[A Patient Who Underwent Resection of Liver Metastases after Receiving Systemic Chemotherapy for Advanced Rectal Cancer and Multiple Liver Metastases].

The patient was a 52-year-old man who had a positive fecal occult-blood test on a medical check-upi n April 2015 and was referred to our hospital in June. Detailed preoperative examinations resulted in a diagnosis of cancer of the lower rectum, multiple liver metastases, and clinical Stage IV . A biopsy showed moderately differentiated tubular adenocarcinoma. All-RAS was wild type, and the patient was asymptomatic. Unresectable advanced rectal cancer was diagnosed, and the patient was scheduled to receive systemic chemotherapy. The patient received a total of 16 courses of combination chemotherapy with 5- fluorouracil, Leucovorin, and oxaliplatin(FOLFOX)plus panitumumab, starting in October 2015. In July 2016, Colonoscopy showed scar findings at the site of the primary rectal cancer lesion. A biopsy revealed no cancer cells. It was difficult to identify the primary lesion on computed tomography, and there was no evidence of clinically significant lymphadenopathy. Positronemission tomography and computed tomography showed shrinkage of the liver metastases, with no accumulation of tracer in the primary lesion or lymph nodes. The primary lesion had a clinical complete response(CR), and the metastatic lesions had a clinical partial response(PR). In October 2016, laparoscopic partial hepatectomy was performed to treat the liver metastases. Histologic examination showed that the liver metastases were from rectal cancer. It is currently under observation.

Serum KL-6 level as an indicator of active or inactive interstitial pneumonitis associated with connective tissue diseases.

OBJECTIVE: To elucidate the cut off levels of serum KL-6 indicating patients with interstitial pneumonitis (IP) and patients with active IP associated with connective tissue diseases (CTDs). METHODS: CTD patients whose serum KL-6 level was measured were included. IP was diagnosed on the basis of medical records including XP/CT findings, and active IP was assumed in case that intervention for IP was newly added. The cut off levels were determined by receiver operating characteristic (ROC) curve analysis. RESULTS: Among 240 (174 females) patients, 67 (42) had IP and 15 (9) had active IP. The ages of patients with and without IP, and with active IP and with inactive IP were 70.3±9.5 and 62.8±15.3, and 72.8±8.1 and 69.6±9.8, respectively. IP was significantly more prevalent in males and the elderly. The KL-6 levels were 990±90 and 301±12 U/mL in patients with and without IP, and 1,905±236 and 726±54 U/mL in those with active IP and with inactive IP, respectively. ROC curve analysis showed a cut off level of 509 U/mL for indicating IP, and that of 1,051-1,060 U/mL for indicating active IP. CONCLUSION: A serum KL-6 level of higher than 500 U/mL is a marker of the presence of IP, and a level of higher than 1,000 U/mL is a marker of the presence of active IP associated with CTDs.

Identification of a novel organic anion transporter mediating carnitine transport in mouse liver and kidney.

This study identifies a novel organic anion transporter Oat9 expressed in mouse liver and kidney. Two variants were detected by screening a mouse liver cDNA library; these varients consist of 1815 (designated Oat9S) and 2165 (Oat9L) base pairs which encode 443 and 551 amino acid proteins, respectively. Oat9S has a predicted structure containing eight transmembrane domains (TMD); whereas, Oat9L possesses twelve TMD. Oat9 mRNA expression was detected in kidney and liver. This transporter was located at the apical side of the late portion of proximal tubules and at the sinusoidal side of hepatocytes. When expressed in Xenopus oocytes, Oat9S mediated the transport of L-carnitine (Km = 2.9 microM), a representative zwitterion, as well as cimetidine (Km = 16.1 microM) and salicylic acid (Km = 175.5 microM), while Oat9L did not show any transport activity. Oat9S-mediated L-carnitine uptake was inhibited by D-carnitine, acetylcarnitine, octanoylcarnitine, betaine, and other organic compounds, suggesting that quaternary ammonium cation bulkiness and relative hydrophobicity are important factors for Oat9S-substrate interactions. Among OATs, Oat9S appears to be the first member to mediate the transport of carnitine and possesses eight TMD. Overall, these new results provide added insight into the structure-activity relationship comprising the organic ion-permeation pathway.

Diminishing impact of preoperative carcinoembryonic antigen (CEA) in prognosis of Dukes' C colorectal cancer.

BACKGROUND: In curable colorectal cancer (CRC), preoperative serum carcinoembryonic antigen (CEA) (preCEA) has been reported to have predictive prognostic value. However, data remains insufficient to support its clinical use. The aim of the current study was to validate the prognostic impact of preCEA in Dukes' C CRC. PATIENTS AND METHODS: The prognostic significance of preCEA for 237 Dukes' C CRC patients assessed retrospectively (between 1990 and 2000: previous cases) and the prospective relevance for 197 counterparts (between 2001 and 2004: recent cases) according to preCEA, were both examined. RESULTS: The previous cases showed the most potent impact of preCEA as an independent prognostic factor (hazard ratio=2.0, p=0.003) among the clinicopathological factors using a multivariate proportional hazard model, while the recent cases did not even show a univariate prognostic impact. A significant difference in the prognosis between the two periods was only found in the patients with elevated preCEA administered adjuvant chemotherapy (ADT) (p=0.03). Between the two terms, a dramatic change of ADT regimens from 5FU alone (p<0.001) to 5FU in combination with leucovorin (p<0.001) and/or irinotecan (p-0.0009/0.005) was introduced, and N2 patient survival was dramatically improved. However, a significant prognostic difference for the elevated preCEA patients with ADT could not be demonstrated by sub-analysis of N1 and N2 disease due to diminished correlation of preCEA and the N factor (p=0.02 to 0.5), indicating that preCEA did not predict chemosensitivity. CONCLUSION: The preCEA is no longer useful in predicting prognosis with Dukes' C CRC patients, because of the loss of preCEA association with the N factor, putatively through undefined diagnostic or therapeutic advancement.

Surgical resection of stage IV colorectal cancer and prognosis.

BACKGROUND: Colorectal cancer (CRC) harbors accumulated genetic alterations with cancer progression, which results in uncontrollable disease. To regulate the most malignant CRC, we have to know the most dismal phenotype of stage IV disease. METHODS: A retrospective review of the Kitasato University Hospital was performed (from 1990 to 2001) to extract the 162 resected stage IV CRC. Clinical variables were tested for their relationship to survival in a multivariate prognostic analysis and revealed the interaction of the prognostic factors. RESULTS: In stage IV CRC with noncurable resection, the most robust univariate predictors for poor prognosis were preoperative high value of CA19-9, peritoneal dissemination, depth of invasion, age, extent of liver metastases, pathologic lymph node metastasis status, and gender as tumor factors, and postoperative therapy, perioperative transfusion, and lymph node dissection extent as treatment factors. Among these factors, postoperative therapy (p < 0.0001), perioperative transfusion (0.0002), CA19-9 (0.001), extent of liver metastases (0.004), and peritoneal dissemination (0.02) were identified as independent prognostic factors by multivariate analysis. Interestingly, among the independent prognostic factors, treatment factors did not depend upon tumor factors and the combination of the three tumor factors (CA19-9, extent of liver metastases, and peritoneal dissemination) can clearly classify the patients into the definite prognostic groups. CONCLUSION: Our results suggested that the most dismal CRC harbors three definite vectors that may represent the strongest phenotype of putative systemic immune (CA19-9), distant metastasis (extent of liver metastases), and local progression (peritoneal dissemination).

Hypertension accelerates diabetic nephropathy in Wistar fatty rats, a model of type 2 diabetes mellitus, via mitogen-activated protein kinase cascades and transforming growth factor-beta1.

Although it is known that diabetic nephropathy is accelerated by hypertension, the mechanisms involved in this process are not clear. In this study we aimed to clarify these mechanisms using male Wistar fatty rats (WFR) as a type 2 diabetic model and male Wistar lean rats (WLR) as a control. Each group was fed a normal or high sodium diet from the age of 6 to 14 weeks. We determined the blood pressure and urinary albumin excretion (UAE). At the end of the study, the expressions of mitogen-activated protein kinases (MAPK) and transforming growth factor-beta1 (TGF-beta1) were examined in the isolated glomeruli by Western blot analysis, and the number of glomerular lesions was determined by conventional histology. High sodium load caused hypertension and a marked increase in UAE in the WFR but not in the WLR. Glomerular volume was increased in the hypertensive WFR. There was no difference among the four groups in the expression of c-Jun-NH2-terminal kinase (JNK). In contrast, the expressions of extracellular signal-regulated kinase 1/2 (ERK1/2) and its upstream regulator, MAPK/ERK kinase 1 (MEK1), were augmented in the hypertensive WFR. Expression of p38 MAPK was increased in the normotensive WFR, and further enhanced in the hypertensive WFR. Moreover, administration of high sodium load to WFR augmented the expression of TGF-beta1. In conclusion, systemic hypertension in WFR accelerates the diabetic nephropathy in type 2 diabetes via MEK-ERK and p38 MAPK cascades. TGF-beta1 is also involved in this mechanism.