Dose reduction of olaparib in older patients: Insights from an analysis of a National Database in Japan.

AIM: Although the advent of a poly polymerase inhibitors has greatly advanced the tailoring of cancer treatment, there is a dearth of real-world evidence on the actual use of olaparib in aging populations, especially those using national-level data. METHODS: We extracted and analyzed all prescriptions of olaparib in female outpatients from the National Database Open Data Japan (NDB Open Data) from April 2019 to March 2021. The recommended standard dose of olaparib is four tablets of the 150 mg formulation per day, while the 100 mg formulation of olaparib can be considered as an alternative dose in the occurrence of hematologic toxicity. We calculated the proportion of 100 mg compared to the 150 mg prescriptions across age groups. A Cochrane-Armitage trend test was used to examine the association of age groups with the proportion of 100 mg prescriptions. RESULTS: The total number of prescriptions of the 100 mg formulation and the 150 mg formulation were 1449 222, and 4233 625, respectively. Overall, 45.1% (2567 513/5682 847 prescriptions) of olaparib were prescribed for patients 65 years of age or older in females. Stratified by age group, the proportion of 100 mg compared to the 150 mg prescriptions significantly increased with age (p < 0.0001). CONCLUSIONS: Given that the 100 mg formulation of olaparib can be considered as an alternative dose in Japan in the occurrence of hematologic toxicity, our observations indicate the dose reduction of olaparib in older patients in Japan. Further investigations are necessary to assess its efficacy and safety at a reduced dose.

Clinical significance of metabolism-related genes and FAK activity in ovarian high-grade serous carcinoma.

BACKGROUND: Administration of poly (ADP-ribose) polymerase (PARP) inhibitors after achieving a response to platinum-containing drugs significantly prolonged relapse-free survival compared to placebo administration. PARP inhibitors have been used in clinical practice. However, patients with platinum-resistant relapsed ovarian cancer still have a poor prognosis and there is an unmet need. The purpose of this study was to examine the clinical significance of metabolic genes and focal adhesion kinase (FAK) activity in advanced ovarian high-grade serous carcinoma (HGSC). METHODS: The RNA sequencing (RNA-seq) data and clinical data of HGSC patients were obtained from the Genomic Data Commons (GDC) Data Portal and analysed ( https://portal.gdc.cancer.gov/ ). In addition, tumour tissue was sampled by laparotomy or screening laparoscopy prior to treatment initiation from patients diagnosed with stage IIIC ovarian cancer (International Federation of Gynecology and Obstetrics (FIGO) classification, 2014) at the Saitama Medical University International Medical Center, and among the patients diagnosed with HGSC, 16 cases of available cryopreserved specimens were included in this study. The present study was reviewed and approved by the Institutional Review Board of Saitama Medical University International Medical Center (Saitama, Japan). Among the 6307 variable genes detected in both The Cancer Genome Atlas-Ovarian (TCGA-OV) data and clinical specimen data, 35 genes related to metabolism and FAK activity were applied. RNA-seq data were analysed using the Subio Platform (Subio Inc, Japan). JMP 15 (SAS, USA) was used for statistical analysis and various types of machine learning. The Kaplan-Meier method was used for survival analysis, and the Wilcoxon test was used to analyse significant differences. P < 0.05 was considered significant. RESULTS: In the TCGA-OV data, patients with stage IIIC with a residual tumour diameter of 1-10 mm were selected for K means clustering and classified into groups with significant prognostic correlations (p = 0.0444). These groups were significantly associated with platinum sensitivity/resistance in clinical cases (χ2 test, p = 0.0408) and showed significant relationships with progression-free survival (p = 0.0307). CONCLUSION: In the TCGA-OV data, 2 groups classified by clustering focusing on metabolism-related genes and FAK activity were shown to be associated with platinum resistance and a poor prognosis.

A pilot study of mobile digital colposcopy in Japanese patients with cervical intraepithelial neoplasm.

Digital colposcopy built around a smartphone is becoming common, and this has advantages for telemedicine and data sharing by taking advantage of smartphone characteristics. However, digital colposcopy itself is not allowed in clinical practice in Japan. The aim of the present study was to investigate the feasibility of mobile digital colposcopy incorporating a smartphone for management of cervical screening in Japanese patients. Patients who underwent colposcopy at Saitama Medical University International Medical Center between July 2019 and February 2020 were enrolled in the present study. The inclusion criteria were women aged 21-65 years old referred for colposcopy following the Japanese standard of care. Written informed consent was obtained from all patients. A total of 40 patients (52 tests) were included in the study. Following the standard of care, acetic acid was applied to the cervix, which was then visualized using a traditional colposcope, with biopsies collected as necessary. The cervix was then visualized and an imaged was captured using a mobile digital colposcope incorporating a smartphone (EVA System; Mobile ODT). All images were collected before biopsy. Images were stored on a secure cloud portal for subsequent evaluation by the provider who performed the conventional colposcopy, and the diagnoses were compared. The present study was approved by the Institutional Review Board of Saitama Medical University International Medical Center (Hidaka, Japan). The match rates for diagnoses were 75%. The match rates for the actual (from conventional colposcopy) and assumed (from digital colposcopy) biopsy sites were 61, 16 and 23%, based on definitions of the 'same', 'almost the same' and 'different', respectively. The present results indicated that ≥75% cases were equivalent in digital colposcopy and conventional colposcopy. This suggests that digital colposcopy may not be inferior to conventional colposcopy.

Corneal endothelial cell therapy: feasibility of cell culture from corneas stored in organ culture.

In 2013, a clinical trial was initiated to investigate cell therapy for the treatment of corneal endothelial decompensation. Cultivating human corneal endothelial cells (CECs) while maintaining their functional phenotype is challenging; therefore, establishment of a confirmed protocol is pivotal for obtaining approval from regulatory authorities for use of cellular therapy products. In this study, we evaluated organ culture (OC) as a storage method for donor corneas used as a raw material for establishing CEC cultures. OC allows storage of corneal tissue for conventional corneal transplantation at 31-37 °C for up to 5 weeks, whereas storage at 4 °C is limited to 2 weeks. We investigated 20 pairs of corneas: one cornea of each pair was stored in OC and the other in cold storage for one week before CEC culture. In 15/20 cases, the CECs assumed a hexagonal sheet-like monolayer structure and expressed endothelial function-related markers. CECs were also obtained from OC corneas that had been stored for 1 (n = 19) and 2 (n = 7) months. As a further test, CECs were cultivated from 5 OC corneas that had been transported from France to Japan. In all cases, these corneas, even after international transport, generated CECs that formed hexagonal monolayers with clinically applicable and sufficiently high cell densities. In conclusion, the CEC cultures required for endothelial cell therapy can be obtained from OC corneas without changing the standard storage operating procedures of the eye banks.

Subclinical thiamine deficiency: What is the most appropriate method of diagnosis and treatment?

OBJECTIVES: The symptoms of thiamine deficiency vary considerably and asymptomatic cases; i.e., subclinical thiamine deficiency (SCTD), are known to exist. However, there is no information available on the treatment of SCTD. METHODS: We report a patient who underwent intravenous thiamine replacement therapy for about a month after being diagnosed with SCTD, but who developed SCTD again about three weeks after finishing the treatment. RESULTS: The patient was a 64-year-old woman who, after starting treatment for cervical cancer, complained of anxiety and underwent an initial psychiatric examination. The psychiatric diagnosis was an adjustment disorder. Based on the possibility of SCTD complications due to her decreased appetite and weight loss, her serum thiamine concentration was measured and found to be low. Therefore, thiamine was administered intravenously for 29 days. At the end of treatment, thiamine administration was discontinued as there were no apparent neuropsychiatric symptoms or problems with appetite. Twenty-three days later, there were still no problems with appetite or neuropsychiatric symptoms, but a follow-up blood sample revealed that her serum thiamine was again below the normal range. SIGNIFICANCE OF RESULTS: Currently, there is no information available regarding the diagnosis and treatment of SCTD in cancer patients. In some cases, such as this case, the deficiency recurs without any symptoms indicative of SCTD; therefore, further examination for diagnosis and treatment is necessary.

The histone methyltransferase SMYD2 is a novel therapeutic target for the induction of apoptosis in ovarian clear cell carcinoma cells.

Previous studies have suggested that histone methylation can modulate carcinogenesis and cancer progression. For instance, the histone methyltransferase SET and MYND domain containing 2 (SMYD2) is overexpressed in several types of cancer tissue. The aim of the present study was to determine whether SMYD2 could serve a therapeutic role in ovarian clear cell carcinoma (OCCC). Reverse transcription-quantitative PCR was used to examine SMYD2 expression in 23 clinical OCCC specimens. Moreover, OCCC cell proliferation and cell cycle progression were also examined following small interfering RNA-mediated SMYD2 silencing or treatment with a selective SMYD2 inhibitor. SMYD2 was significantly upregulated in clinical OCCC specimens, compared with normal ovarian tissue. In addition, SMYD2 knockdown decreased cell viability as determined via a Cell Counting Kit-8 assay. Moreover, the proportion of cells in the sub-G1 phase increased following SMYD2 knockdown, suggesting increased apoptosis. Treatment with the SMYD2 inhibitor LLY-507 suppressed OCCC cell viability. These results suggested that SMYD2 could promote OCCC viability, and that SMYD2 inhibition induced apoptosis in these cells. Thus, SMYD2 inhibitors may represent a promising molecular targeted approach for OCCC treatment.

Diagnostic significance of apical membranous and cytoplasmic dot-like CD26 expression in encapsulated follicular variant of papillary thyroid carcinoma: a useful marker for capsular invasion.

Non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) and invasive encapsulated follicular variant of papillary thyroid carcinoma (EFV-PTC) are indistinguishable preoperatively. CD26 expression in follicular tumor-uncertain malignant potential (FT-UMP) is reported to be clearly higher than in that without capsular invasion. To verify the diagnostic significance of CD26 immunostaining in EFV-PTC, we examined the expression pattern of CD26 in non-invasive EFV-PTC (NIFTP) and invasive EFV-PTC. We performed immunohistochemical analysis using CD26 antibody for 37 NIFTPs and 54 EFV-PTCs (34 minimally invasive EFV-PTCs and 20 widely invasive EFV-PTCs). Most NIFTP samples showed an apical membranous pattern or a cytoplasmic diffuse pattern of expression. Invasive EFV-PTCs more frequently showed a cytoplasmic dot-like pattern, and the labeling indices of tumor cells with cytoplasmic dot-like patterns were significantly higher than those in NIFTPs. The sizes of dots seen in NIFTPs (mean: 1.12 µm) were significantly smaller than in invasive EFV-PTCs (1.33 µm), minimally invasive EFV-PTC (1.27 µm), and widely invasive EFV-PTC (1.38 µm). We, therefore, conclude that cytoplasmic diffuse and/or cytoplasmic dot-like CD26 expression, particularly the larger CD26-positive dots, could be useful markers for capsular invasion in EFV-PTC. CD26 immunostaining, using cell blocks or cytological specimens, may preoperatively distinguish between NIFTP and invasive EFV-PTC.

Detection of MEAF6-PHF1 translocation in an endometrial stromal nodule.

Endometrial stromal nodule (ESN) and low-grade endometrial stromal sarcoma (LG-ESS) are rare uterine tumors known as endometrial stromal tumors (ESTs). In addition to their similarity in morphological features, recent studies have shown that these two tumors share common genetic alterations. In particular, JAZF1-SUZ12 fusion is found with high frequency in both ESN and LG-ESS. In LG-ESS, some minor fusions have also been described, which include rearrangements involving PHF1 and its partner genes, such as JAZF1, EPC1, MEAF6, BRD8, EPC2, and MBTD1. Because of the rarity of ESN, genetic alterations other than JAZF1 fusion have not been investigated in detail. In this study, we performed a next-generation sequencing-based analysis in a case of ESN with peripheral metaplastic bone formation and detected MEAF6-PHF1 fusion, which has been reported in a small subset of uterine LG-ESSs and soft tissue ossifying fibromyxoid tumors. The finding that MEAF6-PHF1 fusion is a background genetic abnormality detected both in ESN and LG-ESS, along with JAZF1-SUZ12, provides further support for the similarity and continuum between these two types of ESTs. Furthermore, the association between metaplastic bone formation and MEAF6-PHF1 fusion may not be limited to soft tissue tumors.

Feasibility of a cryopreservation of cultured human corneal endothelial cells.

Transparency of the cornea is essential for vision and is maintained by the corneal endothelium. Consequently, corneal endothelial decompensation arising from irreversible damage to the corneal endothelium causes severe vision impairment. Until recently, transplantation of donor corneas was the only therapeutic choice for treatment of endothelial decompensation. In 2013, we initiated clinical research into cell-based therapy involving injection of a suspension of cultured human corneal endothelial cells (HCECs), in combination with Rho kinase inhibitor, into the anterior chamber. The aim of the present study was to establish a protocol for cryopreservation of HCECs to allow large-scale commercial manufacturing of these cells. This study focused on the effects of various cryopreservation reagents on HCEC viability. Screening of several commercially available cryopreservation reagents identified Bambanker hRM as an effective agent that maintained a cell viability of 89.4% after 14 days of cryopreservation, equivalent to the cell viability of 89.2% for non-cryopreserved control cells. The use of Bambanker hRM and HCECs at a similar grade to that used clinically for cell based therapy (passage 3-5 and a cell density higher than 2000 cells/mm2) gave a similar cell density for cryopreserved HCECs to that of non-preserved control HCECs after 28 days of cultivation (2099 cells/mm2 and 2111 cells/mm2, respectively). HCECs preserved using Bambanker hRM grew in a similar fashion to non-preserved control HCECs and formed a monolayer sheet-like structure. Cryopreservation of HCECs has multiple advantages including the ability to accumulate stocks of master cells, to transport HCEC stocks, and to manufacture HCECs on demand for use in cell-based treatment of endothelial decompensation.

Histone methyltransferase SMYD2 selective inhibitor LLY-507 in combination with poly ADP ribose polymerase inhibitor has therapeutic potential against high-grade serous ovarian carcinomas.

Dysfunction of histone methylation is known to be related to cancer progression. The histone methyltransferase SMYD2 methylates histone protein H3 and non-histone proteins, including poly ADP ribose polymerase 1 (PARP1). There have been reports of SMYD2 overexpression in several types of cancers. However, there are no reports regarding its role in high-grade serous ovarian carcinomas (HGSOCs). Therefore, we investigated the expression profile and conducted functional analysis on SMYD2 in HGSOC cells. In addition, we verified whether SMYD2 inhibition increases the susceptibility of HGSOC cells to PARP inhibitors. We analyzed the expression of histone methyltransferase SMYD2 by quantitative real-time polymerase chain reaction and immunohistochemistry using HGSOC clinical tissues (n = 35). We performed functional analyses, including cell proliferation assay, cell cycle analysis, and immunoblotting, after treatment with SMYD2 siRNAs and SMYD2 selective inhibitor LLY-507 in HGSOC cells. We also performed colony-formation assay after combination treatment with LLY-507 and PARP inhibitor olaparib in HGSOC cells. The expression profiles of SMYD2 showed significant overexpression of SMYD2 in HGSOC clinical tissues. The knockdown or inhibition of SMYD2 by siRNAs or LLY-507, respectively, suppressed cell growth by increasing the proportion of apoptotic cells. LLY-507 showed additive effect with olaparib in the colony-formation assay. These findings suggest that LLY-507 can be used alone or in combination with a PARP inhibitor for the treatment of patients with HGSOC.

Analysis of skeletal-muscle condition after excessive loading of the lower legs by sequential magnetic resonance imaging.

OBJECTIVES: To determine the changes of muscle conditions of lower leg after stretch shortening cycle exercises by MRI. SUBJECTS AND METHODS: This study included 20 healthy male adult volunteers. After conducting control MRI, each subject performed 3 sets of exercise loading, each set consisting of 100 repetitions of rebound jumping on one foot. MRIs were performed immediately after exercise loading (0 h), 6, 30, and 168 h later. After constructing T1/T2/Fractional Anisotropy (FA)/Apparent Diffusion Coefficient (ADC) maps, the changes of three skeletal muscles of the leg (the tibialis anterior [TA], soleus [SOL], and gastrocnemius [GA]) were quantitatively evaluated in each map at each time point. RESULTS: The T1 and T2 values were prolonged after exercise loading, and there was a delay in the recovery of T1 at 6 and 30 h after exercise loading, as compared to those of T2 values over time. The ADC values were elevated in all three muscles immediately after exercise loading, then recovered more slowly than T1 and T2, and still had not returned to baseline 168 h after exercise loading. The FA value decreased in all three muscles after exercise loading, with the greatest decrease occurring immediately after exercise loading. As with the ADC values, the FA values were slow to recover from the decrease, and had not returned to baseline levels 168 h post-loading. CONCLUSION: The delay of T1 value recovery suggested that the T1 value may reflect the muscle condition like fatigue and damage. Changes in the ADC and FA values over time suggested that structural changes such as minute muscular injuries can be detected by diffusion-weighted MRI. Meanwhile, the changes observed in the T1 and T2 values suggested that the measured relaxation time data reflected not only the water volume in the muscle, but also the muscle condition after exercise loading.

Peyer's patch-immunomodulating glucans from sugar cane enhance protective immunity through stimulation of the hemopoietic system.

The aim of the present study was chemical clarification of in vitro Peyer's patch-immunomodulating polysaccharides in sugar cane molasses, and evaluation of in vivo modulating activity on immune function of T lymphocytes in Peyer's patches and on microenvironment of hemopoietic system. Five kinds of glucans, comprising of dextranase-sensitive and activity-related d-glucosyl moieties, were purified as in vitro Peyer's patch-immunomodulating polysaccharides from the molasses. Oral administration of a glucan-enriched subfraction induced IL-2 and GM-CSF-producing T lymphocytes in Peyer's patches, resulting in enhancement of IL-6 production in a hemopoietic microenvironment to boost neutrophil numbers in the peripheral blood stream. Oral administration of purified glucan or glucan-enrich sub-fraction of sugar cane reduced the number of Plasmodium berghei- or P. yoelii-infected erythrocytes in a murine infection model, using polysaccharide alone or via co-administration with the antimalarial drug, artesunate. These results suggested that Peyer's patch-immunomodulating glucans enhanced protective immunity through axis of Peyer's patches-hemopoietic system.

Computer vision for total laparoscopic hysterectomy.

INTRODUCTION: Laparoscopic surgery is widely performed in various surgical fields, but this technique requires time for surgeons to master. However, at the same time, there are many advantages in visualizing the operative field through a camera. In other words, we can visualize what we cannot see with our own eyes by using augmented reality and computer vision. Therefore, we investigated the possibilities and usefulness of computer vision in total laparoscopic hysterectomy. METHODS: This study was approved by the Mitsui Memorial Hospital ethics committee. Patients who underwent total laparoscopic hysterectomy at Mitsui Memorial Hospital from January 2015 to December 2015 were enrolled. We evaluated 19 cases in which total laparoscopic hysterectomy was performed by the same operator and assistant. We used the Open Source Computer Vision Library for computer vision analysis. The development platform used in this study was a computer operating on Mac OS X 10.11.3. RESULTS: We created panoramic images by matching features with the AKAZE algorithm. Noise reduction methods improved haziness caused by using energy devices. By abstracting the color of the suture string, we succeeded in abstracting the suture string from movies. We could not achieve satisfactory results in detecting ureters, and we expect that creative ideas for ureter detection may arise from collaborations between surgeons and medical engineers. CONCLUSIONS: Although this was a preliminary study, the results suggest the utility of computer vision in assisting laparoscopic surgery.

The oncogene KRAS promotes cancer cell dissemination by stabilizing spheroid formation via the MEK pathway.

BACKGROUND: Peritoneal dissemination is a critical prognostic factor in ovarian cancer. Although stabilized spheroid formation promotes cancer cell peritoneal dissemination in ovarian cancer, the associated oncogenes are unknown. In this study, we assessed the role of the KRAS oncogene in ovarian cancer cell dissemination, focusing on the stability of cells in spheroid condition, as well as the modulation of intracellular signaling following spheroid transformation. METHODS: We used ID8, a murine ovarian cancer cell line, and ID8-KRAS, an oncogenic KRAS (G12 V)-transduced ID8 cell line in this study. Spheroid-forming (3D) culture and cell proliferation assays were performed to evaluate the growth characteristics of these cells. cDNA microarray analysis was performed to identify genes involved in KRAS-associated signal transduction in floating condition. A MEK inhibitor was used to evaluate the effect on cancer peritoneal dissemination. RESULTS: Cell viability and proliferation in monolayer (2D) cultures did not differ between ID8 and ID8-KRAS cells. However, the proportions of viable and proliferating ID8-KRAS cells in 3D culture were approximately 2-fold and 5-fold higher than that of ID8, respectively. Spheroid-formation was increased in ID8-KRAS cells. Analysis of peritoneal floating cells obtained from mice intra-peritoneally injected with cancer cells revealed that the proportion of proliferating cancer cells was approximately 2-fold higher with ID8-KRAS than with ID8 cells. Comprehensive cDNA microarray analysis revealed that pathways related to cell proliferation, and cell cycle checkpoint and regulation were upregulated specifically in ID8-KRAS cells in 3D culture, and that some genes partially regulated by the MEK-ERK pathway were upregulated only in ID8-KRAS cells in 3D culture. Furthermore, a MEK inhibitor, trametinib, suppressed spheroid formation in 3D culture of ID8-KRAS cells, although trametinib did not affect 2D-culture cell proliferation. Finally, we demonstrated that trametinib dramatically improved the prognosis for mice with ID8-KRAS tumors in an in vivo mouse model. CONCLUSIONS: Our data indicated that KRAS promoted ovarian cancer dissemination by stabilizing spheroid formation and that the MEK pathway is important for stabilized spheroid formation. Disruption of spheroid formation by a MEK inhibitor could be a therapeutic target for cancer peritoneal dissemination.

Intraperitoneal neutrophils activated by KRAS-induced ovarian cancer exert antitumor effects by modulating adaptive immunity.

Increased neutrophil counts are a hallmark of a poor prognosis for cancer. We previously reported that KRAS promoted tumorigenesis and increased neutrophil counts in a mouse peritoneal cancer model. In the current study, we evaluated the role of increased neutrophils in cancer progression, as well as their influence on the intraperitoneal microenvironment. A mouse peritoneal cancer model was established using the KRAS-transduced mouse ovarian cancer cell line, ID8-KRAS. Neutrophil function was assessed by neutrophil depletion in ID8-KRAS mice. Neutrophil depletion markedly accelerated tumor formation; this was accompanied by an increase in interleukin-6 concentrations in ascites. Neutrophil depletion significantly decreased the amount of local and systemic CD8+ T cells, while increasing the amount of local CD4+ T cells, accompanied by an increased amount of monocytic myeloid-derived suppressor cells (M-MDSCs) and regulatory T cells (Tregs) (P<0.05). The roles of peritoneal neutrophils (PENs) in CD8+ T cell activation were assessed in vitro. PENs of ID8-KRAS mice had a strong potential to enhance T cell proliferation with a higher expression of the T cell costimulatory molecules OX40 ligand (OX40L) and 4-1BB ligand (4-1BBL), as compared with peripheral blood neutrophils (PBNs). These findings suggest that neutrophils recruited into the KRAS-induced tumor microenvironment (TME) have antitumor properties with the potential to modulate the numbers of M-MDSCs and Tregs and activate CD8+ T cells through T cell costimulatory molecules.

Retained Barium in the Appendix Is Difficult to Distinguish from Surgical Remnants following Laparoscopic Surgery.

Surgical materials, such as gauze, can be accidentally left inside of patients following surgery. This iatrogenic complication should be avoided and is often prevented by routine X-ray analysis after surgical abdominal procedures. We report a case of retained barium in the appendix that was difficult to distinguish from surgical remnants. A 41-year-old Japanese female was diagnosed with uterine leiomyoma and underwent laparoscopic myomectomy. The postoperative X-ray test showed a cord-like material in the lower right abdomen that was not captured in the preoperative X-ray test two months prior to the operation. Because of this difference, the area was reexamined laparoscopically. After examination, we concluded that the cord-like material in X-ray tests was in fact retained barium in the appendix. Barium can be retained in the appendix for long periods of time, and retained barium in the appendix can be captured radiographically and can mimic the appearance of surgical remnants, appearing as a cord-like material. The knowledge above combined with detailed interviews before surgery could prevent such confusion during interpretation of X-ray tests after surgery.

Therapeutic significance of targeting survivin in cervical cancer and possibility of combination therapy with TRAIL.

Loss of p53 function due to human papillomavirus (HPV) infection induces resistance to apoptosis in cervical cancer cells. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which induces apoptosis in a p53-independent manner, may provide an alternative strategy for treating cervical cancer. Survivin, an antiapoptotic protein that is highly expressed in cancer cells, regulates apoptosis and the cell cycle. Here, we investigated the therapeutic potential of targeting survivin, while focusing on the TRAIL-induced apoptosis pathway. The viability and cell cycle of HPV16-positive CaSki and SiHa cells were assessed after survivin knockdown by small interfering RNA (si-survivin). E-cadherin expression was also assessed after si-survivin treatment, using western blotting. SiHa (a TRAIL-resistant cell line) was used for further studies. The small molecule YM155 and resveratrol (RVT; a polyphenol with the potential to suppress survivin expression) were used as survivin inhibitors. The effects of si-survivin and survivin inhibitors on TRAIL- or cisplatin (CDDP)-induced apoptosis were analyzed by annexin-V staining. si-survivin treatment decreased cell viability and led to G2/M arrest, accompanied by morphological changes and E-cadherin upregulation in both CaSki and SiHa cells. si-survivin and YM155 synergistically sensitized TRAIL-resistant SiHa cells to TRAIL-induced apoptosis (p < 0.05). However, si-survivin and YM155 only slightly increased CDDP-induced apoptosis. RVT markedly enhanced TRAIL-induced apoptosis by suppressing survivin expression. Targeting of survivin expression might be an ideal strategy for cervical cancer treatment as it would decrease viable cell number and enhance apoptosis sensitivity. Further, combination therapy with TRAIL, rather than CDDP, may be compatible with the proposed survivin-targeting strategy.

Exploration of assistive technology for uniform laparoscopic surgery.

INTRODUCTION: Laparoscopic surgery is less invasive than open surgery and is now common in various medical fields. However, laparoscopic surgery is more difficult than open surgery and often requires additional time for the operator to achieve mastery. Therefore, we investigated the use of assistive technology for uniform laparoscopic surgery. METHODS: We used the OpenCV2 library for augmented reality with an ArUco marker to detect and estimate forceps positioning. We used Sense HAT as the gyro sensor. The development platforms used were Mac OS X 10.11.3 and Raspberry Pi 3, model B. RESULTS: By attaching the ArUco marker to the needle holder, we could draw a line vertically to the marker. When the needle was held, a cube could be imagined, and both the needle and lines could be used to determine the appropriate position. By attaching the gyro sensor to the camera, we could detect its angle of rotation. We obtained stabilized images by rotating the image by the detected degrees; this was possible for any camera position. CONCLUSIONS: Assistive technology allowed us to obtain consecutive converted images in real time and may be readily applicable to clinical practice.

Detachment from the primary site and suspension in ascites as the initial step in metabolic reprogramming and metastasis to the omentum in ovarian cancer.

Cancer cell metabolism is currently considered to be context dependent, and metabolic reprogramming is being widely investigated. It is known that ovarian cancer often metastasizes to the omentum. Given that the omentum itself contains a high concentration of adipocytes, ovarian cancer is thought to be a good model for research into metabolic reprogramming (particularly the shift to lipid metabolism). The present study investigated the switch to lipid metabolism in the metabolic reprogramming of ovarian cancer cells. The present study first considered the possibility of epigenetic involvement. Using an open database (GSE 85293 and GSE2109), the methylation status and gene expression patterns of the primary tumor site (ovary) and the metastatic tumor site (omentum) were compared. However, no evidence was obtained regarding the involvement of epigenetics (at least in terms of DNA methylation). The influence of suspension in ascites on metabolism was then considered, and a suspension culture was used as an in vitro model. It was demonstrated that ovarian cancer cells that are detached from the primary site and suspended in ascites have enhanced lipid metabolism. Additionally, it was demonstrated that these cells express high levels of the cancer stem cell (CSC) marker cluster of differentiation 44 and c-kit in a balanced manner as they approach the omentum. Accordingly, these cells activate the mammalian target of rapamycin pathway, which is thought to be advantageous for cancer cell metastasis. In conclusion, the present study proposed one explanation for why ovarian cancer cells are likely to disseminate to the peritoneal cavity, and in particular to the omentum.

Application of deep learning to the classification of images from colposcopy.

The objective of the present study was to investigate whether deep learning could be applied successfully to the classification of images from colposcopy. For this purpose, a total of 158 patients who underwent conization were enrolled, and medical records and data from the gynecological oncology database were retrospectively reviewed. Deep learning was performed with the Keras neural network and TensorFlow libraries. Using preoperative images from colposcopy as the input data and deep learning technology, the patients were classified into three groups [severe dysplasia, carcinoma in situ (CIS) and invasive cancer (IC)]. A total of 485 images were obtained for the analysis, of which 142 images were of severe dysplasia (2.9 images/patient), 257 were of CIS (3.3 images/patient), and 86 were of IC (4.1 images/patient). Of these, 233 images were captured with a green filter, and the remaining 252 were captured without a green filter. Following the application of L2 regularization, L1 regularization, dropout and data augmentation, the accuracy of the validation dataset was ~50%. Although the present study is preliminary, the results indicated that deep learning may be applied to classify colposcopy images.