Plasma Sphingosine-1-Phosphate Levels Are Associated with Progression of Estrogen Receptor-Positive Breast Cancer.

Although numerous experiments revealed an essential role of a lipid mediator, sphingosine-1-phosphate (S1P), in breast cancer (BC) progression, the clinical significance of S1P remains unclear due to the difficulty of measuring lipids in patients. The aim of this study was to determine the plasma concentration of S1P in estrogen receptor (ER)-positive BC patients, as well as to investigate its clinical significance. We further explored the possibility of a treatment strategy targeting S1P in ER-positive BC patients by examining the effect of FTY720, a functional antagonist of S1P receptors, on hormone therapy-resistant cells. Plasma S1P levels were significantly higher in patients negative for progesterone receptor (PgR) expression than in those positive for expression (p = 0.003). Plasma S1P levels were also significantly higher in patients with larger tumor size (p = 0.012), lymph node metastasis (p = 0.014), and advanced cancer stage (p = 0.003), suggesting that higher levels of plasma S1P are associated with cancer progression. FTY720 suppressed the viability of not only wildtype MCF-7 cells, but also hormone therapy-resistant MCF-7 cells. Targeting S1P signaling in ER-positive BC appears to be a possible new treatment strategy, even for hormone therapy-resistant patients.

Beneficial Effects of Epigallocatechin-3-O-Gallate, Chlorogenic Acid, Resveratrol, and Curcumin on Neurodegenerative Diseases.

Many observational and clinical studies have shown that consumption of diets rich in plant polyphenols have beneficial effects on various diseases such as cancer, obesity, diabetes, cardiovascular diseases, and neurodegenerative diseases (NDDs). Animal and cellular studies have indicated that these polyphenolic compounds contribute to such effects. The representative polyphenols are epigallocatechin-3-O-gallate in tea, chlorogenic acids in coffee, resveratrol in wine, and curcumin in curry. The results of human studies have suggested the beneficial effects of consumption of these foods on NDDs including Alzheimer's and Parkinson's diseases, and cellular animal experiments have provided molecular basis to indicate contribution of these representative polyphenols to these effects. This article provides updated information on the effects of these foods and their polyphenols on NDDs with discussions on mechanistic aspects of their actions mainly based on the findings derived from basic experiments.

Clinical Sign-Based Rapid Response Team Call Criteria for Identifying Patients Requiring Intensive Care Management in Japan.

Background and Objectives: For effective function of the rapid response system (RRS), prompt identification of patients at a high risk of cardiac arrest and RRS activation without hesitation are important. This study aimed to identify clinical factors that increase the risk of intensive care unit (ICU) transfer and cardiac arrest to identify patients who are likely to develop serious conditions requiring ICU management and appropriate RRS activation in Japan. Materials and Methods: We performed a single-center, case control study among patients requiring a rapid response team (RRT) call from 2017 to 2020. We extracted the demographic data, vital parameters, blood oxygen saturation (SpO2) and the fraction of inspired oxygen (FiO2) from the medical records at the time of RRT call. The patients were divided into two groups to identify clinical signs that correlated with the progression of clinical deterioration. Patient characteristics in the two groups were compared using statistical tests based on the distribution. Receiver operating characteristic (ROC) curve analysis was used to identify the appropriate cut-off values of vital parameters or FiO2 that showed a significant difference between-group. Multivariate logistic regression analysis was used to identify patient factors that were predictive of RRS necessity. Results: We analyzed the data of 65 patients who met our hospital's RRT call criteria. Among the clinical signs in RRT call criteria, respiratory rate (RR) (p < 0.01) and the needed FiO2 were significantly increased (p < 0.01) in patients with severe disease course. ROC curve analysis revealed RR and needed FiO2 cut-off values of 25.5 breaths/min and 30%. The odds ratio for the progression of clinical deterioration was 40.5 times higher with the combination of RR ≥ 26 breaths/min and needed FiO2 ≥ 30%. Conclusions: The combined use of RR ≥ 26 breaths/min and needed FiO2 ≥ 30% might be valid for identifying patients requiring intensive care management.

[A Case of HER2-Positive Recurrent Breast Cancer and Liver Metastases of GIST Treated with Combined Anti-HER2 Therapy and Imatinib].

A 70-year-old female with liver metastases from gastrointestinal stromal tumor(GIST)that were found 3 months after partial gastrectomy for the primary GIST underwent Auchincloss operation for left breast cancer with ipsilateral axillary lymph node metastases. The diagnosis was microinvasive ductal cancer that was pT1miN1M0, pStage ⅡA, hormone receptor negative, and HER2 positive. Given the impact of this cancer on the prognosis of liver metastases of GIST, imatinib therapy, but not adjuvant chemotherapy, was started promptly for breast cancer after surgery. Four months after the surgery, left subclavian lymph node recurrence of breast cancer was found. Since the liver metastases of GIST had been stable, imatinib was discontinued, and paclitaxel and anti-HER2 therapy were administered. After confirming tolerability, imatinib was carefully added in combination. Because the lymph nodes shrank and liver metastases of GIST were stable, both anti-HER2 therapy and imatinib were continued. There are few reports of combined chemotherapy for synchronous double cancer, and we report our experience in which careful treatment was required.

Metastatic seeding of human colon cancer cell clusters expressing the hybrid epithelial/mesenchymal state.

Emerging evidence supports the theory that tumor cell clusters efficiently metastasize to distant organs. However, the roles of epithelial-to-mesenchymal transition (EMT) in metastasizing tumor cell clusters have not yet been fully elucidated. To investigate this issue, tumor fragments were dissected from 40 colorectal cancer (CRC) patients and implanted subcutaneously into immunodeficient mice. We observed that tumors developed from the tumor fragments obtained from 28 of the 40 CRC patients. The tumors were then dissociated into cell suspensions to be orthotopically injected into secondary mice. The tumors from 13 of the 28 patients progressed. Furthermore, metastases formed spontaneously in the liver and lungs from the tumor fragments obtained from 8 of these 13 patients. Moreover, employing a mathematical analysis, we showed that tumor cell clusters seeded these metastases significantly more often than did single tumor cells. Membrane E-cadherin- and nuclear ZEB1-positive tumor cells indicating the hybrid epithelial/mesenchymal state were also detected in primary tumors of various CRC patients, and in the corresponding patient-derived xenografts (PDXs) and circulating tumor cell clusters in the bloodstreams of mice. In contrast, ZEB1 staining was barely detectable in the patient-matched liver metastases presumably developing through mesenchymal-to-epithelial transition. Inhibition of E-cadherin or ZEB1 expression by shRNA notably prevented the PDX-derived tumor organoids from colonizing the liver, when injected intrasplenically into mice, indicating E-cadherin and ZEB1 expressions to be required for their metastatic colonization. Taken together, these findings suggest that the epithelial/mesenchymal state mediates metastatic seeding of human CRC cell clusters into distant organs.

Impact of pectoral nerve block on postoperative pain and quality of recovery in patients undergoing breast cancer surgery: A randomised controlled trial.

BACKGROUND: In recent years, thoracic wall nerve blocks, such as the pectoral nerve (PECS) block and the serratus plane block have become popular for peri-operative pain control in patients undergoing breast cancer surgery. The effect of PECS block on quality of recovery (QoR) after breast cancer surgery has not been evaluated. OBJECTIVES: To evaluate the ability of PECS block to decrease postoperative pain and anaesthesia and analgesia requirements and to improve postoperative QoR in patients undergoing breast cancer surgery. DESIGN: Randomised controlled study. SETTING: A tertiary hospital. PATIENTS: Sixty women undergoing breast cancer surgery between April 2014 and February 2015. INTERVENTIONS: The patients were randomised to receive a PECS block consisting of 30 ml of levobupivacaine 0.25% after induction of anaesthesia (PECS group) or a saline mock block (control group). The patients answered a 40-item QoR questionnaire (QoR-40) before and 1 day after breast cancer surgery. MAIN OUTCOME MEASURES: Numeric Rating Scale score for postoperative pain, requirement for intra-operative propofol and remifentanil, and QoR-40 score on postoperative day 1. RESULTS: PECS block combined with propofol-remifentanil anaesthesia significantly improved the median [interquartile range] pain score at 6 h postoperatively (PECS group 1 [0 to 2] vs. Control group 1 [0.25 to 2.75]; P = 0.018]. PECS block also reduced propofol mean (± SD) estimated target blood concentration to maintain bispectral index (BIS) between 40 and 50 (PECS group 2.65 (± 0.52) vs. Control group 3.08 (± 0.41) µg ml; P < 0.001) but not remifentanil consumption (PECS group 10.5 (± 4.28) vs. Control group 10.4 (± 4.68) µg kg h; P = 0.95). PECS block did not improve the QoR-40 score on postoperative day 1 (PECS group 182 [176 to 189] vs. Control group 174.5 [157.75 to 175]). CONCLUSION: In patients undergoing breast cancer surgery, PECS block combined with general anaesthesia reduced the requirement for propofol but not that for remifentanil, due to the inability of the PECS block to reach the internal mammary area. Further, PECS block improved postoperative pain but not the postoperative QoR-40 score due to the factors that cannot be measured by analgesia immediately after surgery, such as rebound pain. TRIAL REGISTRATION: This trial is registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN000013435).

[A Case of Metachronal Phyllodes Tumors That Presented Bilaterally in the Breast].

A 33-year-old woman underwent resection of a right breast mass, which was diagnosed as a fibroadenoma 15 years ago. Ten years later, a right breast mass appeared again, and it was diagnosed as a fibroadenoma based on core needle biopsy. After observation for a while, the mass increased in size, and she underwent resection of the tumor, which was diagnosed as a borderline-malignant phyllodes tumor. A mass appeared again in the right breast and rapidly expanded. A malignant phyllodes tumor was suspected, and right mastectomy was performed. The pathological diagnosis revealed a benign phyllodes tumor. Four years ago, a left breast mass was also detected. Because the mass was suspected to be a fibroadenoma, it has been observed for a few years. The mass has increased in size since 1 year ago, and another mass emerged 2 months ago. Core needle biopsy of the 2 masses revealed that both were phyllodes tumors. She underwent left mastectomy, and the pathological examination revealed that both masses were benign phyllodes tumors. We report this rare case of metachronal phyllodes tumors that presented bilaterally.

[A Case of Breast Cancer with Metastatic Nodules in Additionally Resected Specimens].

A 68-year-old woman who had leftbreastcancer (cT2N0M0, cStage ⅡA)underwentbreast -conserving therapy and sentinel lymph node biopsy. Pathological diagnosis of the resected specimen revealed a 60mm cancer lesion including a 50 mm invasive ductal carcinoma with surrounding ductal carcinoma in situ, although the pre-operative MRI suggested a 30mm invasive cancer. The surgical margin was positive with the exposure of ductal carcinoma in situ. Additional resection was performed with a resection margin of 20mm from the head-side stump of the previous surgery. Pathological diagnosis of the additionally resected specimen revealed a 6mm invasive carcinoma with its exposure on the surface of the specimen around the new surgical stump distant from the initial surgical margin, where no remnant cancer was noted. She underwent left mastectomy. Pathological diagnosis further revealed 7mm and 2mm invasive carcinomas in the remnant breast. The preoperative imaging was reviewed retrospectively, and it was found that identifying the nodules in the remnant breast was quite difficult based on the images, including MRI. We report a case of breast cancer with metastatic nodules in additionally resected specimens.

Decasilahexahydrotriquinacene and Decasilaisotwistane: σ Conjugation on a Bowl Surface.

The first bowl-shaped oligosilane, hexadecamethyldecasilahexahydrotriquinacene (1), and a related oligosilane, hexadecamethyldecasilaisotwistane (2), were synthesized, and their structures and properties were studied. The results revealed importance of σ conjugation on a bowl surface: the HOMOs of 1 are σ orbitals delocalized on the bowl surface, whereas the LUMO is a pseudo π* orbital on the convex and concave sides of the bowl surface.

Comparison of Number Versus Ratio of Positive Lymph Nodes in the Assessment of Lymph Node Status in Extrahepatic Cholangiocarcinoma.

BACKGROUND: This study aimed to compare the utility of the number of positive lymph nodes with the lymph node ratio (LNR) in predicting survival after resection of extrahepatic cholangiocarcinoma. METHODS: A retrospective analysis of 142 consecutive patients who underwent radical resection of extrahepatic cholangiocarcinoma was performed. A total of 3066 regional lymph nodes were resected. The median number of nodes per patient was 21. The optimal cutoff values for the number of positive nodes and the LNR were determined using the Chi square scores calculated by the Cox proportional hazards regression model. RESULTS: Nodal disease was found in 59 patients (42 %). In the subsequent analysis of the impact that nodal status has on survival, 18 patients with R1/2 resection and 6 patients with paraaortic nodal disease who did not survive for more than 5 years after resection were excluded. The optimal cutoff value for the number of positive nodes was 1, and the optimal cutoff value for the LNR was 5 %. Univariate analysis identified both the number of positive nodes (0, 1, or ≥2; P = 0.005) and the LNR (0, 0-5, or >5 %; P = 0.007) as significant prognostic factors. Multivariate analysis identified the number of positive nodes but not the LNR as an independent prognostic factor (P = 0.012). The 5-year survival rates were 64 % for the patients with no positive nodes, 46 % for the patients with one positive node, and 28 % for the patients with two or more positive nodes. CONCLUSIONS: The number of positive lymph nodes predicts survival better than the LNR after resection of extrahepatic cholangiocarcinoma, provided that nodal evaluation is sufficient.

[A Case of Minimally Invasive Apocrine Carcinoma Derived from Ductal Adenoma].

A 63-year-old woman was found to have a mass in her right breast and visited our hospital to undergo a detailed examination. A histopathological examination by using ultrasound-guided core needle biopsy revealed ductal carcinoma in situ. A partial mastectomy with sentinel lymph node biopsy was performed for the cancer of the right breast. The postoperative histopathological examination indicated apocrine carcinoma with a predominantly intraductal component without lymph node metastasis. The discrimination between ductal adenoma and apocrine carcinoma sometimes becomes a problem in making decisions about treatment. We need to take care when making a diagnosis.

[Study of Breast Cancer Patients Diagnosed Preoperatively with Ductal Carcinoma In Situ].

Although ductal carcinoma in situ(DCIS)is generally cured by surgical resection, it has been suggested that resection is over-treatment for some patients with DCIS. The aim of this study was to reconsider operative indications for patients with DCIS by examining clinicopathological features of 23 patients who underwent surgical resection for DCIS in our institute over a single year. Postoperative histological examination revealed that there were Luminal and HER2-positive subtypes, but no triple negative cancers. We found coincidental invasive ductal carcinoma(IDC)in 5 patients, and in all 5 the tumor size exceeded 60 mm. There was no coincidence of IDC in patients with a Ki-67 index ≤5%. Positive surgical margins were observed in 7 patients, all of which were histologically diagnosed as DCIS. Only 1 of the 7 patients underwent additional surgical resection; the 6 remaining patients, including 2 patients who received no treatment, did not undergo additional resection. All patients including those with positive surgical margins have had a 5-year relapse-free survival. Our findings imply that the subgroup of DCIS patients without IDC could be followed up without surgery.

[Three cases of esophageal carcinoma achieved a pathological complete response after neoadjuvant chemotherapy with cisplatin and 5-fluorouracil].

We report three cases of esophageal carcinoma all of which achieved a pathological complete response after neoadjuvant chemotherapy (NAC) with cisplatin and 5-fluorouracil (CF). All three patients were men with clinical stage II squamous cell carcinoma of the middle thoracic esophagus. We administered 2 courses of CF treatment as NAC and then performed radical esophagectomy. Pathologic examination revealed no viable tumor cells in the resected esophagus. The patients are currently alive with no evidence of disease.

[Locally Advanced Breast Cancer Treated with Halsted's Operation Because of Drug-Induced Lung Injury Caused by Neoadjuvant Chemotherapy--A Case Report].

A 64-year-old woman discovered a mass in her left breast and visited our hospital. A thorough examination resulted in a diagnosis of left, locally advanced breast cancer (cT4bN3, M0, cStage Ⅲc) with muscle invasion and Level Ⅲ lymph node metastases. Because of drug-induced lung disease following 4 courses of adriamycin and cyclophosphamide, the chemotherapy had to be stopped. Halsted's operation and postoperative radiotherapy (50 Gy) were performed. The patient was alive with no evidence of recurrence 9 months after surgery. Although multidisciplinary therapy is recommended in locally advanced breast cancer, chemotherapy sometimes cannot be performed due to factors such as age and physical status. Halsted's operation could be considered as a treatment of choice in patients with locally advanced breast cancer. It is important to choose the treatment strategy based on the condition of the patient.

[Mesorectal Lymph Node Metastasis Arising from Rectal Invasion by an Ovarian Cancer--A Case Report].

A 58-year-old woman presenting with abdominal distension was diagnosed with a tumor in the right ovary. A chest-abdominal-pelvic computed tomography scan revealed multiple lung metastases, multiple liver metastases, and peritoneal dissemination. Invasion of the rectum by peritoneal dissemination of the Douglas' pouch was suspected. She was diagnosed with Stage Ⅳ right ovarian cancer and was treated with preoperative chemotherapy. After chemotherapy, debulking surgery of the abdominal cavity (total hysterectomy, bilateral salpingo-oophorectomy, partial omentectomy, and Hartmann's procedure) was performed. Because there was swelling observed in multiple mesorectal lymph nodes, lymph node dissection was performed based on methods used for rectal cancer surgery. Postoperative histopathological examination revealed multiple mesorectal lymph node metastases arising from ovarian cancer. We suggest that mesorectal lymph node dissection be considered a part of debulking surgery for ovarian cancers that have invaded the rectum.

[A Case of Pneumatosis Cystoides Intestinalis Secondary to Gefitinib Therapy for Lung Adenocarcinoma].

Pneumatosis cystoides intestinalis (PCI) is a relatively rare condition, characterized by subserosal or submucosal air within the bowel wall. Herein, we report a rare case of PCI secondary to treatment with an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI). A 71-year-old man, who had received gefitinib therapy for 2 years and 5 months for lung adenocarcinoma with metastases to the bones and brain, presented with abdominal pain, diarrhea, and vomiting. Computed tomography of the abdomen revealed intramural air in the small bowel, free air in the abdomen, and moderate ascites. A diagnosis of PCI was made, and the patient was managed conservatively by discontinuing gefitinib treatment, because his vital signs were stable and there was no sign of peritonitis. The patient's symptoms gradually improved, and follow-up CT after 1 week revealed that the initial findings had almost completely resolved. Clinicians should note that treatment with gefitinib might cause PCI.

[A case of a large liposarcoma of the chest].

A49 -year-old woman with a growing tumor of the left anterior chest wall was admitted to our hospital. This patient was diagnosed with a malignant well-differentiated tumor by needle biopsy and underwent surgery involving wide resection of the tumor, associated excision of the major pectoralis muscle, and part of the mammary tissue and skin. The tumor measured 14.2×17.8 cm and weighed 1,220 g. Histopathologically, the tumor was confirmed to be a dedifferentiated liposarcoma, and local recurrence and metastasis often occurs in spite of complete surgical resection. However, no local recurrence or metastasis has been detected 2 months post-surgery. The main anatomic sites of liposarcomas are the retroperitoneum and lower extremities; only 19 liposarcoma cases of the anterior chest wall have been reported in Japan.

[Surgical resection after chemotherapy for advanced rectal cancer - report of a case].

Herein, we present a case of advanced rectal cancer surgically resected after chemotherapy. A 65-year-old woman presented with anal pain, and rectal cancer extending beyond the anus was diagnosed. The primary tumor was a well-differentiated adenocarcinoma with a KRAS mutation. Computed tomography revealed cancer invasion into the vagina and sacral and coccygeal bones, and cancer metastases to the bilateral inguinal lymph nodes and the left lung. Sigmoid colostomy and subcutaneous venous port insertion were performed. The patient was treated with modified oxaliplatin, leucovorin, and 5- fluorouracil (FOLFOX6) plus bevacizumab. She showed a partial response according to the Response Evaluation Criteria in Solid Tumors after 13 courses of chemotherapy. The primary tumor was then resected via posterior pelvic exenteration, bilateral inguinal lymphadenectomy, and sacral/coccygeal resection. Histological examination of the resected specimens revealed moderately differentiated adenocarcinoma with vaginal invasion. Metastasis to a right inguinal lymph node was observed. The pathological stage was ypT4bN0M1b, ypStage IV according to the tumor-node-metastasis system of the eighth edition of the Japanese Classification of Colorectal Carcinoma. The pathological response grade of the tumor after chemotherapy was determined to be Grade 1b.

[A case of long-term survival after lateral pelvic lymph node dissection for recurrence as skip metastasis of rectal cancer].

Herein, we present a case of long-term survival after lateral pelvic lymph node dissection for recurrence in the form of skip metastasis of rectal cancer. A 63-year-old man underwent abdominoperineal resection without lateral pelvic lymph node dissection for advanced lower rectal cancer. The histological diagnosis was type 2, 85 × 50 mm, tub1, pT4a, ly0, v1, pPM0, pDM0 and pN0, pStage II (Japanese Classification of Colorectal Carcinoma, 8th edition). Six months after surgery, enhanced computed tomography showed right obturator lymph node metastasis. We performed lateral pelvic lymph node dissection. Histological examination revealed moderately differentiated adenocarcinoma in the right obturator lymph node. The lymph node metastasis was diagnosed as a skip metastasis of the rectal cancer. The patient has had no recurrence for 9 years after resection of the lateral pelvic lymph node.

[A case of curatively resected, locally advanced ascending colon cancer with ileal conduit invasion].

A 71 -year-old man was referred to our hospital because of repeated bowel obstruction. He had previously undergone cystectomy with ileal conduit urinary diversion for the treatment of bladder cancer at the age of 28 years. Computed tomography revealed a mass in the ascending colon. Ileostomy was initially performed because of poor general condition that improved with postoperative nutrition management. Enema findings revealed ascending colon cancer and we therefore decided to perform curative surgery. Intraoperative findings revealed that the ascending colon cancer had invaded the ileal conduit. However, it was confirmed that the ureter-ileal conduit anastomosis and the mesentery of the ileal conduit could be preserved. We performed right colectomy and partial resection of the ileal conduit with curative intent. The pathological stage was pT4bpN0cM0, pStage II. There were no signs of recurrence 15 months after curative surgery.