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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.

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.

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.

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.

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.

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.

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:. Problems with poor circulation often occur when a large defect or a distant region, such as the apex of the nose, is covered with a paramedian forehead flap. Delay technique increases the safety of reconstruction procedures, but it has been used less frequently because a 2-stage surgery is necessary, and various other flaps and techniques have been developed. Method:. We performed the delay technique of paramedian forehead flap at the same time as tumor resection. For the flap, a narrow pedicle of about 1-cm was prepared on the supratrochlear artery and vein, and the incision was extended toward the lateral side conforming to the defect morphology, and a paramedian forehead flap with a design consistent with the esthetic unit containing the defect was prepared. The region below the flap was dissected to create the flap bipedicle, and surgery was completed. Result:. This procedure was used in 4 patients with malignant tumor of the external nose, and the flap survived perfectly in all patients. The postoperative esthetic outcome was also found to be good. Conclusions:. This procedure does not increase the frequency of surgery, circulation in the flap is maintained, the flap pedicle on the supratrochlear artery can be made narrow, and flap thinning can be performed from the beginning. Coverage of an extensive defect is possible because a large flap can be excised, and satisfactory esthetic appearance can be obtained by matching with the esthetic unit. The delay technique for various flaps (not limited to forehead flap alone) should be considered an effective technique for the current treatment of malignant tumors.

Summary Background Reconstruction of the upper eyelid with the same eyelid tissue is desirable because of the ability to achieve eye opening/closing and corneal protection, and a lid switch flap is a useful method. For total defects, almost all of the tissues of the lower eyelid should be used; however, the reconstruction of the lower eyelid donor site has often been undervalued. Reconstruction with an insufficient amount of soft tissue often results in complications such as lagophthalmos and ectropion. Here, we report our method of management of total upper eyelid defects and secondary reconstruction of the lower eyelid donor site. Method A lid switch flap is designed on the lower eyelid as the first operation. As important points, the height of the flap of the anterior lamina should be the same but the conjunctiva as the posterior lamina should be harvested up to the conjunctival fornix to obtain sufficient tissue. After switching the flap, the lower eyelid donor site is reconstructed with sufficient tissue: cheek mucosa, conchal cartilage, and a reverse superficial temporal artery flap as a three-layered structure. Results Three patients were treated using our method, and we achieved favorable results with a sufficient amount of soft tissue for the reconstruction of the lower eyelid. Conclusion Reconstruction of the upper eyelid with sufficient tissue from the lower eyelid is important for eyelid function.

Glioblastoma is a primary brain tumor associated with a poor prognosis due to its high chemoresistance capacity. Cancer stem cells (CSCs) are one of the mechanisms of chemoresistance. Although therapy targeting CSCs is promising, strategies targeting CSCs remain unsuccessful. Abnormal activation of epidermal growth factor receptors (EGFRs) due to amplification, mutation, or both of the EGFR gene is common in glioblastomas. However, glioblastomas are resistant to EGFR tyrosine kinase inhibitors (EGFR-TKIs), and overcoming resistance is essential. Brexpiprazole is a new, safe serotonin-dopamine activity modulator used for schizophrenia and depression that was recently reported to have anti-CSC activity and function as a chemosensitizer. Here, we examined its chemosensitization effects on osimertinib, a third-generation EGFR-TKI with an excellent safety profile, in glioma stem cells (GSCs), which are CSCs of glioblastoma. Brexpiprazole treatment sensitized GSCs to osimertinib and reduced the expression of survivin, an antiapoptotic factor, and the pharmacological and genetic inhibition of survivin mimicked the effects of brexpiprazole. Moreover, co-treatment of brexpiprazole and osimertinib suppressed tumor growth more efficiently than either drug alone without notable toxicity in vivo. This suggests that the combination of brexpiprazole and osimertinib is a potential therapeutic strategy for glioblastoma by chemosensitizing GSCs through the downregulation of survivin expression.

Background:. We have already reported surgical procedures for lobule-type microtia that provide an excellent contour and shape of the ear with minimum sacrifice of the donor. We have succeeded in establishing a standard surgical technique for almost all types of concha-type microtia that effectively uses the remnant ear and can use a unified costal cartilage frame. Methods and Results:. The concept of our technique is that remnant cartilage should be used maximally but that the deformed area should be completely replaced by the costal cartilage frame. The differences between the cartilage frame for lobule-type microtia and that for concha-type microtia are that the lower half beneath the antihelical area and the concha cymba in the base frame are omitted in concha-type microtia. The area from the tragus to the incisura of the tragus in the antihelical-tragal frame is also omitted. The area of the helical crus in the helical frame and the lower half in the antihelix are not immobilized in the base frame and are free edges. On the other hand, the remnant cartilage outside the concha is removed, but the antitragus is preserved. When the cartilage frame and the remnant are incorporated, all of the components of the ear can be provided. Conclusion:. The ears created by our technique have a natural appearance and clear contour.

Background Recently, auriculoplasty with costal cartilage grafting has been successfully used for correcting microtia and creating a clearly refined contour and a natural appearance of the ear. However, several important problems remain unsolved in these techniques. The authors describe an improved technique for harvesting costal cartilage with minimal morbidity and a new procedure for fabricating a cartilage frame that ensures a refined shape and rigid structure of the constructed ear. Methods Costal cartilage is harvested directly with a chisel. This technique enables some of the cartilage at the chest wall to remain intact. The base frame is fabricated by two cartilage blocks partly overlapped on the area of the antihelix. The thickness in the overlapping area emphasizes the contour between the antihelix and the helical crus. To prevent absorption of the cartilage, helical and antihelical parts are created using the outer rigid layer of the harvested cartilage and are covered as much as possible by perichondrium. Results A total of 137 ears in 121 patients were corrected with the authors' technique and followed up for at least 3 years. Almost all of the patients could walk within 2 days after the operation. The structure and contour of the constructed ear were well maintained. Conclusions Attention should be given not only to successful outcomes of construction of the ear but also to minimal morbidity for the patients. Our technique made it possible to construct a cosmetically refined ear that could be maintained for a long period and minimize the pain and deformity of the donor's chest.

Summary Z-plasty is one of the most widely employed techniques in plastic surgery and mainly serves the following purposes: elongation along the axis of the scar, dispersal of the scar followed by breaking up the straight-line scar and realigning the scar within the lines of minimal tension. It is useful especially to release linear-scar contracture, yet difficult for wide scars. This report describes a novel technique to release contracture effectively for any wide scars using a new design called double combined Z-plasty. The design is simple. The main limb is set to incise the wide scar, and this main limb is shared as a peripheral limb by two other Z-plasty designs. From the main limb, each central limb is designed along the margin of the scar in the opposite direction. The main and central limbs have 90° between them. Other peripheral limbs are then designed facing laterally to the intact skin to make 60° for the central limb. After skin incision, two triangular intact skin flaps could be inserted into the wide scar from both sides, making it possible to release contracture. We performed this technique on eight patients. All wounds healed well and scar contracture was satisfactorily released. This procedure is very useful for wide-scar contracture, compared to conventional Z-plasty.

Various techniques for correcting whistling deformities that occurred after primary surgery for cleft lip have been reported. These techniques are mainly intended to correct the lack of volume of the red lip. However, irregularity of the dry-wet lip junction (mucocutaneous junction) in the red lip has rarely been mentioned. If the wet lip is located in an exposed area, not only is the aesthetic appearance poor but also uncomfortable complications such as a crusted or bleeding lip repeatedly occur under a dry condition. A new technique for correcting the irregular line of the dry-wet lip junction is described in this report. The technique is simple. After removal of the exposed wet lip, flaps are designed on both dry lip sides of the defect as M-W-M plasty and are transposed toward the defect. The dog-ears are small; the scar is inconspicuous because it is incorporated with the wrinkle line, and scar contracture is prevented. In addition, more soft tissues may be included to correct a mild whistling deformity.

Summary Background Various procedures for correction of congenital syndactyly of hand or foot have been described. For incomplete syndactyly, some of the reported techniques use only local flaps from surrounding tissues. A novel technique for the correction of incomplete syndactyly, using a dorsal triangular flap and two palmar small flaps, is described in this article. Methods A triangular flap is first marked on the affected web space. The size of the flap should be the same as the unaffected side or other web space. Then a straight line is marked from the proximal apex of the triangle to the level of the metacarpophalangeal (MP) joint. After full skin incision, minimal peripheral undermining is done, and the triangular flap is transposed proximally, as in the Y–V advancement procedure, and sutured. Then two incisions are made from the distal part of the flap, transposing small flaps as in the five-flap method, and closed primarily. Results We treated ten cases of congenital syndactyly of the hand or foot. We were able to correct a good web space without skin grafting in all cases. Conclusion The design for our technique is simple, and the technique can be performed easily. The operation can be performed in a short time, the blood supply of the flap is preserved, the flap has a wide range of motion, and a deep and smooth dorsal slope is produced. This technique is an attractive alternative to previously reported methods for syndactyly correction.

Background It has been suggested that there is a close association of abnormality in auricular muscles with various congenital auricular deformities. However, there has been no investigation to determine what muscles are involved and how they affect the deformity. The authors examined abnormalities of auricular muscles for patients with various auricular deformities. Methods The authors examined 77 auricles of 62 patients with congenital auricular deformities, including cryptotia, Stahl's ear, prominent ear, lop ear, and others. The superior and posterior auricular muscles from the extrinsic auricular muscle group and the auricular oblique and transverse muscles from the auricular intrinsic muscle group were investigated. Results The authors found characteristic features of the abnormality of the muscle for each auricular deformity. In nearly all cases of cryptotia, abnormality was found in the superior auricular, auricular oblique, and auricular transverse muscles. Abnormal insertion was found mainly in the superior auricular muscle and was the main cause of cryptotia. In Stahl's ear, the major abnormality was abnormal insertion of the auricular transverse muscle, which creates an abnormal cartilaginous prominence in the scapha. The abnormality in cases of prominent ear was clearly limited mostly to the auricular transverse muscle and, in some cases, to the posterior auricular muscle. In lop ear, abnormality was mostly found in the auricular transverse muscle, with elongation, and in the superior auricular or auricular oblique muscle in some cases. Conclusions There is a tendency for a specific muscle abnormality to be found in each deformity. It is important to identify the abnormal muscle and correct the abnormality during the operation.