First case of Cutibacterium avidum-infected pelvic lymphocele post-lymphadenectomy for endometrial cancer: A case report.

Background: Pelvic lymphocele (lymphocyst) infection after lymphadenectomy is a rare complication that can cause the spread of inflammation to neighboring organs whose microbiology is not well known. Cutibacterium avidum causes various infections. However, no case reports of C. avidum pelvic lymphocele infection are available; therefore, its clinical characteristics in pelvic lymphocele infections remain unknown. Case presentation: A 38-year-old woman with obesity (body mass index: 38.1 kg/m2) and a history of pelvic lymphadenectomy and chemotherapy for endometrial cancer presented with worsening left lower quadrant (LLQ) pain with fever. Physical examination revealed decreased abdominal bowel sounds and tenderness on LLQ palpation with no signs of peritonitis. Computed tomography (CT) revealed an infected left pelvic lymphocele with inflammation spreading to the adjacent sigmoid colon. Following blood culture, ampicillin/sulbactam (2 g/1 g every 6 h) was administered intravenously. Anaerobic culture bottles revealed gram-positive rods on day 4 of incubation at 37 °C. No other disseminated foci were observed in enhanced whole-body CT and upon transthoracic echocardiography. The isolates grew aerobically and anaerobically on blood agar plates with strong hemolysis. The bacterium was identified as C. avidum using a combination of characteristic peak analysis with matrix-assisted laser desorption ionization (MALDI) and 16S rRNA gene sequencing. The patient was diagnosed with C. avidum pelvic lymphocele infection. Based on penicillin susceptibility, the patient was successfully treated with intravenous ampicillin/sulbactam and de-escalated with intravenous ampicillin (2 g every 6 h) for 10 days, followed by oral amoxicillin (2000 mg/day) for an additional 11 days without drainage. Conclusions: C. avidum should be considered a causative microorganism of pelvic lymphocele infection. Peak analysis using MALDI and distinctive growth on blood agar plates are suitable for identifying C. avidum. Mild pelvic lymphocele caused by C. avidum can be treated with a short course of appropriate antimicrobial treatment without surgical intervention.

Increased angiotensin II coupled with decreased Adra1a expression enhances cardiac hypertrophy in pregnancy-associated hypertensive mice.

Cardiac hypertrophy is a crucial risk factor for hypertensive disorders during pregnancy, but its progression during pregnancy remains unclear. We previously showed cardiac hypertrophy in a pregnancy-associated hypertensive (PAH) mouse model, in which an increase in angiotensin II (Ang II) levels was induced by human renin and human angiotensinogen, depending on pregnancy conditions. Here, to elucidate the factors involved in the progression of cardiac hypertrophy, we performed a comprehensive analysis of changes in gene expression in the hearts of PAH mice and compared them with those in control mice. We found that alpha-1A adrenergic receptor (Adra1a) mRNA levels in the heart were significantly reduced under PAH conditions, whereas the renin-angiotensin system was upregulated. Furthermore, we found that Adra1a-deficient PAH mice exhibited more severe cardiac hypertrophy than PAH mice. Our study suggests that Adra1a levels are regulated by renin-angiotensin system and that changes in Adra1a expression are involved in progressive cardiac hypertrophy in PAH mice.

Aurora kinase blockade drives de novo addiction of cervical squamous cell carcinoma to druggable EGFR signalling.

Oncogenic signalling confers tumour-progression advantages; thus, its pharmacological blockade is the best strategy for cancer chemotherapy. However, drug resistance and heterogeneous dependency of tumour hamper their therapeutic potential, suggesting the necessity for a new ubiquitous modality based on evading drug resistance. Here, we proposed a de novo addiction to oncogenic signalling (Dead-On) concept, wherein specific blockade of target molecules forces cancer cells to develop dependency on an oncogenic signalling. In cervical squamous cell carcinoma cells, Aurora A/B dual blockade elicited rapid addiction to EGFR-Erk signalling, and its pharmacological/genetic inhibition synergistically enhanced anti-cancer activities in vitro, in vivo, and in a patient-derived organoid model. The signal activation was independent of EGFR genetic status, it was triggered by receptor accumulation on the plasma membrane via Rab11-mediated endocytic recycling machinery. These findings support our novel Dead-On concept which may lead to drug discovery as well as expand the adaptation of approved targeted drugs.

Technique for transvaginal removal of large specimen using an Alexis Contained Extraction System during laparoscopic hysterectomy.

OBJECTIVE: Transvaginal removal of large specimens during laparoscopic hysterectomy can be a complex surgical procedure that poses a risk of organ injury and tissue spillage into the abdominal cavity and is associated with extraction of the specimen and manual morcellation. Our objective was to demonstrate a technique for transvaginal removal of large specimens using the Alexis Contained Extraction System (CES) in laparoscopic hysterectomy. METHODS: The technique used for transvaginal removal of large specimens using the Alexis CES was presented in this video. Surgery was performed at a tertiary hospital. RESULTS: Following resection of the specimen during laparoscopic hysterectomy, the Alexis CES was inserted into the abdominal cavity through the umbilical trocar wound. The specimen was placed in a bag to prevent tissue spillage. The ring retractor was guided to the vagina and pulled out transvaginally. By repeatedly turning the ring retractor, tension was applied to the specimen bag, and the vaginal wall was unfolded all around to enable a secure surgical field. During manual morcellation of the specimen in the bag, the retractor was pulled and additionally turned to roll and re-tension the specimen bag when the bag was loosened. The specimen was pushed out of the vagina and safely and effectively extracted without concerns about tissue spillage in the abdominal cavity or related organ injuries. CONCLUSION: The technique for transvaginal removal of large specimens using the Alexis CES enables simple, effective, and safe tissue extraction with contained manual morcellation during laparoscopic hysterectomy.

Laparoscopic Vaginoplasty Procedure Using a Modified Peritoneal Pull-Down Technique with Uterine Strand Incision in Patients with Mayer-Rokitansky-Küster-Hauser Syndrome: Kisu Modification.

Various vaginoplasty procedures have been developed for patients with Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome. Here, we describe a novel laparoscopic vaginoplasty procedure, known as the Kisu modification, using a pull-down technique of the peritoneal flaps with additional structural support to the neovaginal apex using the incised uterine strand in patients with MRKH syndrome. Ten patients with MRKH syndrome (mean age at surgery: 23.9 ± 6.5 years, mean postoperative follow-up period: 17.3 ± 3.7 months) underwent construction of a neovagina via laparoscopic vaginoplasty. All surgeries were performed successfully without complications. The mean neovaginal length at discharge was 10.3 ± 0.5 cm. Anatomical success was achieved in all patients, as two fingers were easily introduced, the neovagina was epithelialized, and the mean neovaginal length was 10.1 ± 1.0 cm 1 year postoperatively. No obliteration, granulation tissue formation at the neovaginal apex, or neovaginal prolapse was recorded. Five of the 10 patients attempted sexual intercourse and all five patients were satisfied with the sexual activity, indicating functional success. Although the number of cases in this case series is few, our favorable experience suggests that the Kisu modification of laparoscopic vaginoplasty procedure is an effective, feasible, and safe approach for neovaginal creation in patients with MRKH syndrome.

Usefulness of Endoscopy for Female Genital Plastic Surgery: A Series of 4 Cases with Genital Malformations.

BACKGROUND Female genital plastic surgery is rare and requires specific patient anatomical information to successfully carry out the appropriate procedure for each female genital malformation. Performing endoscopic surgery can increase the amount of information intraoperatively. We report on our experience of proactively using endoscopy to obtain additional intraoperative information to perform the appropriate surgical procedure suited to each female genital malformation, and evaluate the usefulness of concurrent endoscopy for improved surgical outcomes. CASE REPORT In Case 1, an 18-year-old woman underwent colpoplasty for Mayer-Rokitansky-Küster-Hauser syndrome using the laparoscopic Davydov procedure, wherein the pelvic peritoneum was precisely dissected using light from a laparoscope as a guide. In Case 2, a 25-year-old woman presented with suspected Wunderlich syndrome. Since the junction of the affected uterus with the normal uterus was unclear on preoperative imaging, we performed total hysterectomy of the affected uterus after identifying the anatomical structure by hysteroscopy. In Case 3, a 12-year-old girl with obstructed hemivagina and ipsilateral renal anomaly (OHVIRA) syndrome underwent transvaginal fenestration of the obstructed vaginal wall to prevent future menstrual molimen. Simultaneous hysteroscopy and laparoscopy allowed us to determine the location of a unilateral vaginal wall cyst and drain it safely. In Case 4, a 29-year-old woman had OHVIRA syndrome, and we conducted a laparoscope-based fenestration of the cervical canal safely and accurately. CONCLUSIONS Our series showed how, even for gynecological malformations without established standards for surgical procedure, a safe and minimally invasive surgery can be ensured if the amount of anatomical information is increased via endoscopy.

Real-time intraoperative ureter visualization with a novel Near-Infrared Ray Catheter during laparoscopic hysterectomy for gynecological cancer.

Ureteral injuries are well-known complications of gynecologic surgery, with a higher prevalence in laparoscopic surgery than in laparotomy [1]. The use of near-infrared fluorescent imaging navigation is currently being considered a novel method to identify the ureters intraoperatively and prevent ureteral injuries [2]. The Near-Infrared Ray Catheter (NIRC) fluorescent ureteral catheter is a newly developed device, containing a fluorescent resin that can be recognized by near-infrared irradiation. We found few reports on the use of this catheter in laparoscopic surgery for colon and rectal cancer [3, 4], but no reports in gynecologic surgery. We demonstrate the feasibility, safety, and potential usefulness of the real-time intraoperative visualization of the ureters using a novel NIRC fluorescent ureteral catheter in laparoscopic hysterectomy for endometrial cancer. A 30-year-old woman with early grade 1 endometrioid carcinoma was treated with medroxyprogesterone acetate for fertility preservation. After achieving complete response, she got pregnant and underwent cesarean section. The recurrence of atypical endometrial hyperplasia one year post-delivery prompted a total laparoscopic hysterectomy. Before the laparoscopic surgery began, the NIRC fluorescent ureteral catheters were placed in the ureters under the obtainment of informed consent from the patient. During the surgery, the catheters were successfully visualized by near-infrared fluorescence observation, which helped identify the ureters clearly and prevent ureteral injuries. This novel ureteral imaging navigation is expected to be an effective tool in cases of obesity, severe pelvic adhesion, deep infiltrating endometriosis, and malignancy in gynecologic laparoscopic surgery to clearly identify the ureter and to reduce the risk of ureteral injury.

Bilateral adrenal metastases of endometrial cancer with adrenal insufficiency.

Adrenal metastasis from endometrial cancer is extremely rare and has a poor prognosis, especially for bilateral adrenal metastases. It is usually asymptomatic without any adrenal hormonal abnormalities. A 50-year-old postmenopausal woman presented with acute right-sided back pain and history of occasional abnormal uterine bleeding. She was diagnosed with endometrial cancer with ruptured bilateral adrenal metastases. She underwent total hysterectomy and bilateral salpingo-oophorectomy, and the pathological findings revealed dedifferentiated carcinoma. After three courses of adjuvant chemotherapy, the bilateral adrenal metastases had increased in size, with worsening back pain and adrenal hormone insufficiency. The patient died 6 months after the identification of adrenal tumors. Acute back pain may lead to the identification of a ruptured adrenal metastasis. The possibility of gradual adrenal insufficiency should be considered in bilateral adrenal metastases. Although the prognosis is poor, tumor debulking surgery followed by adjuvant chemotherapy could be suggested to improve the prognosis.

Inappropriate surgery in a patient with misdiagnosed Robert's uterus.

BACKGROUND: Robert's uterus is a rare Mullerian anomaly, which can be described as an asymmetric, septate uterus with a non-communicating hemicavity. Herein, we present the case of a misdiagnosed Robert's uterus, resulting in an invasive and disadvantageous surgery. CASE PRESENTATION: A 16-year-old woman was referred to our department because of dysmenorrhea and suspicion of uterine malformation. We misdiagnosed Robert's uterus as a unicornuate uterus with a non-communicating rudimentary horn and hematometra, and performed laparoscopic hemi-hysterectomy. Although the patient's symptoms were relieved, our surgical procedure left the lateral uterine wall weak, making the patient's uterus susceptible to uterine rupture in any future pregnancy. CONCLUSIONS: Although the early diagnosis of Robert's uterus is challenging, it is important in order to determine appropriate surgical interventions and management for maintaining the quality of life and ensuring safety in future pregnancies.

New Laparoscopic Vaginoplasty Procedure With a Modified Peritoneal Pull-Down Technique in Four Patients With Mayer-Rokitansky-Küster-Hauser Syndrome.

BACKGROUND: Various vaginal reconstructive procedures have been described for patients with Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome. We describe the success of a novel laparoscopic vaginoplasty procedure using an anteroposterior peritoneal pull-down technique. CASE: Four patients with MRKH syndrome underwent a modified laparoscopic Davydov procedure using an anteroposterior peritoneal pull-down technique with a transverse laparoscopic incision below the strand. Anatomical success was achieved in all patients, allowing easy introduction of 2 fingers, an epithelialized neovagina, and a mean length of 8.0 cm (range 7.0-9.0cm). All 3 patients who attempted sexual intercourse were successful, and neovagina size was adequately maintained at the long-term follow-up in the remaining patient. SUMMARY AND CONCLUSION: This novel procedure presents as a feasible and an effective approach for vaginal reconstruction in patients with MRKH syndrome.

Transcriptomic Evaluation of Pulmonary Fibrosis-Related Genes: Utilization of Transgenic Mice with Modifying p38 Signal in the Lungs.

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrosing lung disease that is caused by the dysregulation of alveolar epithelial type II cells (AEC II). The mechanisms involved in the progression of IPF remain incompletely understood, although the immune response accompanied by p38 mitogen-activated protein kinase (MAPK) activation may contribute to some of them. This study aimed to examine the association of p38 activity in the lungs with bleomycin (BLM)-induced pulmonary fibrosis and its transcriptomic profiling. Accordingly, we evaluated BLM-induced pulmonary fibrosis during an active fibrosis phase in three genotypes of mice carrying stepwise variations in intrinsic p38 activity in the AEC II and performed RNA sequencing of their lungs. Stepwise elevation of p38 signaling in the lungs of the three genotypes was correlated with increased severity of BLM-induced pulmonary fibrosis exhibiting reduced static compliance and higher collagen content. Transcriptome analysis of these lung samples also showed that the enhanced p38 signaling in the lungs was associated with increased transcription of the genes driving the p38 MAPK pathway and differentially expressed genes elicited by BLM, including those related to fibrosis as well as the immune system. Our findings underscore the significance of p38 MAPK in the progression of pulmonary fibrosis.

Evaluation of safety and diagnostic performance for flexible hysteroscopy in 1591 outpatient cases.

BACKGROUND: To date, only few large studies are available concerning the safety and diagnostic concordance rates of outpatient flexible hysteroscopy. In our institution, outpatient hysteroscopy has been routinely and educationally applied Kosuke Tsuji to intrauterine lesions; thus, we retrospectively investigated the institution's outpatient flexible hysteroscopy cases. METHODS: A total of 1591 cases of outpatient flexible hysteroscopy conducted at our institution in 2012-2016 were retrospectively analyzed in terms of their clinical background, complications and diagnostic concordance rates. RESULTS: A total of 1591 cases included 546 cases of benign tumors (317 endometrial polyps, 168 myomas and 61 endometrial hyperplasia), 361 cases of atypical endometrial hyperplasia, 571 cases of endometrial cancers and 113 cases of other diagnoses. No major complications, including uterine perforation, occurred. However, one patient (0.06%) was diagnosed with septic shock caused by intrauterine infection that required prolonged immunosuppressive drug administration. Meanwhile, 335 patients diagnosed with benign tumors through outpatient flexible hysteroscopy underwent operation, and the diagnostic concordance rate was 74.6% (250 cases). However, this rate included 14 cases (4.2%) diagnosed with malignant tumors postoperatively. In preoperative endometrial cancer cases, the sensitivity and specificity for cervical invasion diagnosis were 39.4 and 90.8%, respectively. In addition, only one patient manifested positive ascites cytology intraoperatively, possibly caused by outpatient hysteroscopy. CONCLUSIONS: Outpatient flexible hysteroscopy is highly safe, with a slight negligible effect on ascites cytology. However, the diagnosis should be determined by multidisciplinary approaches, as hysteroscopy alone can miss malignancy.

Upregulation of IGF2R evades lysosomal dysfunction-induced apoptosis of cervical cancer cells via transport of cathepsins.

Cervical cancer is the most common gynecological malignancy in the world; however, the survival rates of advanced-stage and recurrent cervical cancer patients remain poor. The multifaced protein insulin-like growth factor 2 receptor (IGF2R) has various ligands, represented as IGF-2 and mannose-6-phosphate (M6P)-tagged proteins. Regarding its antagonistic activity as an IGF1R signal, IGF2R is currently considered a tumor suppressor gene, whereas its significance as an M6P receptor is still unclear. Here, on the basis of transcriptome analysis of TCGA and GEO open datasets, we show that IGF2R is upregulated and correlated with poor prognosis in cervical cancer. Several experiments using cervical cancer cell lines revealed that IGF2R depletion induced apoptosis, decreased cell viability, and increased vulnerability to certain anticancer drug cisplatin. In contrast to its negligible impact in IGF1R signaling, loss of IGF2R disrupted the Golgi-to-lysosome transport of M6P-tagged cathepsins, resulting in decreased lysosomal activity, with their abnormal accumulation and dysfunction of both autophagy and mitophagy, which cause the accumulation of misfolded proteins and production of reactive oxygen species. Taken together, IGF2R has an oncogenic role through transportation of M6P-tagged cargo in cervical cancer and can be used as a predictive biomarker for prognostic classification.

[A Field Survey of Working Conditions of Parents with Children Requiring Medical Care].

The number of children in Japan with disabilities who require medical care is increasing and is estimated to have reached about 17,000 in 2015. Their home care is a great burden on mothers, therefore it is presumed to be hard for the mothers to find outside employment. The aims of this survey are to clarify the working conditions of mothers of children with disabilities that require medical care, and to investigate effective social support for improving their working and economic status. We carried out an original questionnaire survey on parents of children with disabilities who were visiting the University Hospital of Occupational and Environmental Health, Japan or daycare facilities in Kitakyushu City. Seventy-five parents, including 73 mothers, responded. The median age of the enrolled children with disabilities was 9 years old. Thirty-two of the mothers who responded (42.7%, median age 40) were employed, but two-thirds of them were non-regular employees. Twenty-two of the mothers had experienced a loss of work because of their children's disabilities. There were no significant relationships among the working conditions, children's age, size of family and household income. Almost 89% of the mothers desired to get employment for their sense of worth and economic status, but almost 11% did not. This survey clarified that the employment rate of mothers of disabled children with special care needs was low, and that most of those who were employed had non-regular employment. It is important to support the mothers in finding employment for their mental and economic status, and special attention must be paid to the diversity of their needs.

Is antidyslipidemic statin use for cancer prevention a promising drug repositioning approach?

Novel pharmacological therapies are in development for cancer, ranging from conventional chemotherapeutic drugs to molecular targeted drugs, antibody-based drugs, and immune checkpoint inhibitors, which are developed using new technologies. However, the increasing cost of new drug development is increasing the costs of national healthcare and putting pressure on government finances worldwide. Under these circumstances, drug repositioning (i.e. discovering novel effects of existing drugs, thereby allowing their use to treat other diseases) has become a major focus because of reliability and cost reduction. It is becoming increasingly clear that statins (currently used for treating dyslipidemia) can be effective in the prevention of coronary disease, heart failure, and arrhythmia. Epidemiological as well as basic research studies and epidemiological surveys have showed that statins have a suppressive effect on cancers and that they have an antitumor effect on colorectal, prostate, breast, cervical, endometrial, and ovarian cancers. Given the pharmacological mechanism of action of statins, they may have an antitumor effect on cancer types in which the mevalonate pathway is activated as well as on tumors with p53 mutations. To investigate this further, it would be necessary to conduct a large-scale survey after confirming the clinical background of patients as well as their mutational status, and therefore, great hope has been placed on the role of academia and public institutions. Thus, there is an urgent need for researchers to be actively involved in investigator-initiated clinical trials.

Warburg effect in Gynecologic cancers.

Mammalian cells produce energy by oxidative phosphorylation under aerobic conditions. However, in the 1920s, Otto Warburg reported the so-called "Warburg effect" in which cancer cells produce ATP that is biased toward glycolysis rather than mitochondrial oxidative phosphorylation not only in anaerobic environment but also in aerobic environment. Glucose is converted into lactate without going into mitochondria after being metabolized in glycolysis. Compared with oxidative phosphorylation, the glycolysis has a faster ATP production rate but it is very inefficient, resulting in cancer cells consuming a large amount of glucose. Increased glucose metabolism has become a biomarker for cancer cells and has led to the development of positron emission tomography with fluorodeoxyglucose. Till date, the Warburg effect has been an inefficient system for cancer cells with regard to efficient energy production, but since the consumption of oxygen can be suppressed as the tumor grows in mass, it is thought that the Warburg effect is advantageous in this situation wherein the tumor can increase despite the lack of vessels. In addition, an increased lactate by the glycolysis causes acidosis in the microenvironment of tissues, which is thought to damage the surrounding normal tissues and favor the invasion and metastasis of cancer. Thus, Warburg effect is one of the key mechanisms for cancer development and will be the next promising target. In this review, we introduce key players that can be targeted in the Warburg effect and outline the prospects of treatment, targeting the Warburg effect in gynecological cancer.

Erratum: Recent advances in the molecular mechanisms of Mayer-Rokitansky-Küster-Hauser syndrome.

[This corrects the article DOI: 10.3892/br.2017.929.].

SIM2l attenuates resistance to hypoxia and tumor growth by transcriptional suppression of HIF1A in uterine cervical squamous cell carcinoma.

Despite chemoradiotherapy being one of the most important modalities in advanced cervical cancer, there is a lack of both usable biomarkers to predict treatment outcome and of knowledge about the mechanism of refractoriness to the therapy. Here we identified a transcriptional factor Single-minded homolog 2 (SIM2) as an independent predictive biomarker for uterine cervical squamous cell carcinoma (CvSCC). The retrospective study showed that high expression level of SIM2 was correlated to good survival in CvSCC patients. SIM2 knockdown in CvSCC cell lines showed resistance to hypoxia with increased expression of HIF1A and its target genes. Loss of SIM2 also caused growth promotion, resistance to ROS, and radiation in 3D culture. Furthermore, SIM2 knockdown suppressed tumor growth with increased HIF-1α expression and angiogenesis in vivo. On the other hand, SIM2 long isoform (SIM2l)-overexpressed cells had contrary results, indicating the long isoform plays a key role for maintenance of these phenotypes. These data indicated that SIM2l has a potential to be precision medicine for CvSCC patients and that anti-angiogenesis therapy might be usable for SIM2lLow poor survivors.

Aberrant chromatin remodeling in gynecological cancer.

Epigenetic regulatory mechanisms are a current focus in studies investigating cancer. Chromatin remodeling alters chromatin structure and regulates gene expression, and aberrant chromatin remodeling is involved in carcinogenesis. AT-rich interactive domain-containing protein 1A (ARID1A) and SWItch/sucrose non-fermentable-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a, member 4 are remodeling factors that are mutated in numerous types of cancer. In gynecological cancer, ARID1A mutations have been identified in 46-57% of clear cell carcinoma and 30% of endometrioid carcinoma. Mutations of chromodomain helicase, DNA-binding protein 4 have been detected in 17-21% of endometrial serous cancer, and mutations of ARID1A and mixed-lineage leukemia 3 occur in 36 and 27% of uterine carcinosarcoma, respectively. These data suggest that aberrant chromatin remodeling is a potential cause of cancer, and have led to the development of novel proteins targeting these processes. Additional accumulation of information on the mechanisms of chromatin remodeling and markers for these events may promote personalized anticancer therapies.