic strategy. Although the therapeutic effects of surgical resection of bulky LNs before standard treatment have been reported in several retrospective studies, well-planned randomized clinical studies are lacking. Therefore, the aim of the Korean Gynecologic Oncology Group (KGOG) 1047/DEBULK trial is to investigate whether the debulking surgery of bulky or multiple LNs prior to concurrent chemoradiation therapy (CCRT) improves the survival rate of patients with cervical cancer IIICr diagnosed by imaging tests. METHODS: The KGOG 1047/DEBULK trial is a phase III, multicenter, randomized clinical trial involving patients with bulky or multiple LN metastases in cervical cancer IIICr. This study will include patients with a short-axis diameter of a pelvic or para-aortic LN ≥2 cm or ≥3 LNs with a short-axis diameter ≥1 cm and for whom CCRT is planned. The treatment arms will be randomly allocated in a 1:1 ratio to either receive CCRT (control arm) or undergo surgical debulking of bulky or multiple LNs before CCRT (experimental arm). CCRT consists of extended-field external beam radiotherapy/pelvic radiotherapy, brachytherapy and LN boost, and weekly chemotherapy with cisplatin (40 mg/m²), 4-6 times administered intravenously. The primary endpoint will be 3-year progression-free survival rate. The secondary endpoints will be 3-year overall survival rate, treatment-related complications, and accuracy of radiological diagnosis of bulky or multiple LNs. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05421650; Clinical Research Information Service Identifier: KCT0007137.

Lugol's Solution Reduces Positive Margins and Residual Disease After the Large Loop Excision of Transformation Zone.

OBJECTIVE: This study aimed to examine whether the intraoperative use of Lugol's solution reduces the proportion of positive resection margins (RMs) using the data of women who underwent large loop excision of the transformation zone (LLETZ). MATERIALS AND METHODS: A total of 1,751 consecutive women with cervical intraepithelial neoplasia (CIN) who underwent LLETZ with or without Lugol's solution were retrospectively retrieved from each database of 3 university hospitals in South Korea. Outcomes included positive RMs and residual disease pathologically confirmed within 6 months after LLETZ. RESULTS: Positive RMs were noted in 345 cases (19.7%). Among 1,507 women followed up, residual disease was diagnosed in 100 cases (6.6%) (69/308 cases with positive RMs; 31/1,199 cases with negative RMs). The Lugol's solution group was less likely to have positive RMs (11.8% vs 25.5%, p < .01), to require additional surgical intervention (5.4% vs 10.2%, p < .01), and to have residual disease (4.9% vs 8.0%, p = .02). On multiple logistic regression analysis, Lugol's solution reduced the proportion of positive RMs (adjusted odds ratio [aOR], 0.31). Age (50 years or older; aOR, 1.64), preconization cervical cytology (aOR, 1.53), high-risk human papillomavirus (aOR, 1.75), and CIN 2 or 3 (aOR, 2.65) were independent risk factors for margin positivity ( p < .01 for all except high-risk human papillomavirus of p = .05). CONCLUSIONS: Lugol's solution optimizes CIN treatment by reducing the proportion of positive RMs and residual disease after LLETZ.

Clinical efficacy of a novel method of fertility-preserving adenomyomectomy in infertile women with diffuse adenomyosis.

Beneficial and detrimental effect of surgical adenomyomectomy is still controversial in infertile women with severely diffuse adenomyosis. The primary objective of this study was to assess whether a novel method of fertility-preserving adenomyomectomy could improve pregnancy rates. The secondary objective was to evaluate whether it could improve dysmenorrhea and menorrhagia symptoms in infertile patients with severe adenomyosis. A prospective clinical trial was conducted between December 2007 and September 2016. Fifty women with infertility due to adenomyosis were enrolled in this study after clinical assessments by infertility experts. A novel method of fertility-preserving adenomyomectomy was performed on 45 of 50 patients. The procedure included T- or transverse H-incision of the uterine serosa followed by preparation of the serosal flap, excision of the adenomyotic tissue using argon laser under ultrasonographic monitoring, and a novel technique of suturing between the residual myometrium and serosal flap. After the adenomyomectomy, the changes in the amount of menstrual blood, relief of dysmenorrhea, pregnancy outcomes, clinical characteristics, and surgical features were recorded and analyzed. All patients obtained dysmenorrhea relief 6 months postoperatively (numeric rating scale [NRS]; 7.28 ±â€…2.30 vs 1.56 ±â€…1.30, P < .001). The amount of menstrual blood decreased significantly (140.44 ±â€…91.68 vs 66.33 ±â€…65.85 mL, P < .05). Of the 33 patients who attempted pregnancy postoperatively, 18 (54.5%) conceived either by natural means, in vitro fertilization and embryo transfer (IVF-ET), or thawing embryo transfer. Miscarriage occurred in 8 patients, while 10 (30.3%) had viable pregnancies. This novel method of adenomyomectomy resulted in improved pregnancy rates, as well as relief of dysmenorrhea and menorrhagia. This operation is effective in preserving fertility potential in infertile women with diffuse adenomyosis.

Preservation of the ovarian reserve and hemostasis during laparoscopic ovarian cystectomy by a hemostatic agent versus suturing for patients with ovarian endometriosis: study protocol for randomized controlled, non-inferiority trial (PRAHA-2 trial).

BACKGROUND: Endometriosis (EMS) can be implanted everywhere, especially in pelvic organs. EMS can be asymptomatic, but it can result in pelvic pain and infertility by inducing local inflammation and pelvic adhesion. The prevalence of EMS is about 10% in reproductive-age women and higher in women with pelvic pain or infertility. For young patients with ovarian EMS, laparoscopic ovarian cystectomy is effective in relieving pelvic pain and preventing local recurrence. However, there is a concern that the ovarian reserve would decrease after the operation because of the removal of a part of the normal ovarian tissue and thermal damage during hemostasis, which depends on the types of hemostasis such as bipolar electrocoagulation, suturing, and the use of a hemostatic agent. In this study, we aim to evaluate the protective effect for the ovarian reserve and hemostasis between a hemostatic agent and suturing during laparoscopic ovarian cystectomy for patients with ovarian EMS. METHODS: This study is a randomized controlled, non-inferiority trial, where a total of 90 patients with ovarian EMS will be randomly assigned to the experimental (hemostatic agent) and control (suturing) groups. In the control group, a barbed suture will be applied for hemostasis, whereas a hemostatic agent will be applied in the experimental group. If two methods are insufficient, bipolar electrocoagulation will be applied for complete hemostasis. As the primary endpoint, the reduction rate of serum anti- Müllerian hormone (AMH) levels reflecting the ovarian reserve will be compared between the two groups 12 weeks after surgery. As secondary endpoints, we will compare the reduction rate of AMH level 48 weeks after surgery, the time required to complete hemostasis, the success rate of hemostasis within 10 min, and adverse events associated with operation. DISCUSSION: We expect that the protective effect for the ovarian reserve and hemostasis may be comparable between the two methods, suggesting that a hemostatic agent may be preferred considering that it is easy to use during laparoscopic ovarian cystectomy. TRIAL REGISTRATION: ClinicalTrials.gov NCT04643106 . Registered on 22 November 2020.

Anti-N-methyl-D-aspartate Receptor Encephalitis: a Rare Complication of Ovarian Teratoma.

Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is a potentially life-threatening but reversible autoimmune disorder characterized by psychiatric symptoms, cognitive dysfunction, speech dysfunction, seizures, movement disorder, decreased level of consciousness, and autonomic dysfunction or central hypoventilation. It occurs predominantly in young women and approximately half of them have underlying tumors, mainly ovarian teratoma. A 24-year old woman was admitted because of fever, headache, abnormal movement and decreased mental status. Five cycles of plasmapheresis improved her neurological and mental status. Anti-NMDAR antibodies in her CSF and serum were positive, and computed tomography revealed a 1-cm sized mass suggestive of mature cystic teratoma arising from the right ovary. We promptly performed laparoscopic right ovarian cystectomy. She was discharged after 2 weeks with mild memory deficit. Prompt removal of ovarian teratoma and multidisciplinary care are particularly important for good outcome.

Type-Specific Viral Load and Physical State of HPV Type 16, 18, and 58 as Diagnostic Biomarkers for High-Grade Squamous Intraepithelial Lesions or Cervical Cancer.

PURPOSE: High rate of false-positive tests is a major obstacle to use human papillomavirus (HPV) detection as a diagnostic tool for high-grade squamous intraepithelial lesions or cervical cancer (HSIL+). We investigated whether type-specific viral load or physical state of HPV 16, 18, and 58 are useful biomarkers for HSIL+. MATERIALS AND METHODS: Type-specific viral loads of E6 and E2 genes in cervical cells from 240, 83, and 79 HPV 16-, 18-, and 58-infected women, respectively, were determined using real-time polymerase chain reaction. Viral loads were normalized to cellular DNA (copy/cell). Total and integrated viral loads and physical state were compared between HSIL+ and controls, and diagnostic value was determined using receiver operating characteristic analysis. RESULTS: Viral loads of HPV 16, 18, and 58 were significantly different in lesions in the same pathologic grade. High type-specific total viral loads were significantly associated with HSIL+ (odds ratio [OR], 14.065, 39.472, and 7.103 for HPV 16, 18, and 58, respectively). High integrated viral load was related to HSIL+ in women with HPV 16 (OR, 8.242), and integrated state was associated with HSIL+ in women with HPV 18 (OR, 9.443). Type-specific total viral load was significantly associated with HSIL+ (area under curve, 0.914, 0.937, and 0.971 for HPV 16, 18, and 58, respectively), indicating an excellent performance in detecting HSIL+. CONCLUSION: Type-specific total viral load may be a powerful diagnostic marker for HSIL+ in HPV 16-, 18-, and 58-infected HSIL+ lesions. If demonstrated in all other high-risk HPV types, this method can lead to a paradigm shift in the strategy of equivocal cytologic abnormalities.

Laparoscopic management is feasible for nonobstetric surgical disease in all trimesters of pregnancy.

BACKGROUND: Nonobstetric surgical interventions are required in some women during pregnancy. The most common nonobstetric conditions requiring surgery during pregnancy are acute appendicitis and cholecystitis. This study aimed to evaluate pregnancy outcomes and complications following surgical procedures for presumed nonobstetric surgical interventions during pregnancy, and to compare the outcomes between the laparoscopic and open approaches. METHODS: We conducted a retrospective study of patients who underwent laparoscopic or open surgery during pregnancy for nonobstetric surgical indications at our institution between 2008 and 2016. RESULTS: A total of 62 consecutive patients who underwent surgical intervention due to nonobstetric causes during pregnancy were included in our study. Of these, 35 (56.5%) were managed with laparoscopy and 27 (43.5%) with the open approach. Patients who underwent laparoscopy had a significantly shorter hospital stay and lower pain score on postoperative day 2 than those who underwent open surgery (5.5 vs. 7.2 days, p = 0.03 and 1.4 vs. 2.4, p < 0.01, respectively). There were no significant differences in operative complications between both groups. In advanced pregnancy (gestational age ≥ 23 weeks), 7 patients (41.2%) were managed with laparoscopy and 10 (58.8%) with the open approach. No differences in surgical complications were found between both groups in advanced pregnancy as well. CONCLUSIONS: In our study, laparoscopic surgery was found to be feasible and safe in the late second and third trimesters as well as in the first and early second trimesters without adverse effects on pregnancy.

Estrogen-induced acute pancreatitis: A case report and literature review.

Estrogens are commonly used in gynecologic area, such as oral contraception, hormone replacement therapy, and in vitro fertilization-embryo transfer. Although estrogen is a common cause of acute drug-induced pancreatitis, there has been paucity of report in Korea. Clinical course of estrogen-induced acute pancreatitis is usually mild to moderate, but fetal case can occur. In addition, there can be a latency from the first administration to the symptom. Therefore, physicians should consider the possibility of the disease when a woman taking estrogen or previous history of taking estrogen presents with acute abdominal pain. Here, we report a case of estrogen-induced acute pancreatitis that occurred during the preparation for embryo transfer.

Human papillomavirus genotypes and cofactors causing cervical intraepithelial neoplasia and cervical cancer in Korean women.

OBJECTIVE: Infection with human papillomavirus (HPV) is a necessary cause of cervical cancer, but the risk associated with the various viral types and related cofactors have not been adequately assessed in Korean women. This study aimed to investigate the genotype distribution of HPV and cofactors related to cervical carcinogenesis in Korean women. MATERIALS AND METHODS: We conducted a hospital-based case-control study in 215 women with histologically confirmed cervical neoplasia (111 cases of cervical intraepithelial neoplasia [CIN] and 104 cases of invasive cervical cancer [ICC]) and 1214 healthy control women. Polymerase chain reaction-based dot blot assays were used for detection of 16 high-risk HPV types. To clarify the cofactors, we administered questionnaires evaluating smoking, drinking, and sexual and reproductive history from women infected with HPV. RESULTS: Human papillomavirus was detected in 86.5% of the women with CIN and 96.2% of the women with ICC compared to 14.6% of the control women. The most common HPV types were, in descending order of frequency, types 16, 58, 18, 33, and 66 for CIN, and types 16, 18, 31, and 33 for ICC. Among the control women, HPV 16, 66, 33, 58, 18, and 31 were the most common types. Smoking and higher number of births (≥3) were associated with CIN (odds ratio [OR], 2.49; 95% confidence interval [CI], 1.21-5.15, and OR, 2.67; 95% CI, 1.36-5.28, respectively). This relationship was also found in the women with ICC (OR, 3.42; 95% CI, 1.59-7.38, and OR, 2.17; 95% CI, 1.08-4.38, respectively) compared to controls. In addition, the circumcision of sexual partner and the sexual habit of condom use were protective factors for ICC (OR, 0.47; 95% CI, 0.24-0.90, and OR, 0.19; 95% CI, 0.06-0.57, respectively). CONCLUSION: Human papillomavirus types 16, 18, 31, 33, and 58 are the major causative genotypes for cervical carcinogenesis in Korean women. Smoking and multiparity seem to be the most significant cofactors.

A multicenter, randomized, double-blind, placebo-controlled trial evaluating the efficacy and safety of a far infrared-emitting sericite belt in patients with primary dysmenorrhea.

OBJECTIVE: To determine the efficacy and safety of a sericite which emits far infrared rays in the management of primary dysmenorrhea. DESIGN: A multicenter randomized double-blind placebo-controlled trial. SETTING: One hundred four patients with primary dysmenorrhea were randomized to wear a sericite or placebo belt during sleep for 3 menstrual cycles, and followed for 2 menstrual cycles. Hot packs were used to heat the ceramics and ensure slight pain relief in both groups. MAIN OUTCOME MEASURES: The main outcome measures were the severity of dysmenorrhea assessed by a 10-point visual analog scale (VAS) and the number of patients who took analgesics at each menstrual cycle. Safety was evaluated by physical examination and self-reporting of adverse events. RESULTS: The baseline VAS scores were 7.27±0.19 in the experimental group and 7.38±0.19 in the control group. The severity of dysmenorrhea gradually decreased during the treatment period in both groups, with major improvements observed in the third treatment cycle (4.96±0.30 in the experimental group and 5.69±0.30 in the control group, p=0.087). During the follow-up period, the decreased VAS score was maintained in the experimental group, whereas the VAS score gradually returned to baseline in the control group, which resulted in significant difference between the groups (5.08±0.31 vs. 6.47±0.31 at cycle 5, difference -1.39 [95% CI, -2.25 to -0.53], p=0.0017). The number of patients who took analgesics decreased in both groups, but the differences were not statistically significant. No serious adverse events related to wearing the sericite belt occurred. CONCLUSIONS: Our data suggest that a far infrared-emitting sericite belt with a hot pack might be used as an effective and safe non-pharmacologic treatment option for women with primary dysmenorrhea, with a prolonged effect after treatment.

Diastolic forward flow in the fetal main pulmonary artery and its implication for fetal cardiac cycle evaluation.

OBJECTIVES: To examine if the fetal main pulmonary artery diastolic forward flows (MPADFs) are detected consistently, if the waves from fetal MPADFs coincide with those from atrial contractions, and the reproducibility of the cardiac cycle measurements using this technique. METHODS: Two examiners performed a fetal pulsed Doppler echocardiography of the four chamber (4CV), ductal arch (DA) and short axis (SA) views on 44 women with singleton pregnancies. Time intervals between atrial contraction peaks and those between MPADF peaks were compared. Atrioventricular (AV) and ventriculoatrial (VA) intervals were measured from MPADF waves in DA and SA views and compared between observers. Intraclass correlation coefficients (ICCs) were calculated as a measure of inter-observer reproducibility. RESULTS: In all observations, MPADFs were demonstrated. The mean time intervals between atrial contraction peaks from 4CV and those between MPADF peaks from DA and SA views were not significantly different. The mean AV and VA intervals were not significantly different between observers. Comparison of measurements of two observers had substantial agreements. CONCLUSIONS: Our data show that MPADFs can be found consistently and coincide with atrial contractions. As cardiac cycle measurements can be done with considerable reproducibility, this technique may be useful in assessing fetal cardiac cycle.

Cyclooxygenase-2 is an independent predictor of poor prognosis in uterine leiomyosarcomas.

INTRODUCTION: Cyclooxygenase-2 (COX-2) is a well-known enzyme that promotes tumor growth and metastasis. Cyclooxygenase-2 is upregulated in a number of human epithelial tumors, but data about the significance of COX-2 in mesenchymal tumors are lacking. The purpose of this study was to determine COX-2 expression in uterine sarcomas and whether a relationship exists between COX-2 expression and clinicopathologic outcomes. METHODS: Immunohistochemical staining for COX-2 was performed on paraffin-embedded tissue blocks of 49 uterine sarcomas (30 leiomyosarcomas, 14 endometrial stromal sarcomas, and 5 carcinosarcomas). Positive staining was defined as moderate or strong staining in 5% or more of tumor cells. RESULTS: Four of 30 leiomyosarcomas, 1 of 14 endometrial stromal sarcomas, and 2 of 5 carcinosarcomas were positive for COX-2 expression. In leiomyosarcomas, COX-2 expression correlated with tumor stage with marginal significance (P = 0.058). Patients with leiomyosarcoma positive for COX-2 expression had a lower overall survival rate than those without COX-2 expression (P = 0.025). In the multivariate Cox proportional hazards regression model, COX-2 expression, tumor stage, and mitotic count were independently associated with overall survival in leiomyosarcomas. CONCLUSIONS: Our data suggest that immunohistochemically determined COX-2 expression is an independent prognostic factor in uterine leiomyosarcomas. Assessment of COX-2 status might be useful for determining the prognosis in patients with uterine leiomyosarcomas.

P53 codon 72 and p21 codon 31 polymorphisms and susceptibility to cervical adenocarcinoma in Korean women.

The aims of this study were to evaluate the genotype frequencies of p53 codon 72 and p21 codon 31 in cervical adenocarcinoma patients and controls, and the association between the specific genotype or genotype combination of these polymorphisms and the risk of cervical adenocarcinoma in Korean women. Genotyping was performed using DNA from cervical biopsy specimens collected from 53 patients with cervical adenocarcinoma, of whom 34 were HPV 16 or 18 positive, and from the cervical exfoliated cells from 286 control women, of whom 48 were positive for HPV 16 or 18. For the determination of p53 polymorphisms genomic DNA was examined by PCR amplification of the specific allele assay, and for the determination of p21 polymorphisms DNA was examined by the PCR-RFLP assay using BsmAI. We found significant differences in genotype frequencies of both genes between the two groups (p < 0.001). The p53 genotypes containing the Pro allele were significantly associated with cervical adenocarcinoma with an OR of 2.89 (95% CI 1.54-5.42). Also, homozygous carriers of the p21 Ser allele showed a substantially increased risk of developing cervical adenocarcinoma (OR 2.07; 95% CI 1.13-3.79) compared to genotypes containing the Arg allele. In addition, the combination of the Pro allele containing genotypes of p53 and the Ser homozygous genotype of p21 posed a remarkably increased risk (OR 5.22; 95% CI 2.24-12.16), although the interaction of the two genes could not be found. These significant differences were intensified in groups with high-risk HPV infection (types 16 or 18).

Low initial human papilloma viral load implicates worse prognosis in patients with uterine cervical cancer treated with radiotherapy.

PURPOSE: To evaluate whether human papillomavirus (HPV) viral load measured in cervical smear and HPV type 18 are associated with radiotherapy outcomes in uterine cervical cancer. PATIENTS AND METHODS HPV DNA: was semiquantitatively measured in the cervical smears of 169 radiotherapy patients. HPV viral load was classified as low or high according to median HPV DNA titer and examined for its prognostic value. The multivariable Cox proportional hazards model was used to adjust for covariates. A relapse-predicting model was constructed to classify three risk groups for disease-free survival (DFS), which were used for internal validation. RESULTS: Patients with lower HPV viral load showed worse DFS in univariate analysis. HPV type 18, younger patient age, stage group, nodal status, histologic grade, and histologic type were other prognostic factors for poor DFS. Among these factors, all except stage group were associated with HPV viral load. Multivariate analysis showed the strong influence of HPV viral load for poor DFS. The prognostic model developed using our outcome data performed well in predicting the risk of relapse. CONCLUSION: Our data suggest that HPV viral load is a strong independent prognostic factor for DFS. HPV type 18 showed a significant relationship with poor radiotherapy outcome in univariate analysis, but not in multivariate analysis.

Expression of MMP-2, MMP-9, and urokinase-type plasminogen activator in cervical intraepithelial neoplasia.

Matrix metalloproteinase-2 (MMP-2), MMP-9, and urokinase-type plasminogen activator (uPA) are important factors for cancer invasion and metastasis, degrading the extracellular matrix. They are also associated with angiogenesis. Angiogenic phenotype is another feature of high-grade cervical intraepithelial neoplasia (CIN). However, their associations with the progression of low-grade CIN to high-grade CIN are unexplored. We investigated whether these proteolytic enzyme expressions correlate with the progression of CIN. A total of 39 paraffin-embedded specimens from 10 patients with CIN grade 1, nine with CIN grade 2, and 20 with CIN grade 3 were assessed immunohistochemically by specific antibodies against MMP-2, MMP-9, and uPA. MMP-9 expression was higher in CIN 3 lesions (47.4%) than in CIN 1 (22.2%) and CIN 2 (20.2%) lesions, although the difference failed to reach statistical significance. The expression level of uPA and MMP-2 was not associated with the grade of CIN lesions. Interestingly, we found a significant association between expressions of uPA and MMP-2 (P= 0.028). Our results suggest that MMP-9 might play a role in the progression of CIN.

NF-kappaB as a potential molecular target for cancer therapy.

Nuclear factor kappaB (NF-kappaB), a transcription factor, plays an important role in carcinogenesis as well as in the regulation of immune and inflammatory responses. NF-kappaB induces the expression of diverse target genes that promote cell proliferation, regulate apoptosis, facilitate angiogenesis and stimulate invasion and metastasis. Furthermore, many cancer cells show aberrant or constitutive NF-kappaB activation which mediates resistance to chemo- and radio-therapy. Therefore, the inhibition of NF-kappaB activation and its signaling pathway offers a potential cancer therapy strategy. In addition, recent studies have shown that NF-kappaB can also play a tumor suppressor role in certain settings. In this review, we focus on the role of NF-kappaB in carcinogenesis and the therapeutic potential of targeting NF-kappaB in cancer therapy.