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The deregulation of the FOXM1 transcription factor is a key molecular alteration in ovarian cancer, contributing to the development and progression of ovarian cancer via activation of the target genes. As such, FOXM1 is a highly attractive therapeutic target in the treatment of ovarian cancer, but there has been no clinically tested FOXM1 inhibitor to date. We investigated in this study the effects of domatinostat, a class I-selective HDAC inhibitor currently in the clinical stage of development as a cancer therapeutic, on the expression of FOXM1 and viability of ovarian cancer cells. Cell viability, as well as protein and mRNA expression of FOXM1 and its transcriptional target survivin, was examined after domatinostat treatment of TOV21G and SKOV3 ovarian cancer cell lines in the absence or presence of cisplatin and paclitaxel. The effect of FOXM1 knockdown on survivin expression and those of genetic and pharmacological inhibition of survivin alone or in combination with the chemotherapeutic agents on cell viability were also examined. Domatinostat reduced the protein and mRNA expression of FOXM1 and survivin and also the viability of ovarian cancer cells alone and in combination with cisplatin or paclitaxel at clinically relevant concentrations. Knockdown experiments showed survivin expression was dependent on FOXM1 in ovarian cancer cells. Survivin inhibition was sufficient to reduce the viability of ovarian cancer cells alone and in combination with the chemotherapeutic agents. Our findings suggest that domatinostat, which effectively targets the FOXM1–survivin axis required for the viability of ovarian cancer cells, is a promising option for the treatment of ovarian cancer.

Background: Risk for lower extremity musculoskeletal injury increases after sport-related concussion (SRC) and may result from unresolved motor control deficits. Muscle weakness is a deficit that could contribute to musculoskeletal injury risk. Hypothesis: Athletes with SRC will demonstrate quadriceps and hamstring muscle weakness at the time of return to sport and 30 days later compared with controls. Study Design: Prospective matched cohort. Level of Evidence: Level 3. Methods: A total of 31 athletes with SRC (CONCUSSION) were matched by sex, age, and activity level to controls (CONTROL). Testing was conducted at initial assessment and 30 days later; initial assessment in CONCUSSION occurred when cleared for return to play. Isokinetic testing assessed quadriceps and hamstring strength of the dominant and nondominant legs at 60 and 180 deg/s. Peak torque values were normalized to body mass (N-m/kg). Data were analyzed with repeated measures general linear models (group × time), and effect sizes were calculated. Results: Analysis at 60 deg/s included 26 matched pairs (15 male per group) and at 180 deg/s included 30 matched pairs (17 males per group). Time from concussion to initial assessment was 21.3 (7.8) mean (standard deviation) days. No significant interactions or main effects were detected ( P > 0.05). Across muscle groups, legs, and testing speeds, effect sizes at initial assessment were small ( d = 0.117 to 0.353), equating to a strength deficit in CONCUSSION of 0.04 to 0.18 N-m/kg, and effect sizes were further reduced at 30-day follow-up (d = −0.191 to 0.252). Conclusion: In athletes with SRC, quadriceps and hamstring strength were decreased only minimally at return to play compared with controls and the difference lessened over 30 days. Clinical Relevance: Strength deficits may not be a major contributor to increased lower extremity musculoskeletal injury risk after SRC. Strength training could be implemented before return to play after SRC to mitigate any strength deficits.

Nuclear protein of the testis (NUT) midline carcinoma (NMC) is a rare malignant tumor expressing NUT with BRD4/3 rearrangements and is sometimes misdiagnosed as germinoma, especially in alpha-fetoprotein (AFP)-elevated cases. A 28-year-old man had a mediastinal tumor with multiple bone metastases and elevated AFP levels. Imaging/laboratory findings led to a pathological diagnosis of extragonadal germinoma. After unsuccessful treatment with etoposide-cisplatin, he was re-diagnosed with sarcoma due to vimentin-positive findings. He was treated with adriamycin-ifosfamide, which resulted in disease-control. A posthumous examination clarified the NUT rearrangement. Even in cases with characteristic findings, such as elevated AFP levels and vimentin positivity, NMC should be considered as a differential diagnosis. We note, however, that adriamycin-ifosfamide has some efficacy in such cases.

Chemical reactions at the interface of reactive solutions are of importance for a full understanding of solution reactions. We investigate the chemical reaction induced by the collision of two droplets. The extent of the reaction is measured by analyzing spectra and images of the Raman scattered light emerging from the interface of the colliding droplets of H2SO4 and NH3 aqueous solutions. The obtained product concentration is lower than that expected from a simple diffusion model. The result indicates that a fresh interface is produced at the periphery of the mixing region of the colliding droplets. This study provides the basis to extend this method to measure rapid chemical reactions at the interface of colliding droplets.

Cancer stem cells (CSCs) are in general characterized by higher resistance to cell death and cancer therapies than non-stem differentiated cancer cells. However, we and others have recently revealed using glioma stem cells (GSCs) as a model that, unexpectedly, CSCs have specific vulnerabilities that make them more sensitive to certain drugs compared with their differentiated counterparts. We aimed in this study to discover novel drugs targeting such Achilles’ heels of GSCs as anti-GSC drug candidates to be used for the treatment of glioblastoma, the most therapy-resistant form of brain tumors. Here we report that domatinostat (4SC-202), a class I HDAC inhibitor, is one such candidate. At concentrations where it showed no or minimal growth inhibitory effect on differentiated GSCs and normal cells, domatinostat effectively inhibited the growth of GSCs mainly by inducing apoptosis. Furthermore, GSCs that survived domatinostat treatment lost their self-renewal capacity. These results suggested that domatinostat is a unique drug that selectively eliminates GSCs not only physically by inducing cell death but also functionally by inhibiting their self-renewal. Our findings also imply that class I HDACs and/or LSD1, another target of domatinostat, may possibly have a specific role in the maintenance of GSCs and therefore could be an attractive target in the development of anti-GSC therapies.

Background High-grade meningiomas are aggressive tumors with high morbidity and mortality rates that frequently recur even after surgery and adjuvant radiotherapy. However, limited information is currently available on the biology of these tumors, and no alternative adjuvant treatment options exist. Although we previously demonstrated that high-grade meningioma cells were highly sensitive to gemcitabine in vitro and in vivo, the underlying molecular mechanisms remain unknown. Methods We examined the roles of hENT1 (human equilibrative nucleoside transporter 1) and dCK (deoxycytidine kinase) in the gemcitabine sensitivity and growth of meningioma cells in vitro. Tissue samples from meningiomas (26 WHO grade I and 21 WHO grade II/III meningiomas) were immunohistochemically analyzed for hENT1 and dCK as well as for Ki-67 as a marker of proliferative activity. Results hENT1 and dCK, which play critical roles in the intracellular transport and activation of gemcitabine, respectively, were responsible for the high gemcitabine sensitivity of high-grade meningioma cells and were strongly expressed in high-grade meningiomas. hENT1 expression was required for the proliferation and survival of high-grade meningioma cells and dCK expression. Furthermore, high hENT1 and dCK expression levels correlated with stronger tumor cell proliferative activity and shorter survival in meningioma patients. Conclusions The present results suggest that hENT1 is a key molecular factor influencing the growth capacity and gemcitabine sensitivity of meningioma cells and also that hENT1, together with dCK, may be a viable prognostic marker for meningioma patients as well as a predictive marker of their responses to gemcitabine.

Background/aim Despite advances in treatment modalities, the visual prognosis of retinoblastoma still remains unsatisfactory, underscoring the need to develop novel therapeutic approaches. Materials and methods The effect on the growth of six human retinoblastoma cell lines and a normal human fibroblast cell line of CEP1347, a small-molecule kinase inhibitor originally developed for the treatment of Parkinson's disease and therefore with a known safety profile in humans, was examined. The role of the P53 pathway in CEP1347-induced growth inhibition was also investigated. Results CEP1347 selectively inhibited the growth of retinoblastoma cell lines expressing murine double minute 4 (MDM4), a P53 inhibitor. Furthermore, CEP1347 reduced the expression of MDM4 and activated the P53 pathway in MDM4-expressing retinoblastoma cells, which was required for the inhibition of their growth by CEP1347. Conclusion We propose CEP1347 as a promising candidate for the treatment of retinoblastomas, where functional inactivation of P53 as a result of MDM4 activation is reportedly common.

722 patients who returned to the intensive care unit( ICU) after completing the cardiac surgery and closing the median sternotomy from Jan 2010 to Feb 2021 at our hospital were divided into 3 groups according to the different sternal closures. Sternum was fixed with 6 wires alone in group A (n=333), with 2 absorbable plates and 6 wires in group B( n=259) or with 3 titanium plates with 20 screws and 4 wires in group C (n=130). Background characteristics were not different between the 3 groups. Total number of 3 complications (postsurgical bleeding, mediastinitis and delayed cardiac tamponade) was significantly less in group B and C than group A. Among them postsurgical bleeding needed hemostasis surgery was significantly less in group C than in group A. Surgical nor hospital mortality were not significantly different in 3 groups. Postsurgical complications were significantly less when the sternum closure was fixed with plates( absorbable, not absorbable).

Adrenocortical oncocytic tumors are rare. As the Weiss criteria overestimate the malignancy of oncocytic tumor due to histological hallmarks, the Lin-Weiss-Bisceglia system (LWB system) is required for an accurate diagnosis of the malignant potential of an oncocytic tumor. We report two cases diagnosed as an oncocytic tumor with uncertain malignant potential (borderline) and an oncocytic tumor (benign) based on the LWB system, both of which were diagnosed as malignant based on the Weiss criteria. Case 1 : A man in his 20s was referred to our hospital for treatment of a left adrenal tumor. A non-functional pheochromocytoma or adrenal cancer was suspected. He underwent surgical resection of the left adrenal tumor and left kidney. The specimen was positive for 3 of the 9 Weiss criteria, but met one minor criterion in the LWB system. He was diagnosed with an oncocytic tumor with uncertain malignant potential (borderline). Case 2 : A woman in her 40s was referred to our hospital for treatment of a left adrenal tumor. Under the possibility of adrenal cancer, she underwent surgical resection of the left adrenal tumor. The specimen was positive for 3 of the 9 Weiss criteria, but the specimen met no criteria in the LWB system. She was diagnosed with an oncocytic tumor (benign). There has been no recurrence of the oncocytic tumor as of 2 years of follow-up in the two patients.

Background: Fear avoidance after musculoskeletal injury is avoiding activity due to fear of pain and contributes to persistent symptoms, depression, and disability. Little is known about fear avoidance for sport (athletic fear avoidance) in athletes with sport-related concussion (SRC). Hypothesis: Athletic fear avoidance after SRC would be elevated at the start of rehabilitation, improve over time, and be associated with postconcussion recovery outcomes. Study Design: Observational study. Level of Evidence: Level 4. Methods: Athletes in rehabilitation after SRC participated. Testing at initial and discharge visits and 6-month follow-up included Athletic Fear Avoidance Questionnaire (AFAQ), Postconcussion Symptom Scale (PCSS), Profile of Mood States (POMS), and Dizziness Handicap Inventory (DHI). Differences were explored in AFAQ score at initial testing based on sex or age (Results: A total of 48 athletes participated: 28 completed initial testing only (INITIAL ONLY), and 20 completed all testing (LONGITUDINAL). Across cohorts, the mean (SD) AFAQ score at initial testing was 24.3 (7.6) points, with no significant difference by sex or age. AFAQ, PCSS, POMS, and DHI scores improved in LONGITUDINAL; the effect size was large from initial to discharge testing (1.0, 1.0, 1.0, and 1.2, respectively) and variable from discharge to follow-up testing (0.52, -0.34, -0.08, and 0.02, respectively). AFAQ scores increased from discharge to follow-up in 3 athletes and were consistently above the mean value in 2 athletes. AFAQ score was significantly correlated to the other questionnaire scores at each timepoint (range, r = 0.36-0.75). Conclusion: Athletic fear avoidance was elevated at the start of SRC rehabilitation, improved over time in most patients, and was associated with postconcussion symptoms, mood, and disability. Clinical Relevance: Athletic fear avoidance may impact recovery after SRC.

We report a case of hereditary breast and ovarian cancer(HBOC)in a young adult. A 31-year-old woman consulted at our hospital for a lump on her left breast. Ultrasonography revealed an irregular-shaped mass. A core needle biopsy was performed, and the pathological diagnosis was invasive ductal carcinoma. There were multiple enlarged lymph nodes in the axilla and internal mammary areas but no evidence of metastasis. She underwent mastectomy and axially dissection. The pathological findings from the surgically resected specimens showed scirrhous carcinoma positive for ER and PgR and negative for HER2/neu protein expression. The tumor size was 16 mm, and 3 axillary lymph node metastases were seen. We identified the pathological stage as T1cN3bM0, stage ⅢC. She received chemotherapy, radiotherapy, and endocrine therapy after surgery. At present, 1 year after surgery, the patient is alive without recurrence. With a low age of onset and a family history of ovarian cancer, she was diagnosed with HBOC as a result of breast cancer susceptibility gene(BRCA)genetic testing. In addition to the recommended surveillance, prophylactic surgery will be performed in the future.

To clarify the pudendal sensory nerve(PSN)play in preventing fecal incontinence(FI)after low anterior resection(LAR) for lower rectal cancer, the PSN function was studied at 6 months after LAR. A total of 36 patients aged 42.0 to 79.0 years (23 males and 13 females with a mean age of 62.0 years)who underwent LAR for laparoscopic radical cystectomy(LRC) were enrolled in the present study. Based on postoperative F1, these patients were divided into 2 groups[group A; patients with FI(n=12), group B; patients without FI(continence, n=24)]. These were compared with group C(n=32, control subjects, 18 males and 14 females aged 40.0 to 76.0 years with a mean age of 61.8 years). Anal mucosal electric sensitivity (AMES)threshold was measured [at the upper 1 cm oral side from dentate line(DL); a, DL; b, and lower zones 1 cm anal side from DL; c]. FI after LAR was also evaluated by the Wexner score(WS). All patients were pathological Stage Ⅰ(25 patients: T1, N0, M0; 11 patients: T2, N0, M0). Group A had a significantly larger proportion of males than group B(p0.05). The distance of anastomosis from anal verge(DAAV)in group A(2.4±1.8 cm)was significantly shorter than in group B(4.4±0.9 cm)(p0.001). WS from 6 to 10 comprised 25.0% of group A, 11 to 15 comprised 50.0%, and 16 to 20 comprised 25.0%. All patients in group A(WS; 8 or more)were incontinent. In contrast, all patients in group B(WS; 0) and C(WS; 0)were continent. Patients in pre-operative defecation(WS; 0)were also continent. On the AMES(a, b, c), sensitivity of patients in group A(6.4±1.1, 5.1±0.5, 4.9±0.6 mA)was significantly higher than in groups B(2.6±0.5, 2.4 ±0.4, 2.5±0.6 mA)and C(2.3±0.4, 2.1±0.4, 2.3±0.5 mA)at all zones(p0.001). FI after LAR with a short DAAV, especially male, may be PSN dysfunction due to operative damage of PSN.

The demerit of pylorus-preserving gastrectomy(PPG)is the postprandial abdominal fullness(PAF)with gastric stasis in the remnant stomach(GSRS). We investigated the relationship between clinical findings and GSRS, and between GSRS and interdigestive migrating motor complex(IMMC)in PPG patients. A total of 30 patients(17 men and 13 women, mean age of 62.3 years)after PPG for early gastric cancer(Billroth Ⅰ)were divided into 2 groups(group A; 18 patients with GSRS, group B; 12 patients without GSRS). The relationship between GSRS including clinical findings and IMMC was studied from 1.5 to 3 years after operation. A catheter equipped with a micro-tip force transducer was inserted transnassally into the remnant stomach and duodenum in a supine position, and the IMMC was studied. All patients were Stage ⅠA(mucosal cancer, no lymph node metastasis, no distant metastasis). The remnant stomach was 1/3 compared with stomach size before operation. The length of the antral cuff in group A(1.5±0.2 cm)was significantly shorter than group B(3.2±0.3 cm)(p =0.0004). Appetite was significantly recognized in group B compared with group A(p=0.0067). PAF was significantly recognized in group A compared with group B(p=0.0001). Reflux esophagitis was found in group A more than group B. Early dumping syndroms did not found significant differences in both groups. In endoscopic esophagogastric finding of the remnant stomch, gastritis with GSRS was significantly found in group A compared with group B(p=0.0001). The IMMC was significantly recognized in group B compared with group A(p0.0001). The occurrence of the PAF due to the GSRS may be caused by abscens of the IMMC.

A 17-year-old man received continuous ambulatory peritoneal dialysis (CAPD) catheter implantation and had started peritoneal dialysis. Perfusion failure of peritoneal dialysis catheter occurred one month after the catheter implantation. Transcatheter contrast examination revealed catheter obstruction about 4-5 cm from the catheter tip. We performed reduced port surgery to remove the obstruction. Laparoscopy revealed that the omentum was adhered to the abdominal wall and wrapped the catheter. We diagnosed the cause of catheter malfunction as omentum wrapping. We removed the omentum from the catheter, and repositioned the catheter into the Douglas fossa. Although CAPD worked successfully after the operation, perfusion failure recurred one month after the operation. The patient requested discontinuation of CAPD and change to hemodialysis. Therefore, we removed the CAPD catheter. The catheter was adhered to the omentum. Reduced port surgery for peritoneal dialysis catheter obstruction has the advantage of being minimally invasive and is a reliable procedure, but further studies are needed to reduce the recurrence rate of perfusion failure and to establish the procedure after perfusion failure.

Glioblastoma (GBM) is one of the deadliest of all human cancers. Developing therapies targeting GBM cancer stem cells or glioma stem cells (GSCs), which are deemed responsible for the malignancy of GBM due to their therapy resistance and tumor-initiating capacity, is considered key to improving the dismal prognosis of GBM patients. In this study, we found that folate antagonists, such as methotrexate (MTX) and pemetrexed, are selectively cytotoxic to GSCs, but not to their differentiated counterparts, normal fibroblasts, or neural stem cells in vitro, and that the high sensitivity of GCSs to anti-folates may be due to the increased expression of RFC-1/SLC19A1, the reduced folate carrier that transports MTX into cells, in GSCs. Of note, in an in vivo serial transplantation model, MTX alone failed to exhibit anti-GSC effects but promoted the anti-GSC effects of CEP1347, an inducer of GSC differentiation. This suggests that folate metabolism, which plays an essential role specifically in GSCs, is a promising target of anti-GSC therapy, and that the combination of cytotoxic and differentiation therapies may be a novel and promising approach to effectively eliminate cancer stem cells.

A novel coupling device composed of a combination of microlens and pillar having an approximately $8~\mu \text{m}$ diameter and $20~\mu \text{m}$ height and grown from single-mode fiber (SMF) core end is proposed. This device was successfully fabricated by using a self-written waveguide and dipping method with UV-curable resin. Theoretical and experimental studies were done. A high coupling efficiency of more than −0.97dB was obtained for coupling to an ultrahigh numerical aperture (0.41) SMF with a spot diameter of $3.7~\mu \text{m}$ at a $1.55~\mu \text{m}$ wavelength in place of a silicon chip with an integrated spot-size converter. In contrast, it is only −4.0dB by a conventional SMF.

Background/aim Although epidermal growth factor receptor (EGFR) is frequently activated in lung and pancreatic cancers, the efficacy of EGFR tyrosine kinase inhibitors (EGFR-TKIs) is limited. Recently, brexpiprazole, an antipsychotic drug, was reported to chemosensitize glioma cells to osimertinib, a third-generation EGFR-TKI, by suppressing survivin, an anti-apoptotic protein, but their combinational effects on lung and pancreatic cancers remain unknown. The aim of this study was to examine the combinational effects of brexpiprazole and osimertinib on lung and pancreatic cancer cells in vitro and in vivo. Materials and methods YM155, a suppressor of survivin, siRNA, and immunoblot were used to examine the role of survivin in osimertinib-resistance. The effect of drugs on cell viability in vitro was examined by trypan blue staining. The in vivo effects of drugs on tumor growth were examined using a xenograft mouse model. Results Brexpiprazole exerted combinational effects with osimertinib in vitro. Pharmacological and genetic suppression of survivin chemosensitized the cells to osimertinib. Moreover, the combination of brexpiprazole and osimertinib effectively suppressed tumor growth in a mouse xenograft model. Conclusion Brexpiprazole is a promising drug for lung and pancreatic cancer in combination with osimertinib.

From the perspective of psycho-oncology, antipsychotics are widely used for patients with cancer. Although some antipsychotic drugs have anti-tumor effects, these antipsychotic drugs are not applicable for cancer patients because of their severe side effects. Brexpiprazole, a novel serotonin-dopamine modulator with an improved side effect profile, was developed as a drug that is structurally and pharmacologically related to aripiprazole, which was reported to have anti-cancer effects. However, it remains unknown whether brexpiprazole has anti-cancer effects. In this study, we examined whether brexpiprazole has anti-tumor effects in cancer cells and cancer stem cells (CSCs) of glioblastoma, pancreatic cancer, and lung cancer. Brexpiprazole suppressed cell growth and induced cell death in the cancer cells and the CSCs, and decreased the CSC properties of the CSCs. Brexpiprazole did not exert any cytotoxic effects on non-cancer cells at the anti-cancer effect-inducing concentration. In the cancer cells and the CSCs, brexpiprazole reduced the expression of survivin, an anti-apoptotic protein, whose reduction sensitizes tumor cells to chemotherapeutic reagents. In the preclinical model in which pancreatic CSCs were subcutaneously implanted into nude mice, brexpiprazole suppressed tumor growth, in addition to reducing the expression of Sox2, a marker for CSCs, and survivin. This suggests that brexpiprazole is a promising antipsychotic drug with anti-tumor effects and an improved safety profile.

Klotho is one of the known anti-aging genes, and functions as an inhibitor of the insulin-like growth factor 1(IGF-1) pathway. However, the clinical significance of Klotho expression in cancer tissues have not been elucidated yet. In this study, we aimed to investigate the clinical significance of Klotho expression in breast cancer patients. We evaluated Klotho expression through immunohistochemical analysis and evaluating Ki-67 positive cell index in 142 patients who underwent surgery for breast cancer in our hospital. There was no significant correlation between age, menopausal state, historical type, hormone status, HER2 status, and distant metastases. High expression of Klotho was observed in the non-invasive compared to the invasive ductal carcinomas. The number of metastatic lymph nodes, clinical stage, and tumor size were correlated to Klotho expression level in the cancer tissues. The Klotho positive group exhibited low score for Ki-67 positive cell index than the Klotho negative group. No significant correlation in cumulative survival rates between Klotho positive and Klotho negative groups was observed. The Klotho negative group exhibited good prognosis than the Klotho positive group for the disease- free survival after the operation. These results suggest that the analysis Klotho expression in the breast cancer tissues using immunohistochemistry is a useful tool to assess the disease-free survival for breast cancer patients.

Background/aim Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are key drugs in cancer treatment due to their minor adverse effects and outstanding anticancer effects. However, drugs for overcoming EGFR-TKI resistance are not in clinical use so far. Therefore, to overcome resistance, we focused on lurasidone, a new antipsychotic drug, due to its mild adverse effect profile from the viewpoint of drug repositioning. Materials and methods We explored the effects of lurasidone alone or in combination with EGFR-TKI on the growth of osimertinib-resistant cancer cells the anti-apoptotic marker expression such as survivin, and autophagy levels by LC-3B expression. Results Within a non-toxic concentration range in normal cells, lurasidone and osimertinib combination therapy showed a growth-inhibitory effect in osimertinib-resistant cancer cells in vitro and in vivo. Furthermore, lurasidone decreased survivin expression and mildly induced autophagy. Conclusion Lurasidone may increase the sensitivity to osimertinib in osimertinib-resistant cancer cells in drug repurposing.

Glioma stem cells (GSCs), the cancer stem cells of glioblastoma multiforme (GBM), contribute to the malignancy of GBM due to their resistance to therapy and tumorigenic potential; therefore, the development of GSC-targeted therapies is urgently needed to improve the poor prognosis of GBM patients. The molecular mechanisms maintaining GSCs need to be elucidated in more detail for the development of GSC-targeted therapy. In comparison with patient-derived GSCs and their differentiated counterparts, we herein demonstrated for the first time that phospholipase C (PLC)ε was highly expressed in GSCs, in contrast to other PLC isoforms. A broad-spectrum PLC inhibitor suppressed the viability of GSCs, but not their stemness. Nevertheless, the knockdown of PLCε suppressed the survival of GSCs and induced cell death. The stem cell capacity of residual viable cells was also suppressed. Moreover, the survival of mice that were transplanted with PLCε knockdown-GSCs was longer than the control group. PLCε maintained the stemness of GSCs via the activation of JNK. The present study demonstrated for the first time that PLCε plays a critical role in maintaining the survival, stemness, and tumor initiation capacity of GSCs. Our study suggested that PLCε is a promising anti-GSC therapeutic target.

Microbiome analysis has attracted attention in recent years as a tool to monitor individual health status. In particular, gut microbiota is closely related to autoimmunity, and detailed study of gut microbiota may enable prediction of the health status of individuals.Here, we aimed to conduct a detailed study to identify gastric cancer-specific gut microbiota and compare the data between patients with gastric cancer and healthy individuals. Toward this, we extracted DNA from feces of patients with advanced gastric cancer enrolled in the observational/translational study, the DELIVER trial (JACCRO GC-08: UMIN000030850) which evaluated clinical outcomes of nivolumab and developed host-related biomarkers for nivolumab in 500 patients with advanced gastric cancer, and obtained their sequence data at an average of 5 Gbps using whole-genome shotgun sequencing. We then performed genus classification and functional pathway analysis using Kyoto Encyclopedia of Genes and Genomes (KEGG).We analyzed differences in bacterial composition using the data of 476 Japanese patients with advanced gastric cancer (median age 70y, median BMI 20.0, 71% male, 37.0% of patients with relapse, 55.5% with previous gastrectomy) and public database of 106 healthy cases. Bifidobacterium, Anaerostipes, and Parabacteroides were predominant in the healthy individuals, whereas Streptococcus, Lactobacillus, and Odoribacter were predominant in patients with advanced gastric cancer. Furthermore, the KEGG pathway analysis showed that butanoate and pyruvate metabolism were enriched in the healthy individuals, whereas factors such as ABC transporters and ribosomes were enriched in the patients with advanced gastric cancer. Clustering analysis broadly classified the patients with advanced gastric cancer and healthy individuals into two clusters, and the clustering using pathway data enabled clearer classification of the patients with advanced gastric cancer and healthy individuals than the clustering using flora analysis. Additionally, the healthy individuals had higher bacterial flora diversity compared to the patients with advanced gastric cancer.We thus successfully identified the molecular characteristic of microbial genera and functional pathways in the gut in patients with advanced gastric cancer. We conclude that fecal metagenomic shotgun sequencing analysis might be used to detect gastric cancer. Citation Format: Ryo Matoba, Hiroshi Iijima, Yasuhiro Sakamoto, Ryohei Kawabata, Atsushi Ishiguro, Yusuke Akamaru, Yosuke Kito, Hiroshi Yabusaki, Jin Matsuyama, Masazumi Takahashi, Akitaka Makiyama, Takahisa Suzuki, Masahiro Tsuda, Hisateru Yasui, Jun Hihara, Toru Masuzawa, Hiroyuki Okuda, Junji Kawada, Shuhei Suzuki, Hisato Kawakami, Takako Eguchi Nakajima, Kei Muro, Wataru Ichikawa, Masashi Fujii, Yu Sunakawa. Molecular characteristics of gut microbiota in patients with gastric cancer: The DELIVER trial (JACCRO GC-08) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5957.

To clarify the pudendal motor nerve(PMN)play in preventing fecal incontinence(FI)after low anterior resection(LAR) for lower rectal cancer, the PMN function was studied at early postoperative period after LAR. A total of 30 patients aged 43 to 78 years (21 men and 9 women with a mean age of 62.4 years) who underwent LAR for LRC were enrolled in the present study. Based on postoperative FI, these patients were divided into 2 groups(group A: patients with FI[n=10], group B: patients without FI[continence, n=20]). These were compared with group C(n=28, control subjects, 18 men and 10 women aged 46 to 76 years with a mean age of 60.2 years). Magnetic stimulation at the S2-4 sacral levels has been shown to activate the PMN root of the cauda equina. PMN latency(PMNL)at posterior sides of the anal canal was studied. FI after LAR was also evaluated by the Wexner score(WS). All patients were pathological Stage Ⅰ(20 patients: T1, N0, M0; 10 patients: T2, N0, M0). Group A had a significantly larger proportion of men than group B(p0.05). The distance of anastomosis from anal verge(DAAV)in group A(2.4±1.7 cm)was significantly shorter than in group B(4.4±0.9 cm)(p0.001). WS from 8 to 10(mean: 9.25)comprised 20.0% of group A, 11 to 15(mean: 13.5)50.0%, and 16 to 20(mean: 18.5)comprised 30.0%. All patients in group A(WS: 8 or more)were incontinent. In contrast, all patients in group B(WS: 0)and C(WS: 0)were continent. Patients in pre-operative defecation(WS: 0)were also continent. As for PMNL, the conduction delay in group A(7.9±0.9 ms)was significantly longer than in groups B(4.1±0.6 ms)and C(3.9±0.3 ms) (p0.001, respectively). FI after LAR with a short DAAV may be EAS dysfunction due to damage of PMN.

A 68-year-old woman had undergone mastectomy for right breast cancer when she was 60 years of age. The histopathological diagnosis had been scirrhous carcinoma, T1N0M0, stage Ⅰ. She had received anastrozole as the adjuvant therapy for 5 years. Eight years after the operation, she consulted our department because of a lump on the right chest wall. The metastatic work-up revealed no evidence of metastases. Tumorectomy was performed. Histopathological findings from the surgically resected specimens showed scirrhous carcinoma, positive for ER and PgR, and negative for HER2/neu protein expression. The Ki-67 positive cell index was 25%. Therefore, we diagnosed the patient with local recurrence of breast cancer. Since surgical margins were positive, irradiation was performed at the recurrence site, and letrozole was administered. Local recurrence is a target of the curative treatment and requires a multidisciplinary approach, including surgery, drugs, and radiation therapy. We report a case of local recurrence of breast cancer 8 years after mastectomy.

Background Malignant meningioma is an aggressive tumor that requires adjuvant radiotherapy after surgery, yet there has been no standard systemic therapy established so far. We recently reported that malignant meningioma cells are highly sensitive to gemcitabine; however, it remains unknown whether or how gemcitabine interacts with ionizing radiation (IR) in malignant meningioma cells. Methods We examined the radiosensitization effects of gemcitabine using malignant meningioma cell lines and xenografts and explored the underlying mechanisms. Results Gemcitabine sensitized malignant meningioma cells to IR through the induction of senescence both in vitro and in vivo. Gemcitabine augmented the intracellular production of reactive oxygen species (ROS) by IR, which, together with cell growth suppression/senescence induced by this combination, was inhibited by N-acetyl-cysteine, suggesting a pivotal role for ROS in these combinatorial effects. Navitoclax, a senolytic drug that inhibits Bcl-2 proteins, further enhanced the effects of the combination of gemcitabine and IR by strongly inducing apoptotic cell death in senescent cells. Conclusion These results not only indicate the potential of gemcitabine as a candidate radiosensitizer for malignant meningioma, but also reveal a novel role for gemcitabine radiosensitization as a means to create a therapeutic vulnerability of senescent meningioma cells to senolytics.

Postoperative recurrence from microscopic residual disease must be prevented to cure intractable cancers, including pancreatic cancer. Key to this goal is the elimination of cancer stem cells (CSCs) endowed with tumor-initiating capacity and drug resistance. However, current therapeutic strategies capable of accomplishing this are insufficient. Using in vitro models of CSCs and in vivo models of tumor initiation in which CSCs give rise to xenograft tumors, we show that dexamethasone induces expression of MKP-1, a MAPK phosphatase, via glucocorticoid receptor activation, thereby inactivating JNK, which is required for self-renewal and tumor initiation by pancreatic CSCs as well as for their expression of survivin, an anti-apoptotic protein implicated in multidrug resistance. We also demonstrate that systemic administration of clinically relevant doses of dexamethasone together with gemcitabine prevents tumor formation by CSCs in a pancreatic cancer xenograft model. Our study thus provides preclinical evidence for the efficacy of dexamethasone as an adjuvant therapy to prevent postoperative recurrence in patients with pancreatic cancer.

We report the case of a phyllodes tumor of the breast occurring near a postoperative scar of fibroadenoma of the breast. The patient was a 41-year-old female who had a lump in the left breast, and underwent surgical resection of the tumor 5 years ago at another hospital.The pathological diagnosis of the tumor was fibroadenoma, and surgical margin was negative. The patient underwent ultrasonography every year at the treatment hospital.Five years later, the patient noticed a tumor in her left breast and visited our hospital.The tumor was 30mm in diameter and situated near the postoperative scar.A core needle biopsy for breast tumor led to the diagnosis of a phyllodes tumor.Surgical resection was performed with 5mm margins, and pathological analysis of the surgical specimen revealed a benign phyllodes tumor.The surgical margins were not involved.One year and 6 months after surgery, no metastases or recurrence were reported.

We report a case of papilloma of the breast with rapid growth in a 39-year-old female who had a lump in the left breast. The follow-up for the breast tumor was performed at another hospital.Three years after her first visit, 3 tumors measuring 1.8 cm, 0.5 cm, and 0.3 cm in diameter were detected. The patient visited our hospital to diagnose these tumors. We performed core needle biopsy for the tumor, and the pathological diagnosis was benign papilloma.After 1 year, the tumor grew to 3.0 cm in diameter, and we repeated the core needle biopsy. The pathological diagnosis remained as benign papilloma; however, the ultrasonography and MRI results showed that the tumor was malignant.Surgical resection was performed for the tumors, and pathological analysis of the surgical specimen revealed 3 benign papillomas with no involvement of the surgical margin.Six years after surgery, no recurrence was reported.

Background Data on FOLFIRINOX as a second-line chemotherapy for advanced pancreatic cancer are limited. In the JASPAC06 study—a nationwide, multicenter, observational study—FOLFIRINOX for patients with unresectable or recurrent pancreatic cancer as any line of treatment showed favorable efficacy and safety in Japanese clinical practice. Methods We performed exploratory analyses of patients with unresectable or recurrent pancreatic cancer who received FOLFIRINOX as the second-line chemotherapy in Japanese clinical settings. Results Of the 399 evaluable patients, 44 were eligible for inclusion in the analysis. The patients’ characteristics were as follows: median age, 62 years; men, 26 (59%); Eastern Cooperative Oncology Group-Performance status 0/1, 30 (68%)/14 (32%); disease status, recurrent/local/metastatic: 4 (9%)/8 (18%)/32 (73%). The initial dose was reduced in 28 (64%) patients. The median time to treatment failure and number of cycles were 4.5 (range, 0.2–19.1) months and 6 cycles (range, 1–13 or more), respectively. The major grade 3/4 adverse events were neutropenia in 29 (66%), leucopenia in 17 (39%), anorexia in 7 (16%), febrile neutropenia in 5 (11%), and anemia in 5 (11%) patients. The median overall survival, progression-free survival, and 1-year survival rates were 10.3 (95% confidence interval [CI], 7.2–13.3), 4.1 (95% CI, 2.6–5.5) months, and 30%, respectively. Conclusion Our findings suggest that FOLFIRINOX as a second-line chemotherapy for advanced pancreatic cancer was effective in patients with a good performance status. It displayed toxicity similar to that observed with its use as a first-line treatment.

Despite several clinical trials with encouraging findings, effective standard systemic therapies have yet to be established for malignant meningioma and the prognosis of these patients remains poor. Accumulating preclinical and clinical evidence suggests that gemcitabine is effective against malignant meningioma. To identify drugs with therapeutic effects that may be enhanced in combination with gemcitabine, we screened drugs that have been tested in preclinical and clinical trials for meningioma. In IOMM-Lee and HKBMM malignant meningioma cells, gemcitabine enhanced the growth inhibitory effects of the mTOR inhibitor everolimus, the clinical benefits of which have been demonstrated in patients with meningioma. The synergistic growth inhibitory effects of this combination were accompanied by cellular senescence characterized by an increase in senescence-associated β-galactosidase activity. To enhance the effects of this combination, we screened senolytic drugs that selectively kill senescent cells, and found that navitoclax, an inhibitor of anti-apoptotic BCL-2 family proteins, effectively reduced the number of viable malignant meningioma cells in combination with everolimus and gemcitabine by inducing apoptotic cell death. The suppression of tumor growth in vivo by the combination of everolimus with gemcitabine was significantly stronger than that by either treatment alone. Moreover, navitoclax, in combination with everolimus and gemcitabine, significantly reduced tumor sizes with an increase in the number of cleaved caspase-3-positive apoptotic cells. The present results suggest that the addition of gemcitabine with or without navitoclax to everolimus is a promising strategy that warrants further evaluation in future clinical trials for malignant meningioma.

Background AS602801, a novel inhibitor of c-Jun N-terminal kinase (JNK), suppresses tumor initiation capacity and metastatic potential of cancer stem cells (CSCs). However, it remains unknown whether this inhibitor can chemosensitize CSCs. Materials and methods Using A2780 CSLC, a CSC line derived from ovarian cancer, this study examined the combinational effects of AS602801 and carboplatin or paclitaxel and explored the mechanism of those effects. Results AS602801 chemosensitized A2780 CSLC cells to carboplatin and paclitaxel. With respect to the mechanism of chemosensitization, the expression of survivin, an anti-apoptotic protein, was reduced by AS602801. Pharmacological and genetic inhibition of survivin chemosensitized the cells to carboplatin and paclitaxel. Suppression of survivin by AS602801 was also observed in other types of CSCs and non-CSCs. Conclusion AS602801, which reduces survivin expression, can chemosensitize ovarian CSCs and is a candidate drug that targets the chemoresistance, tumor-initiating capacity and metastasis of CSCs.