Metabolome analysis is an approach to investigate cell characteristics from the metabolites that are constantly produced and changed by those cells. We conducted a metabolome analysis of the response of 786-O renal cell carcinoma (RCC) cells to histone deacetylase (HDAC) inhibitors, which are expected to increase anticancer drug sensitivity, and compared the response with that of drug-resistant cells. Trichostatin A (TSA), an HDAC inhibitor, increased the sensitivity of 786-O cells to sunitinib. Moreover, TCA cycle and nucleotide metabolism of the cells were promoted. The findings that acetylated p53 (active form) and early apoptotic cells were increased suggests that the mechanism involved enhancement of mitochondrial metabolism and function. In addition, established sunitinib-resistant RCC cells were exposed to a combination of sunitinib and TSA, resulting in significant growth inhibition. Principal component analysis revealed that the parent and resistant cells were obviously different, but approximately half their fluctuations were illustrated by the same pathways. In summary, it was suggested that TSA reduced sunitinib resistance by triggering intracellular metabolome shifts in energy metabolism. This was the first recognized mechanism of action of TSA as an HDAC inhibitor.

Cancer patients often suffer from severe pain related to bone metastasis. We encountered a patient in whom the addition of topical non-steroidal anti-inflammatory drugs (NSAIDs) for persistent pain related to bone metastasis during therapy with opioids and oral NSAIDs reduced pain, improving activities of daily living (ADL). Fentanyl patches, celecoxib, denosumab, and topical NSAIDs (loxoprofen tape, felbinac) were administered to a 72-year-old patient with gastric cancer and pain related to bone metastasis. Pain control was favorable, with a numerical rating scale (NRS) score of 2 and Japanese version Support Team Assessment Schedule (STAS-J) score of 1. Intervention by pharmacists for the use of topical NSAIDs decreased both the NRS and STAS-J scores to zero, improving ADL. The results suggest that topical NSAIDs relieve bone-metastasis-related pain, improving ADL. When bone-metastasis-related pain is localized, the prescription of topical NSAIDs should be considered, and positive intervention by pharmacists regarding their usage should be promoted.

A 67-year-old woman who had undergone laparoscopic proximal gastrectomy for early gastric cancer 10 months previously was admitted to our hospital due to dysarthria. Brain MRI demonstrated acute multiple small infarcts in the right middle cerebral artery (MCA) and the right posterior inferior cerebellar artery (PICA) territory, and she was diagnosed as embolic stroke. Anticoagulant therapy did not prevent further ischemic stroke. No embolic sources were detected by MR angiography, carotid duplex sonography, transthoracic and transesophageal echocardiography, and Holter electrocardiography. We also performed upper gastrointestinal endoscopy and contrast-enhanced CT of the thoracoabdominal area, but there was no evidence of local recurrence or lymph node metastases of gastric cancer. As the ALP and D-dimer levels were gradually increasing, we performed PET/CT, which revealed fluorodeoxyglucose (FDG) uptake in the vertebra bone, and disseminated carcinomatosis of bone marrow with early gastric cancer was diagnosed after bone marrow biopsy on Day 41. After undergoing chemotherapy, she had no further stroke and died on Day 207.

A 68-year-old male with abdominal pain and vomiting was brought to our hospital by ambulance. Computed tomography showed multiple intussusceptions with pseudokidney signs in the jejunum and ileocecum, and a tumor of 5 cm in diameter in the left lower lobe of the lung. We performed an emergent operation, as a release of multiple intussusceptions was difficult by conservative treatment. There were two intussusceptions, in the jejunum and the ileocecum. We performed a partial resection of the jejunum and a resection of the ileocecum. Histopathological examination of the resected specimens and a biopsy specimen collected by bronchoscopy allowed us to diagnose multiple intussusceptions due to small intestine metastases from a pleomorphic carcinoma of the lung. This case is presented here, with a review of the literature.

The patient was a 63-year-old man with a chief complaint. Upper endoscopic examination revealed a semicircular type 2 lesion, sized 24-28 cm, on the incisor teeth and a 3 cm sized elevated lesion directly above the EGJ. When biopsy was performed, squamous cell carcinoma(SCC)was detected. In this case, lymph node metastasis and multiple liver metastases were observed, and diagnosis at the first examination was cT3N2M1(HEP), Stage Ⅳ. After 7 months of chemotherapy, he underwent right thoracic esophageal subtotal resection, 3-field lymph node dissection, posterior mediastinal gastric tube reconstruction, and partial hepatectomy. Despite receiving postoperative chemotherapy, he showed recurrence in the liver(S8). Four additional courses of chemotherapy were administered and partial hepatectomy(S8)was performed, without the appearance of new lesions. He was considered to be cured 1 year and 6months after starting the treatment and was followed- up without chemotherapy. However, 4 months later, chemotherapy was resumed when right adrenal and abdominal wall metastases and liver recurrence(S3)were found. After that, the regimen was modified, and he continued treatment. More than 4 years have passed since the start of treatment, but the treatment has been continued without a decline in ADL.

A 77-year-old woman presented with peritoneal metastases from a pancreatic neuroendocrine tumor(p-NET). At the age of 56 years, she underwent distal pancreatectomy for p-NET, which was pathologically diagnosed as G2. She underwent right hemihepatectomy for liver metastasis(S6)from the p-NET 10 years post-pancreatectomy. Eight years post-hepatectomy, radiofrequency ablation(RFA)was attempted for liver metastasis(S4)from the p-NET. However, RFA was not completed because of hematoma development along the needle tract of RFA. She underwent partial hepatectomy for this lesion 6 months post-RFA. Two years post-RFA, localized peritoneal metastases on the right diaphragm were detected. She underwent en bloc tumor resection with partial resection of the diaphragm. She remains alive and well with no evidence of disease 2 years post-resection of the peritoneal metastases from the p-NET.

A 74-year-old man with anemia visited our department. Esophagogastroduodenoscopy showed a type 2 lesion from the angulus to the antrum. Histopathological findings indicated gastric neuroendocrine carcinoma. Colonoscopy showed a type 1 lesion at the cecum. Distal gastrectomy was performed with D1+lymph node dissection, Roux-en-Y reconstruction, and ileocecal resection with D3 lymph node dissection. The patient was pathologically diagnosed with large-cell neuroendocrine carcinoma in the stomach, pT4a(SE), med, INF a>>b-c, ly1-2, v1(SM, EVG), pN0, pM0, pStageⅡB, and adenocarcinoma (tub1>tub2)of the cecum, pT2(MP), ly1(HE), v1(EVG, SM), pN0, pM0, pStageⅠ. Postoperatively, he received oral S-1 as an adjuvant chemotherapy. His postoperative course was uneventful without any recurrence over 18 months.

A 73-year-old man underwent a subtotal stomach preserving pancreaticoduodenectomy(SSPPD)for biliary carcinoma without regional lymph node metastasis. Although S-1 was administrated as adjuvant chemotherapy after the operation, the serum CA19-9 level was gradually elevated, and a liver metastasis of 27mm in diameter was detected in Couinaud's segment 8 during chemotherapy. We administrated gemcitabine(GEM)and cisplatin(CDDP)combination therapy(GC therapy). The liver tumor was immediately shrunk to 6mm and kept up the PR state after 15 courses of GC therapy. A stereotactic body radiation therapy(SBRT)was performed 1 year 8 months after the operation. The patient has been alive without recurrence for 4 years since the SBRT. Although systemic chemotherapy is the standard treatment for the recurrence of biliary carcinoma, a loco-regional therapy such as SBRT may be an effective alternative when a patient has a solitary metastasis to the liver with no other evidence of recurrence.

An 84-year-old woman presented with a 9mm sized solitary liver metastasis in liver S8 18 months after the surgery for sigmoid colon cancer. The patient was treated with stereotactic body radiation therapy(SBRT)for local control, because the patient chose not to undergo surgery or chemotherapeutic treatment for metastatic liver cancer. SBRT is a minimally invasive treatment with a very short treatment period. Therefore, it may be considered as an alternative treatment for patients who are not suitable for surgery.

A-67-year old man was diagnosed with gastric cancer and a liver tumor. Extended left hemihepatectomy combined with caudate lobectomy and distal gastrectomy with lymph node dissection were performed. Histological examination revealed synaptophysin and CD56positive tumor cells with a solid and rosette structure, which was diagnosed as endocrine carcinoma (EC). Additionally, a tubular adenocarcinoma was present in the stomach. The liver tumor presented as EC with tumor thrombus in the left portal vein. Finally, the patient was diagnosed with gastric EC(pT3[SS], pN0, P0, CY0, M1[HEP], Stage Ⅳ, R0). He received 6courses of the adjuvant chemotherapy with cisplatin(CDDP)plus irinotecan(CPT-11), and has been alive without recurrence for 21 months post-operation. Gastric EC is a rare subtype of gastric cancer. The resection of liver metastasis of gastric EC may improve patients' prognosis and QOL. CDDP-based chemotherapy is recommended, due to the regimen for small cell lung cancer.

A 66-year-old man had an elevated CEA level. Further examinations showed a pancreatic head tumor. A pancreaticoduodenectomy was then performed. The histopathological examination showed a mixed tumor of papillary adenocarcinoma and neuroendocrine cancer. In addition, a tumor in the upper lobe of the right lung was found 18 months after the initial pancreatic resection, and the bronchoscope indicated lung metastasis. The patient underwent partial pneumonectomy. After the pneumonectomy, he received S-1 chemotherapy. Thirty -nine months after the pneumonectomy, CEA was slightly elevated. We changed the chemotherapy to gemcitabine and nab-paclitaxel without further examinations to confirm the recurrence. The patient discontinued chemotherapy after CEA fell within the normal range. He has been alive without tumor relapse for 64 months since the second operation for the lung metastasis. We report a successful case of lung resection for lung metasta- sis from pancreatic cancer.

An 81-year-old man was referred to our hospital. Upper gastrointestinal endoscopy revealed a type 2 tumor in the antrum of the stomach. The histopathological findings showed a moderately differentiated HER2-negative adenocarcinoma. Two low-density areas of 17mm and 26mm in diameter were observed in the liver S6 and S8respectively at the CT scan. Nine courses of S-1 plus oxaliplatin(SOX)therapy were administered to this patient with gastric cancer and liver metastases. Since both the primary tumor and the liver metastases were significantly reduced by the chemotherapy, distal gastrectomy(D2 dissection)and partial liver resection(liver S6, S8)were performed. The histopathological findings revealed no tumor cells in the primary tumor, lymph nodes, and liver metastases, with a histologic effect of Grade 3. The patient underwent adjuvant therapy with S-1. He has been alive without recurrence for 11 months post-surgery.

Central nervous system intravascular lymphoma sometimes includes multiple lesions mimicking cerebral infarction. Herein, we report our experience with a case of intravascular large B-cell lymphoma (IVLBCL) with multiple hemorrhages. A 53-year-old woman was admitted to our hospital with clonic convulsions of the left upper limb. Brain MRI revealed a large number of high-intensity areas on FLAIR and low-intensity areas on susceptibility-weighted imaging (SWI). Chest CT showed bilateral multiple high-density lesions in the lungs. Biopsy of pulmonary lesions revealed no abnormal cells. Levetiracetam was administered to prevent the seizures that were assumed to occur due to the cerebral cortex lesions; however, convulsive seizure recurred with a depressed level of consciousness. On a repeat brain MRI examination, severe, multiple new lesions were shown to have developed bilaterally in the cerebral cortex and white matter, exhibiting spotty low intensities on SWI. Biopsy of a new cerebral lesion was carried out and the lesion was pathologically diagnosed as IVLBCL with hemorrhages. IVLBCL should be noted as one of the differential diagnoses not only in case with multiple infarct lesions, but also in case with multiple hemorrhages.

Outcomes of treatment for malignant pediatric tumors including leukemia are improving by conventional multimodal treatment with strong chemotherapy, surgical resection, radiotherapy, and bone marrow transplantation. However, patients with advanced neuroblastoma, metastatic Ewing's sarcoma family of tumor (ESFT), and metastatic osteosarcoma continue to have an extremely poor prognosis. Therefore novel therapeutic strategies are urgently needed to improve their survival. Apoptotic cell death is a key mechanism for normal cellular homeostasis. Intact apoptotic mechanisms are pivotal for embryonic development, tissue remodeling, immune regulation, and tumor regression. Genetic aberrations disrupting programmed cell death often underpin tumorigenesis and drug resistance. Moreover, it has been suggested that apoptosis or cell differentiation proceeds to spontaneous regression in early stage neuroblastoma. Therefore apoptosis or cell differentiation is a critical event in this cancer. We extracted many compounds from natural plants (Angelica keiskei, Alpinia officiarum, Lycaria puchury-major, Brassica rapa) or synthesized cyclophane pyridine, indirubin derivatives, vitamin K3 derivatives, burchellin derivatives, and GANT61, and examined their effects on apoptosis, cell differentiation, and cell cycle in neuroblastoma and ESFT cell lines compared with normal cells. Some compounds were very effective against these tumor cells. These results suggest that they may be applicable as an efficacious and safe drug for the treatment of malignant pediatric tumors.

Metastatic meningiomas are extremely rare, and generally have poor prognosis. We report a case of atypical meningioma with good clinical course despite metastasis 9 years after the initial surgery. CASE:A 58-year-old woman visited a nearby hospital with complaints of hemiplegia and aphasia. MRI showed a large left frontal meningioma;she was referred to our department where she underwent a tumor resection(Simpson Grade I). Histopathological finding revealed fibrous meningioma in the prominent part of the tumor. Additionally, a small lesion with high Ki-67 labeling index was identified;therefore, the final diagnosis was atypical meningioma. Nine years postoperatively, a hepatic mass found incidentally and was resected by digestive surgery;a histological diagnosis of metastatic atypical meningioma was established. Thirteen years after the first operation, routine MRI showed enlargement of the local recurrent lesions in the tumor resection cavity. She underwent a reoperation(Simpson Grade I)at our department, and subsequently, discharged without any neurological deficits. Findings were not suggestive of atypical meningioma. Studies report three good prognostic factors in patients with metastatic meningioma-histologically benign primary tumor, long interval between initial diagnosis and metastasis, and asymptomatic metastatic lesion.

A 65-year-old man was admitted to our institution with vomiting and right flank pain. Computed tomography (CT) imaging showed a 21-cm retroperitoneal multilocular cystic tumor which had been identified four years previously. It had increased from 17 to 21 cm. The initial diagnosis was cystic lymphangioma because it was a clear cystic tumor without a boundary or a solid component in the first CT, but later CT revealed an unclear boundary with surrounding organs suggesting malignancy. We decided to resect the tumor because it was symptomatic and might be malignant. The tumor was then resected along with surrounding organs because invasion was suspected. Pathological findings indicated a diagnosis of cystic lymphangioma with chronic inflammation and confirmed complete resection of the tumor. The patient has remained free of recurrence at one year after surgery. This experience indicates that cystic lymphangioma should be completely resected to prevent recurrence.

A 70-year-old woman, with an 8 cm tumor in the left kidney and multiple lung tumor and was diagnosed with Renal Cell Carcinoma (cT3aN0M1). The kidney tumor were unresectable and we started treatment with Tyrosine Kinase Inhibitors (sunitinib, pazopanib, axitinib, temsirolimus), but they failed because of disease progression or adverse events. We used nivolumab for 5th line treatment; then, interstitial pneumonia was observed. The renal tumor shrunk and pulmonary metastatic foci revealed prominent disappearance. The renal tumor became resectable and we tried nephrectomy. Pathological findings were clear cell carcinoma with marked necrosis, hyperplasia and internal bleeding.

(Case) A 56-year-old woman who complained of urinary frequency and macrohematuria. Abdominal US, enhanced CT and MRI revealed a left renal tumor. A left radical nephrectomy was performed in May 1997, and the pathological diagnosis was renal fibrosarcoma. Follow-up computed CT was performed routinely. A metastatic lesion in the right lung revealed 19 months after the nephrectomy.She underwent partial pneumonectomy in January 1999, and the pathological diagnosis was also fibrosarcoma. She was followed up until 2009 without recurrence.In 2015, she was admitted in the Department of Orthopedics due to femoral neck fracture in 2015, thus we could find out she was alive, tumor-free 18 years after the nephrectomy. We added the immunohistochemistical study to her specimen of kidney and lung, and the diagnosis was changed to undifferentiated/unclassified sarcoma. (Conclusion) Metastatic renal sarcoma has a poor prognosis in general. We experienced a long-term survival case of undifferentiated/unclassified renal sarcoma with lung metastasis, and report it with some literature review.

(Objective) The aim of this study is to investigate the treatment outcome of laparoscopic radical prostatectomy (LRP). (Patients and methods) The study cohort consisted of 926 hormone-naïve patients with localized prostate cancer who underwent LRP at the Hiroshima Endourological Association from January 2007 to December 2016. (Results) The mean age was 69.4 years, the mean initial PSA was 9.1 ng/ml, and the mean follow-up period was 40.3 months. The D'Amico Risk Classification was Low: 232 cases, Intermediate: 344 cases, and High: 350 cases. Nerve preservation was performed bilaterally for 138 patients and unilaterally for 181 patients. The mean operative time was 181.0 minutes and the mean estimated blood loss was 360.7 ml. As the number of experienced cases increased, the operative time was significantly shorter and the estimated blood loss was significantly decreased. According to Clavien-Dindo classification, the ratio of perioperative complication degree IIIa or above was 4.0% (37 cases). The pathological results were Gleason score (GS) ≤6: 174 cases, GS7: 514 cases, GS ≥8: 232 cases, pT2≥: 704 cases, pT3a: 172 cases, pT3b: 47 cases, pT4: 3 cases, pN0: 917 cases, and pN1: 9 cases. Positive surgical margins were found in 278 cases (30.0%). The biochemical recurrence-free survival rate at 5 years was 78.1%. In multivariate analysis, age (≥70 yrs), initial PSA (≥10 ng/ml), biopsy GS (GS ≥8), cancer positive core ratio at biopsy (≥30%), pT (pT≥3), pathological GS (GS≥8), positive surgical margin and total number of patients in the facility were predictive factors of postoperative biochemical PSA recurrence. Younger age and nerve preservation were found to be predictive factors for the early recovery of urinary continence after surgery, with 88% regaining urinary continence at 12 months after surgery. (Conclusion) This study revealed the clinical outcome and appropriate candidates for LRP in Japanese patients.

Renal cell carcinoma (RCC) metastasis to the bladder is rare. We report two cases that occurred metachronously during pazopanib treatment for other metastases. To our knowledge, this is the first report to demonstrate bladder metastasis from RCC during molecular targeted therapy with pazopanib. (Case 1) A woman in her 60s was referred to our department for evaluation of an incidental right renal tumor. Dynamic CT showed a 6 cm renal cell carcinoma. In February 201X she underwent laparoscopic right radical nephrectomy, revealing clear cell carcinoma (grade 1>2), stage pT3aN0M0. In February 201X+1 she complained of left pelvic pain. She was found to have metastasis to two iliac bones and an occipital bone. She received pazopanib, in addition to a bone modifying agent and radiotherapy for the iliac bones. After 8 months, she complained of asymptomatic gross hematuria in spite of having stable disease for bone metastasis. Cystoscopy showed a 1 cm solitary sessile nonpapillary tumor on the posterior wall. She underwent transurethral resection of bladder tumor (TUR-BT). Histological examination showed metastatic RCC. Thereafter she received sequential therapies (axitinib, sunitinib, nivolumab). She remains alive without recurrence in the bladder 51 months after TUR-BT. (Case 2) A woman in her 60s presented to our department with a complaint of painless gross hematuria. A dynamic CT showed an 8.5 cm renal cell carcinoma and multiple lung metastases. In March 201Y she underwent right radical nephrectomy, revealing clear cell carcinoma (grade 2>3), stage pT2aN0M1. In June 201Y she started pazopanib. After 9 months CT showed a bladder tumor in addition to progression of lung metastases. Cystoscopy showed a 1 cm solitary sessile nonpapillary tumor at dome. She underwent TUR-BT. Histological examination showed metastatic RCC. She had no recurrence in the bladder during follow-up although she died of RCC.