A novel perfusion culture system for screening mitochondrial toxicity in primary mouse hepatocytes.

The liver microphysiological system (MPS) model is an in-vitro culture method that mimics physiological blood flow, which enhances basal cellular functions. However, the liver MPS model has not been tested in the preclinical stage because of its obscure utility. It can overcome the major problem of conventional systems-rapid loss of mitochondrial activity in cultured hepatocytes due to limited oxygen supply-by supplying oxygen to cultured hepatocytes using a perfusion device. In this study, we developed a new perfusion culture system that can detect mitochondrial toxicity. Primary mouse hepatocytes were cultured under perfusion condition for 48 hr. The hepatocytes showed increased oxygen consumption and reduced lactate release. These results indicated that the ATP-production pathway was switched from glycolysis to mitochondrial oxidative phosphorylation in the perfusion culture system. Furthermore, ATP levels were considerably reduced in the perfusion culture system after exposure to phenformin, a mitochondrial complex I inhibitor. To summarize, the perfusion culture system could improve the mitochondrial activity in primary mouse hepatocytes, and thus, has potential implications in the detection of mitochondrial toxicity.

[Orolingual Angioedema after Recombinant Tissue Plasminogen Activator Treatment in Acute Cardiogenic Cerebral Embolism Patient Using Olmesartan: A Case Report].

Recombinant tissue plasminogen activator (rt-PA), which is used to treat acute cerebral infarction, may cause angioedema immediately after administration particularly in patients who are taking angiotensin-converting enzyme (ACE) inhibitors. On the other hand, unlike ACE inhibitors, angiotensin II receptor blockers (ARBs) do not act directly on bradykinin, and are therefore considered an alternative to ACE inhibitors in patients with bradykinin-related side effects. We report a case of orolingual angioedema in an 82-year-old male patient who is taking ARB, which occurred after rt-PA administration for acute cerebral infarction. The patient, who has been on medications for hypertension including ARB (olmesartan 40 mg/day) and for hyperuricemia, was transported to our hospital with the chief complaint of right conjugate deviation of the eyes and left hemiplegia. Head magnetic resonance imaging revealed cerebral infarction in the right mesencephalic artery area including the insular cortex. He was diagnosed with cardiogenic cerebral embolism, and rt-PA administration was started 4 h after onset. The patient developed eyelid edema 2.5 h after the start of administration, and orolingual angioedema and breathing difficulty 15.5 h after. The patient was treated with methylprednisolone, d-chlorpheniramine maleate, and famotidine, and the symptoms improved gradually in 1.5 h. We should pay attention to the occurrence of orolingual angioedema not only at the beginning of rt-PA administration but also for a long time thereafter when it is used in patients taking ARBs.

Novel Platform for Regulation of Extracellular Vesicles and Metabolites Secretion from Cells Using a Multi-Linkable Horizontal Co-Culture Plate.

Microfluidics is applied in biotechnology research via the creation of microfluidic channels and reaction vessels. Filters are considered to be able to simulate microfluidics. A typical example is the cell culture insert, which comprises two vessels connected by a filter. Cell culture inserts have been used for years to study cell-to-cell communication. These systems generally have a bucket-in-bucket structure and are hereafter referred to as a vertical-type co-culture plate (VTCP). However, VTCPs have several disadvantages, such as the inability to simultaneously observe samples in both containers and the inability of cell-to-cell communication through the filters at high cell densities. In this study, we developed a novel horizontal-type co-culture plate (HTCP) to overcome these disadvantages and confirm its performance. In addition, we clarified the migration characteristics of substances secreted from cells in horizontal co-culture vessels. It is generally assumed that less material is exchanged between the horizontal vessels. However, the extracellular vesicle (EV) transfer was found to be twice as high when using HTCP. Other merits include control of the degree of co-culture via the placement of cells. We believe that this novel HTCP container will facilitate research on cell-to-cell communication in various fields.

Effects of proton pump inhibitors on severe haematotoxicity induced after first course of pemetrexed/carboplatin combination chemotherapy.

WHAT IS KNOWN AND OBJECTIVE: Pemetrexed/carboplatin combination chemotherapy has shown efficacy as a first-line treatment for advanced non-small-cell lung cancer. However, severe haematotoxicity is often observed during this combination chemotherapy. Some studies have suggested that concomitant drugs may be the risk factors for severe adverse events. However, those studies identified the predictive risk factors without paying attention to the relative dose intensities (RDIs) of the anticancer drugs. The objective of this study was to clarify the effects of concomitant drugs on the severe haematotoxicity induced by pemetrexed/carboplatin combination chemotherapy using multiple logistic regression analysis incorporating RDIs of the anticancer drugs. METHODS: We retrospectively reviewed the records of 61 patients who had received first-line treatment with this combination chemotherapy at Yamato Municipal Hospital between April 2011 and May 2017. Severe haematotoxicity was defined as grade 3 or 4 according to the Common Terminology Criteria for Adverse Events, version 4.0. To clarify the influence of concomitant drugs on haematotoxicity, we performed multiple logistic regression analysis. RESULTS: Among the 61 patients, 18 (29.5%) developed grade 3 or 4 haematotoxicity. Multiple logistic regression analysis showed that body weight <54.5 kg [odds ratio: 5.21, 95% confidence interval (CI): 1.17-23.08, P = 0.030], haemoglobin <12.0 g/dL [odds ratio: 7.13, 95% CI: 1.54-33.11, P = 0.012], and coadministration of proton pump inhibitors (PPIs) [odds ratio: 5.34, 95% CI: 1.06-26.94, P = 0.042] were significantly associated with severe haematotoxicity in patients receiving pemetrexed/carboplatin combination chemotherapy after adjustment using non-steroidal anti-inflammatory drugs and RDIs of the anticancer drugs. WHAT IS NEW AND CONCLUSION: Multiple logistic regression analysis incorporating RDIs of the anticancer drugs revealed that low baseline body weight, low baseline haemoglobin level, and coadministration of PPIs were the independent risk factors for predicting severe haematotoxicity induced by pemetrexed/carboplatin combination chemotherapy.

Effect of Intraarticular Triamcinolone Acetonide Injection for Wrist Pain in Rheumatoid Arthritis Patients: A Statistical Investigation.

BACKGROUND: A significant number of patients on long-term treatment and users of biologics complain of wrist pain due to synovial proliferation and arthropathic changes. Synovectomy or joint arthroplasty is often indicated for such patients, but many refuse surgery. For these patients triamcinolone acetonide was injected into the dorsum of the wrist, and evaluated the clinical benefit and safety of the wrist joint. METHODS: We injected triamcinolone acetonide into the dorsum of the wrist. We evaluated the clinical benefit and safety of intraarticular triamcinolone acetonide by analyzing data on (1) the number of injections, (2) decrease in visual analog scale pain, (3) changes in carpal height ratio, radio carpal distance ratio, and radial rotation angle in X-ray imaging, and (4) the adverse reactions of triamcinolone acetonide injection on the subcutaneous tissue and extensor tendons. RESULTS: 1. The number of injections per patient over 3 years 8 months was 1 for 44 wrists, 2 for 21 wrists, 3 for 17 wrists, 4 for 6 wrists, 5 for 3 wrists, 6 for 3 wrists, 7 for 2 wrists, 9 for 2 wrists, 12 for 4 wrists, and 13 for 1 wrist. 2. The overall mean VAS improved from 79 mm at baseline to 11 mm post-injection. 3. In the grade I and II group, CHS, RCDR and RRA were not statistically significant. In the grade III and IV group, CHR showed a significant decrease. 4. Neither subcutaneous atrophy nor extensor tendon rupture was reported. CONCLUSIONS: More than 90% of patients of all disease grades responded to an average of 1 to 4 injections per year.

Prognostic impact of primary tumor resection and lymph node dissection in stage IV colorectal cancer with unresectable metastasis: a propensity score analysis in a multicenter retrospective study.

BACKGROUND: Retrospective studies have shown that primary tumor resection improves the prognosis of patients with colorectal cancer with unresectable metastasis (mCRC). Prognostic significance of lymph node dissection (LND) in mCRC has not been examined previously. The aim of this study was to investigate the prognostic impact of primary tumor resection and LND in mCRC. METHODS: A total of 1,982 patients with mCRC from January 1997 to December 2007 were retrospectively studied. The impact of primary tumor resection and LND on overall survival (OS) was analyzed using Cox proportional hazards model and propensity score analysis to mitigate the selection bias. Covariates in the models for propensity scores included treatment period, institution, age, sex, carcinoembryonic antigen, tumor location, histology, depth, lymph node metastasis, lymphovascular invasion, and number of metastatic organs. RESULTS: In a multivariate analysis, primary tumor resection and treatment in the latter period were associated with an improved OS, and age over 70 years, female sex, lymph node metastasis, and multiple organ metastasis were associated with a decreased OS. In the propensity-matched cohort, patients treated with primary tumor resection showed a significantly better OS than those without tumor resection (median OS 13.8 vs. 6.3 months; p = 0.0001). Furthermore, among patients treated with primary tumor resection, patients treated with D3 LND showed a significantly better OS than those with less extensive LND (median OS 17.2 vs. 13.7 months; p < 0.0001). CONCLUSIONS: It was suggested that primary tumor resection with D3 LND improves the survival of patients with mCRC.

Number of Lymph Nodes in Rectal Cancer is Correlated with Response to Preoperative Chemoradiotherapy but is not Associated with Patient Survival.

BACKGROUND/AIMS: We aimed to clarify the oncological significance of the number of lymph nodes in rectal cancers treated with preoperative chemoradiotherapy. METHODOLOGY: We studied 126 curatively operated patients with clinical T3-T4 and M0 rectal cancers. The number of lymph nodes and clinicopathological features were compared between the patients treated with surgery alone (OP group, n = 45) and those treated with preoperative chemoradiotherapy (50-50.4 Gy in 25-28 fractions with tegafur-uracil and leucovorin, CRT group, n = 81). Factors influencing lymph node count and its prognostic significance were analyzed. RESULTS: The CRT group had significantly fewer lymph nodes than the OP group (12.4 vs. 21.1, P < 0.0001). High histological regression of rectal lesions was significantly correlated with decreased lymph node count in the CRT group. In the OP group, the 5-year cancer-specific survival rate of the patients with 12 or more lymph nodes was significantly better than those with fewer than 12 lymph nodes (75.1% vs. 33.3%, P = 0.02); in the CRT group, on the other hand, these survival rates did not differ (84.5% vs. 77.5%, P = 0.6). CONCLUSIONS: The number of lymph nodes in rectal cancer was correlated with the response of primary rectal lesions to chemoradiotherapy, and was not associated with patient survival.

[The present status of home care medicine and regional medical co-operation at a regional cancer base hospital].

Kohka Public Hospital(KPH), approved as a regional cancer base hospital in February 2008, has concentrated on cancer treatment and care. KPH developed a Division of Home Care Medicine last year. A home care doctor visited and treated various patients, including cancer patients by co-operating with the Visiting Nurse Station; this resulted in an increase in home care patients but not of home deaths. To increase the cases of home care medicine, we believe that collaboration with other institutes and the creation of a regional network conference consisting of doctors, nurses, pharmacists, dental doctors, home helpers, and regional administrators is necessary. Via the conference, we recognized the need to obtain more information and create a system of collaborative home medication and care for cancer patients.

Chromosomal instability (CIN) phenotype, CIN high or CIN low, predicts survival for colorectal cancer.

PURPOSE: To examine whether chromosomal instability (CIN) phenotype, determined by the severity of CIN, can predict survival for stages II and III colorectal cancer (CRC). PATIENTS AND METHODS: We determined microsatellite instability (MSI) and loss of heterozygosity (LOH) status in 1,103 patients (training [n = 845] and validation [n = 258] sets with stages II and III CRC). The LOH ratio was defined as the frequency of LOH in chromosomes 2p, 5q, 17p, and 18q. According to the LOH ratio, non-MSI high tumors were classified as CIN high (LOH ratio ≥ 33%) or CIN low (LOH ratio < 33%). CIN-high tumors were subclassified as CIN high (mild type; LOH ratio < 75%) or CIN high (severe type; LOH ratio ≥ 75%). We used microarrays to identify a gene signature that could classify the CIN phenotype and evaluated its ability to predict prognosis. RESULTS: CIN high showed the worst survival (P < .001), whereas there was no significant difference between CIN low and MSI high. CIN high (severe type) showed poorer survival than CIN high (mild type; P < .001). Multivariate analysis revealed that CIN phenotype was an independent risk factor for disease-free and overall survival, respectively, in both the training (P < .001 and P = .0155) and validation sets (P < .001 and P = .0076). Microarray analysis also revealed that survival was significantly poorer in those with the CIN-high than in the CIN-low gene signature (P = .0203). In a validation of 290 independent CRCs (GSE14333), the CIN-high gene signature showed significantly poorer survival than the CIN-low signature (P = .0047). CONCLUSION: The CIN phenotype is a predictive marker for survival and may be used to select high-risk patients with stages II and III CRC.

Radiation-induced apoptosis of peripheral blood lymphocytes is correlated with histological regression of rectal cancer in response to preoperative chemoradiotherapy.

PURPOSE: The response of rectal cancer to preoperative chemoradiotherapy (PRT) varies widely among patients, and predictors of the response remain to be elucidated. The purpose of this study is to investigate whether radiation-induced apoptosis (RIA) of peripheral blood lymphocytes (PBLs) reflects the underlying intrinsic radiosensitivity of rectal cancer. METHODS: Forty-one patients with clinical T3-4, M0 low rectal cancers, treated with PRT and curative surgery, were retrospectively studied. PBLs were obtained from blood samples of the patients, irradiated at 0, 2, 8, and 16 Gy in vitro, and analyzed for RIA by flow cytometry using Annexin V (AV) and propidium iodide (PI). The correlation of the RIA of PBLs and histological regression of rectal cancer in response to PRT was examined. RESULTS: Both the proportions of AV+/PI- PBLs (early apoptosis) and AV+/PI + PBLs (late apoptosis) were significantly higher in patients with high histological regression than in those with low histological regression. Age, sex, tumor size, and clinical T and N stages did not affect the RIA of PBLs. CONCLUSIONS: This study showed that the RIA of PBLs is correlated with the histological regression of rectal cancer in response to PRT and suggested that the radiosensitivity of rectal cancer might be estimated by the RIA of PBLs.

Tumor location is a prognostic factor in poorly differentiated adenocarcinoma, mucinous adenocarcinoma, and signet-ring cell carcinoma of the colon.

PURPOSE: Cancers which arise in the proximal and distal colon are suggested to be different clinically, pathologically, and genetically. The aim of this study is to clarify whether clinical behavior of colonic poorly differentiated adenocarcinoma, mucinous adenocarcinoma, and signet-cell carcinoma (Por/Muc/Sig cancers), minor and aggressive subpopulation in colonic cancers, differs in accordance with the tumor location. METHODS: A total of 3,175 patients with curatively resected colonic cancers were studied. Clinical and pathological features were compared between Por/Muc/Sig cancers and well or moderately differentiated adenocarcinomas (Wel/Mod cancers) and between proximal and distal cancers in each histologic type. RESULTS: Por/Muc/Sig cancers (n = 213) were more advanced in the TNM stage and showed worse disease-specific survival than Wel/Mod cancers (n = 2,692). In Por/Muc/Sig cancers, but not in Wel/Mod cancers, proximal cancers showed significantly better disease-specific survival than distal cancers (88.9% vs. 76.5%, p = 0.0234), and a multivariate analysis showed that proximal tumor location was an independent predictor of fair prognosis (hazard ratio (HR), 0.458; 95% confidence interval (CI), 0.218-0.961; p = 0.0390). In addition, female gender also was an independent predictor of fair prognosis in Por/Muc/Sig cancers (HR, 0.373; 95% CI, 0.151-0.922) and not in Wel/Mod cancers. CONCLUSIONS: Proximal Por/Muc/Sig cancers were suggested to be a distinct subpopulation with a favorable oncologic outcome. Tumor location and gender might be helpful in the risk stratification after curative surgery for Por/Muc/Sig cancers.

Skin metastasis from sigmoid colon cancer.

Skin metastases from visceral cancers are rare and the reported incidence from all visceral cancers is 1.4% to 10%. Skin metastases from colorectal cancers account for only 5% of metastatic skin cancers, among which scalp metastases are very rare. We describe a 53-year-old man with scalp metastasis derived from sigmoid colon cancer that was diagnosed and surgically resected in 2005. Metastatic lung tumors that developed thereafter were surgically resected and then chemotherapy was administered. However, metastatic brain tumors occurred in 2008, and these were treated by gamma-knife radiosurgery. Around the same time, a raised lesion that appeared on the scalp was diagnosed as skin metastasis and treated with best supportive care. Thereafter, the brain metastases continued to spread, and the patient died in October 2008.

A case of marked response to preoperative chemoradiotherapy for rectal cancer with para-aortic lymph node metastasis.

A 67-year-old man had rectal cancer with para-aortic lymph node metastasis. Prior to surgical resection, tegafur-uracil and leucovorin had been administered orally as chemotherapy, and radiotherapy (50.4 Gy) was applied for the rectum and para-aortic lymph nodes. Low anterior resection was then performed, followed by 45 cycles of chemotherapy in total. Enlargement of the left axillary lymph nodes was noted during treatment, but nodes shrank in response to treatment with bevacizumab + FOLFIRI (i.e., irinotecan + 5-fluorouracil/leucovorin). As of the time of writing, 36 months after diagnosis, no swelling of the para-aortic lymph nodes was evident and chemotherapy was being continued. This patient was alive after achieving response to neoadjuvant therapy comprising chemotherapy and irradiation of the para-aortic lymph nodes, along with postoperative chemotherapy. This therapeutic approach of preoperative chemotherapy plus irradiation of the primary lesion and para-aortic lymph nodes has potential as an effective treatment.

Severance of a ventriculoperitoneal shunt catheter implanted between the cerebral ventricle and peritoneal cavity, resulting in protrusion from the anus.

One rare complication of a ventriculoperitoneal (VP) shunt is perforation of the gastrointestinal tract by the catheter. We report a case in which the catheter severed spontaneously inside the peritoneal cavity, creating a communication between the intestinal tract and the peritoneal cavity. The patient was a 41-year-old man who presented with a VP shunt catheter protruding from the anus. Computed tomography showed that the VP shunt catheter, which had been put in place 25 years earlier, had severed spontaneously. The distal end had then perforated and entered the intestinal tract. The patient was hospitalized and emergency surgery was performed to repair the intestinal tract perforation caused by the end of the VP shunt catheter. Laparotomy revealed that the catheter had perforated the sigmoid colon. The VP shunt catheter was removed, and the perforation in the intestinal tract was closed by suturing. The patient was discharged on postoperative day 20.

A case of lung squamous cell carcinoma with metastases to the duodenum and small intestine.

Gastrointestinal metastasis of lung cancer is fairly rare, and metastasis to the duodenum is very uncommon. We report a case of duodenum and small intestine metastases of lung squamous cell carcinoma. The patient was a 66-year-old man. He was diagnosed with lung squamous cell carcinoma (T4N3M1 [mediastinum, cervical lymph node, and duodenum metastases], stage IV). He noted a sense of abdominal fullness on the evening of the day chemoradiotherapy was given, and emergency surgery was performed for suspected perforation of the digestive tract. Intraoperative findings included a tumor in the small intestine with a perforation at the tumor site; partial resection of the small intestine, including the tumor, was performed. Small intestine metastasis of lung cancer was diagnosed following histopathologic examination. When lung cancer patients complain of abdominal symptoms, it is important to consider gastrointestinal metastases in diagnosis and treatment.

Benefit of tegafur-uracil and leucovorin in chemoradiotherapy for rectal cancer.

BACKGROUND/AIMS: Concomitant chemotherapy increases the therapeutic effect of preoperative radiotherapy for rectal cancer. The aim was to investigate the clinical benefit of tegafur-uracil (UFT) and leucovorin (LV) in preoperative chemoradiotherapy for rectal cancer. METHODOLOGY: Patients who had undergone curative resections of rectal cancers following preoperative radiotherapy (50-50.4Gy) with UFT and LV (CRT group: n=30) or radiotherapy without chemotherapy (RT group: n=33) were studied. Clinical outcomes were compared between both groups. RESULTS: Responders to preoperative therapy (>66% pathological resolution of their cancer) comprised 56.7% and 36.4% of the CRT and RT groups, respectively. Complete response was observed in 10.0% and in 6.1% of the CRT and RT groups, respectively. Pathological lymph node metastasis was positive in 10.0% and in 39.4% of the CRT and RT groups, respectively (p=0.0001). Sphincter-preserving surgery was performed in more patients in the CRT group than in the RT group (63.3% vs. 36.4%, p=0.04). Anastomotic leakage or pelvic abscess was seen in 6.7% and 27.3% of the CRT and RT groups, respectively. Anal function, estimated by the frequency of defecation and the Wexner incontinence score, was equally fair in both groups. CONCLUSIONS: Administration of UFT and LV enhanced the pathological response to preoperative radiotherapy, especially that of lymph node metastasis, and increased the frequency of sphincter-preserving surgery without compromising postoperative course.

Invasive micropapillary carcinoma of the ascending colon--a report of a case.

Micropapillary carcinoma (MC) has been recently recognized to be a rare but distinctive variant of adenocarcinoma. At present, only a limited number of colorectal MC cases have been reported. We present a case of MC of the ascending colon with distant metastasis. A 61-year-old female patient was hospitalized with a complaint of abdominal pain. A diagnostic work-up revealed cancer of the ascending colon with multiple lung metastases. The patient underwent a right hemicolectomy with lymph node dissection. A peritoneal nodule was observed in the abdominal cavity during surgery, and this nodule was also resected. The pathologic findings of the colon tumor revealed components of conventional tubular adenocarcinoma and micropapillary carcinoma. Lymph nodes and a peritoneal nodule revealed tubular adenocarcinoma. MC is a rare disease but has high malignant potential. In the present case the tumor was small in size, but the patient had a peritoneal and multiple lung metastases.

Perforation of the small bowel due to metastasis from tongue cancer.

Distant small bowel metastases from head and neck squamous cell carcinomas are extremely rare, and tongue cancer metastasizing to the small bowel has not been previously reported. We describe a 40-year-old male patient who underwent subtotal gross laryngectomy for squamous cell carcinoma of the tongue in February 2007 and then presented in November 2008 with severe abdominal pain. Abdominal computed tomography (CT) and X-rays revealed free air, suggesting intestinal perforation. Emergency surgery revealed a 10-mm perforation at the ileum and a palpable hard tumor at the perforation site. The ileum was resected, and pathologic findings showed squamous cell carcinoma at the perforation site, which was consistent with metastasis from tongue cancer.