Adult genitourinary sarcoma: analysis using hospital-based cancer registry data in Japan.

BACKGROUND: Genitourinary sarcomas are rare in adults and few large-scale studies on adult genitourinary sarcoma are reported. We aimed to elucidate the clinical characteristics, survival outcomes, and prognostic factors for overall survival of adult genitourinary sarcoma in Japan. METHODS: A hospital-based cancer registry data in Japan was used to identify and enroll patients diagnosed with genitourinary sarcoma in 2013. The datasets were registered from 121 institutions. RESULTS: A total of 116 men and 39 women were included, with a median age of 66 years. The most common primary site was the kidney in 47 patients, followed by the paratestis in 36 patients. The most common histological type was liposarcoma in 54 patients, followed by leiomyosarcoma in 25 patients. The 5-year overall survival rates were 57.6%. On univariate analysis, male gender, paratestis as primary organ, and histological subtype of liposarcoma were predictive of favorable survival while primary kidney, bladder, or prostate gland location were predictive of unfavorable survival. On multivariate analysis, primary paratestis was an independent predictor of favorable survival while primary kidney, bladder, or prostate gland were independent predictors of unfavorable survival. CONCLUSIONS: This is the first report showing the clinical characteristics and survival outcomes of adult genitourinary sarcoma in Japan using a real-world large cohort database.

Retroperitoneal sarcoma: a 10-year follow-up analysis using hospital-based cancer registry data in Japan.

OBJECTIVES: We sought clinical characteristics, survival outcomes, and prognostic factors for overall survival of retroperitoneal sarcoma in Japan. METHODS: A Japanese hospital-based cancer registry database with a pivotal 10-year follow-up was used to identify and enroll patients, registered from 106 institutions, diagnosed with retroperitoneal sarcoma in 2008-2009. Treating hospitals were divided by hospital care volume; high-volume hospitals and low-volume hospitals were defined as ≥ 4 and < 4 cases/year, respectively. RESULTS: A total of 91 men and 97 women were included, with a median age of 64 years. The most common histological type was liposarcoma in 101 patients, followed by leiomyosarcoma in 38 patients. The 5-year and 10-year overall survival rates were 44.1 and 28.3%. The majority of patients (n = 152, 80.9%) were treated at low-volume hospitals. High-volume hospital patients had higher 10-year overall survival rates than low-volume hospital patients (51.2% vs 23.2%, P = 0.026). Multivariate analysis revealed age over 60 years, treatment in low-volume hospitals and chemotherapy were independent predictors of unfavorable survival while treatment with surgery was an independent predictor of favorable survival. CONCLUSIONS: The possibility of surgical removal was suggested to be the most important prognostic factor for retroperitoneal sarcoma. Better survival was shown in patients treated at high-volume hospitals in our series.

Maediastinal germ cell tumors: analysis using hospital-based cancer registry data in Japan.

OBJECTIVES: Mediastinal germ cell tumors are rare and few large-scale studies on mediastinal germ cell tumors are reported. We aimed to investigate the clinical characteristics and survival outcomes of patients with mediastinum germ cell tumors in Japan. METHODS: A hospital-based cancer registry data in Japan was used to identify and enroll patients diagnosed with mediastinal germ cell tumors in 2012-2013. The datasets were registered from 80 institutions. RESULTS: The selection criteria were met by 123 patients, the majority of whom were male. The median age at diagnosis was 39 years (range 25-89 years) and the most common age groups at diagnosis was 30-39 years, followed by 40-49 years and ≥ 50 years. The histology of non-seminoma (55.3%) was slightly more frequent than that of seminoma (44.7%). The most common histological subtype in non-seminoma was yolk sac tumor, followed by mixed germ cell tumor. The 5-year survival of seminoma and non-seminoma were 96.4% and 57.3%, respectively (p < 0.001). Non-seminomatous mediastinal germ cell tumors, malignant teratomas, mixed germ cell tumors, and yolk sac tumors had comparable survival rates, while those with choriocarcinoma showed the worst prognosis. CONCLUSIONS: This is the first report showing the clinical characteristics and survival outcomes of mediastinal germ cell tumors in Japan using a real-world large cohort database.

The prognostic impact of treatment centralization in patients with testicular germ cell tumors: analysis of hospital-based cancer registry data in Japan.

BACKGROUND: To identify the prognostic impact of treatment centralization in patients with testicular germ cell tumors (TGCT). METHODS: We used a hospital-based cancer registry data in Japan to extract seminoma and non-seminoma cases that were diagnosed in 2013, histologically confirmed, and received the first course of treatment. To compare the 5-years overall survival (OS) rates of patients stratified by institutional care volume, we performed a Cox proportional hazards regression analysis using inverse probability of treatment weighting (IPTW) method to adjust patient backgrounds. RESULTS: A total of 1767 TGCT patients were identified. The 5-years OS rates for stage II and III TGCT patients treated at low-volume institutions (< 7 cases) were significantly worse than high-volume institutions (≥ 7 cases) (91.2% vs. 83.4%, p = 0.012). Histological stratification revealed that 5-year OS rates for stage II and III seminoma patients in the low-volume group were significantly worse than the high-volume group (93.5% vs. 84.5%, p = 0.041). Multivariate OS analysis using an IPTW-matched cohort showed that institutional care volume was an independent prognostic factor (hazard ratio 2.13 [95% confidence interval: 1.23-3.71], p = 0.0072). CONCLUSION: Our results indicate that stage II and III TGCT patients experience lower survival rates at low-volume institutions and would benefit from treatment centralization.

CEP-1347 Boosts Chk2-Mediated p53 Activation by Ionizing Radiation to Inhibit the Growth of Malignant Brain Tumor Cells.

Radiation therapy continues to be the cornerstone treatment for malignant brain tumors, the majority of which express wild-type p53. Therefore, the identification of drugs that promote the ionizing radiation (IR)-induced activation of p53 is expected to increase the efficacy of radiation therapy for these tumors. The growth inhibitory effects of CEP-1347, a known inhibitor of MDM4 expression, on malignant brain tumor cell lines expressing wild-type p53 were examined, alone or in combination with IR, by dye exclusion and/or colony formation assays. The effects of CEP-1347 on the p53 pathway, alone or in combination with IR, were examined by RT-PCR and Western blot analyses. The combination of CEP-1347 and IR activated p53 in malignant brain tumor cells and inhibited their growth more effectively than either alone. Mechanistically, CEP-1347 and IR each reduced MDM4 expression, while their combination did not result in further decreases. CEP-1347 promoted IR-induced Chk2 phosphorylation and increased p53 expression in concert with IR in a Chk2-dependent manner. The present results show, for the first time, that CEP-1347 is capable of promoting Chk2-mediated p53 activation by IR in addition to inhibiting the expression of MDM4 and, thus, CEP-1347 has potential as a radiosensitizer for malignant brain tumors expressing wild-type p53.

The MDM2-p53 Axis Represents a Therapeutic Vulnerability Unique to Glioma Stem Cells.

The prevention of tumor recurrence by the successful targeting of glioma stem cells endowed with a tumor-initiating capacity is deemed the key to the long-term survival of glioblastoma patients. Glioma stem cells are characterized by their marked therapeutic resistance; however, recent evidence suggests that they have unique vulnerabilities that may be therapeutically targeted. We investigated MDM2 expression levels in glioma stem cells and their non-stem cell counterparts and the effects of the genetic and pharmacological inhibition of MDM2 on the viability of these cells as well as downstream molecular pathways. The results obtained showed that MDM2 expression was substantially higher in glioma stem cells than in their non-stem cell counterparts and also that the inhibition of MDM2, either genetically or pharmacologically, induced a more pronounced activation of the p53 pathway and apoptotic cell death in the former than in the latter. Specifically, the inhibition of MDM2 caused a p53-dependent increase in the expression of BAX and PUMA and a decrease in the expression of survivin, both of which significantly contributed to the apoptotic death of glioma stem cells. The present study identified the MDM2-p53 axis as a novel therapeutic vulnerability, or an Achilles' heel, which is unique to glioma stem cells. Our results, which suggest that non-stem, bulk tumor cells are less sensitive to MDM2 inhibitors, may help guide the selection of glioblastoma patients suitable for MDM2 inhibitor therapy.

[Minimally Invasive Aortic Valve Replacement for Aortic Valve Infective Endocarditis Complicated by Septic Arthritis of the Sternoclavicular Joint:Report of a Case].

A 54-year-old man with a history of atopic dermatitis was admitted to our hospital for persistent fever and multiple arthralgias unresponsive to antibiotics. On the second day of hospitalization, Staphylococcus aureus was detected in the blood culture, and debridement for presumed pyogenic arthritis was performed on the patient's bilateral wrists and right ankle joints. Echocardiography showed evidence of infective endocarditis of the aortic valve. The patient's fever persisted after drainage of multiple joint abscesses, and blood cultures remained positive. A right sternoclavicular joint abscess that had been noted on computed tomography (CT) at the time of admission had not decreased in size on repeat CT performed 10 days post-admission. After additional drainage of the sternoclavicular joint abscess on the 15th day, the patient's fever subsided, and blood culture was negative. On the 29th day, an aortic valve replacement was performed via a right anterior thoracotomy to prevent sternal osteomyelitis. The postoperative course was uneventful, and the patient was discharged on the 35th day after valve surgery. One year after the surgery, he continues to take antibiotics, and recurrence of infection has not been observed.

Domatinostat Targets the FOXM1-Survivin Axis to Reduce the Viability of Ovarian Cancer Cells Alone and in Combination with Chemotherapeutic Agents.

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.

[Recurrent Breast Cancer with Bone Metastasis Effectively Treated with Abemaciclib plus Endocrine Therapy-A Case Report].

We report a case of recurrent breast cancer with bone metastasis in a premenopausal woman. A 46-year-old woman underwent mastectomy for right breast cancer 6 years ago. Histopathological diagnosis was invasive ductal carcinoma, T2N3aM0, stage ⅢC. She received adjuvant chemotherapy and irradiation followed by tamoxifen. Four and a half years after surgery, serum tumor marker levels elevated, and bone metastasis in the sacral region was revealed by PET-CT scan. After suppressing ovarian function with LH-RH agonist, we switched the endocrine therapy from tamoxifen to letrozole with a CDK4/6 inhibitor. Five months after starting administration of abemaciclib, the bone metastasis disappeared on PET-CT. The elevated tumor markers normalized and have continued to decrease. Abemaciclib combined with endocrine therapy was significantly effective as first-line treatment for premenopausal women with metastatic breast cancer.

[Elderly Advanced Breast Cancer Effectively Treated with Locoregional Therapy-A Case Report].

We report a case of advanced breast cancer in an elderly patient effectively treated with locoregional therapy. The patient was an 81-year-old woman who presented with an increasing right breast lump. The tumor was 55 mm in diameter, accompanied by fixation to pectoral muscle. A core needle biopsy for right breast tumor led to a diagnosis of mucinous carcinoma, positive for estrogen receptor(ER)and progesterone receptor(PgR), negative for HER2/neu. The Ki-67 positive cell index was 10%. A bone scintigraphy revealed multiple bone metastases, so, we confirmed the diagnosis as T4cN2aM1, Stage Ⅳ. She initiated endocrine therapy by letrozole. By changing the endocrine therapy to toremifene followed by fulvestrant, the therapy achieved a partial response. However, the size of the primary tumor increased accompanied by bleeding, and surgical resection of the right breast was performed for local control. The locoregional surgery was effective, improving the patient's quality of life. She was administered lapatinib as anti-HER2 therapy in addition to the endocrine therapy. Two years and 6 months after surgery, there has been no worsening of bone metastasis or appearance of visceral metastasis.

Inhibition of the Phospholipase Cε-c-Jun N-Terminal Kinase Axis Suppresses Glioma Stem Cell Properties.

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.

HDAC Class I Inhibitor Domatinostat Preferentially Targets Glioma Stem Cells over Their Differentiated Progeny.

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.

[Adrenocortical Oncocytic Tumor : A Report of Two Cases].

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.

[Comparison of Three Methods of Sternal Closure after Open Heart Surgery:Analysis of 722 Cases for 11 Years].

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).

Therapeutic targeting of pancreatic cancer stem cells by dexamethasone modulation of the MKP-1-JNK axis.

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.

Chemical Reactions at the Interface Periphery of Colliding Droplets Studied by Raman Image Analysis.

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.

Targeting Folate Metabolism Is Selectively Cytotoxic to Glioma Stem Cells and Effectively Cooperates with Differentiation Therapy to Eliminate Tumor-Initiating Cells in Glioma Xenografts.

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 Case of Perfusion Failure of Peritoneal Dialysis Catheter Treated by Reduced Port Surgery].

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.

[Prediction of Prognosis in Breast Carcinoma Using Klotho Immunohistochemistry].

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.

[Hereditary Breast and Ovarian Cancer(HBOC)in a Young Adult-A Case Report].

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.