levoleucovorin and Fibrosis

Some clinical studies have indicated the patients with Alzheimer's disease (AD) display an increased risk of cardiovascular disease (CVD). Here, to examine the relationship between AD and CVDs, we investigated the changes in heart function in triple-transgenic late-stage AD model mice (3× Tg-AD; APPSwe, PS1M146V, and tauP301L). We fed the AD mice folic acid (FA) or folinic acid (FN) and analyzed the protective effects of the compounds on the heart; specifically, 20-month-old triple-transgenic AD mice, weighing 34-55 g, were randomly allocated into three groups-the AD, AD + FA, and AD + FN groups-and subject to gastric feeding with FA or FN once daily at 12 mg/kg body weight (BW) for 3 months. Mouse BWs were assessed throughout the trial, at the end of which the animals were sacrificed using carbon dioxide suffocation. We found that BW, whole-heart weight, and left-ventricle weight were reduced in the AD + FA and AD + FN groups as compared with the measurements in the AD group. Furthermore, western blotting of excised heart tissue revealed that the levels of the hypertrophy-related protein markers phospho(p)-p38 and p-c-Jun were markedly decreased in the AD + FA group, whereas p-GATA4, and ANP were strongly reduced in the AD + FN group. Moreover, the fibrosis-related proteins uPA, MMP-2, MEK1/2 and SP-1 were decreased in the heart in both AD + FN group. In summary, our results indicate that FA and FN can exert anti-cardiac hypertrophy and fibrosis effects to protect the heart in aged triple-transgenic AD model mice, particular in FN.

Topics: Aged; Alzheimer Disease; Animals; Cardiomegaly; Disease Models, Animal; Fibrosis; Folic Acid; Humans; Leucovorin; Mice; Mice, Transgenic

To evaluate the prognostic value of posttreatment fibrosis in human PDAC patients, and to compare a type I collagen targeted MRI probe, CM-101, to the standard contrast agent, Gd-DOTA, for their abilities to identify FOLFIRINOX-induced fibrosis in a murine model of PDAC.. Ninety-three chemoradiation-treated human PDAC samples were stained for fibrosis and outcomes evaluated. For imaging, C57BL/6 and FVB mice were orthotopically implanted with PDAC cells and FOLFIRINOX was administered. Mice were imaged with Gd-DOTA and CM-101.. In humans, post-chemoradiation PDAC tumor fibrosis was associated with longer overall survival (OS) and disease-free survival (DFS) on multivariable analysis (OS. In humans, post-chemoradiation tumor fibrosis is associated with OS and DFS. In mice, our MR findings indicate that translation of collagen molecular MRI with CM-101 to humans might provide a novel imaging technique to monitor fibrotic response to therapy to assist with prognostication and disease management.

Topics: Aged; Animals; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Chemoradiotherapy, Adjuvant; Collagen; Disease-Free Survival; Female; Fibrosis; Fluorouracil; Follow-Up Studies; Heterocyclic Compounds; Humans; Irinotecan; Leucovorin; Magnetic Resonance Imaging; Male; Mice; Middle Aged; Molecular Imaging; Molecular Probes; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Organometallic Compounds; Oxaliplatin; Pancreas; Pancreatectomy; Pancreatic Neoplasms; Prognosis; Retrospective Studies; Survival Analysis; Xenograft Model Antitumor Assays

We evaluated the impacts of a series of novel histopathological factors on clinical-surgical outcomes and survival of patients who underwent surgery for colorectal cancer liver metastasis, with and without neoadjuvant chemotherapy.. A prospective database including 150 consecutive patients who underwent 183 hepatic resections for metastatic colorectal cancer was evaluated. Among them, 74 (49.3%) received neoadjuvant chemotherapy before surgery. The histopathological factors studied were: a) microsatellitosis, b) type and pattern of tumour growth, c) nuclear grade and the number of mitoses/mm(2), d) perilesional pseudocapsule, e) intratumoural fibrosis, f) lesion cellularity, g) hypoxic-angiogenic perilesional growth pattern, and h) the tumour normal interface.. Three or more metastatic lesions, R1 resection margins, and <50% tumour necrosis were prognostic factors for a worse OS, but only the former was confirmed to be an independent prognostic factor in the multivariate analysis. Furthermore, tumour fibrosis <40% and cellularity >10% were predictive of a worse neoadjuvant therapy response, but these findings were not confirmed in the multivariate analysis. Finally, tumour necrosis <50%, cellularity >10%, and TNI >0.5 mm were prognostic factors for a worse DFS and AS in the univariate but not in the multivariate analysis.. Several factors seem to influence the outcomes of surgery for colorectal cancer liver metastasis, especially the number of the lesions, the margins of resection, the percentage of necrosis and fibrosis, as well as the cellularity and the TNI.

Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Capecitabine; Carcinoma; Cetuximab; Colorectal Neoplasms; Databases, Factual; Deoxycytidine; Fibrosis; Fluorouracil; Hepatectomy; Humans; Leucovorin; Liver; Liver Neoplasms; Metastasectomy; Mitotic Index; Multivariate Analysis; Necrosis; Neoadjuvant Therapy; Neoplasm Grading; Organoplatinum Compounds; Oxaloacetates; Panitumumab; Prognosis; Retrospective Studies; Tumor Burden

FOLFOX-4 (folinic acid/5-fluorouracil/oxaliplatin) chemotherapy is used to treat patients with colorectal liver metastases. We aimed to assess hepatic histopathological responses to neoadjuvant FOLFOX-4 chemotherapy in patients with colorectal liver metastases. We selected all patients (n = 54) treated with FOLFOX-4 for colorectal liver metastases between June 2002 and June 2005. Only 25 underwent hepatectomy and formed the study group. Histological responses were assessed in the study group and a matched control group (n = 25) that did not receive neoadjuvant chemotherapy. The median (IQR) body mass index in the study and control groups was 24 (22-26) and 24 (23-25) kg/m(2), respectively, (P = NS). Complete histological resolution of tumour occurred in six (24%) patients in the study group. Median residual tumour cellularity was less (35 vs 70%) and fibrosis greater (50 vs 5%) in patients in the study group when compared with controls (P < 0.001). The liver surrounding the tumour was steatotic in 17 (68%) patients in the study group and five (20%) controls (P = 0.001). Hepatic sinusoidal dilatation was more pronounced in patients in the study group than in controls (P < 0.001). The response to FOLFOX-4 was associated with tumour necrosis, fibrosis and inflammation. More than two thirds of patients undergoing hepatectomy after FOLFOX-4 had steatosis despite being non-obese.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colorectal Neoplasms; Fatty Liver; Female; Fibrosis; Fluorouracil; Hepatectomy; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Retrospective Studies

Intra-abdominal and retroperitoneal fibrosis has been described as secondary to intraperitoneal (IP) administration of several chemotherapeutic agents, including carboplatin, mitoxantrone, and the combination of 5-fluorouracil and cisplatin. The IP administration of floxuridine (FUDR) is an effective and minimally toxic treatment for patients with metastases to the peritoneum. An increasing number of patients with colorectal, gastric, or ovarian carcinoma are treated with IP chemotherapy.. The authors report two patients with metastatic colon carcinoma who experienced severe intra-abdominal fibrosis presenting as an intra-abdominal mass mimicking recurrence in one patient and diffuse encasement of the bowel in the other, after the administration of IP FUDR and leucovorin.. Two patients with Stage III colon adenocarcinoma received postoperative adjuvant 5-fluorouracil and levamisole. They subsequently presented with a rise in carcinoembryonic antigen level and isolated liver metastasis. They underwent hepatic lobectomy with postoperative intra-arterial hepatic FUDR and systemic 5-fluorouracil and leucovorin. They each had an intra-abdominal recurrence, which was resected and treated with postoperative IP FUDR and leucovorin. They then presented with a diffuse pattern of IP fibrosis with no tumor identified.. IP FUDR and leucovorin therapy can be associated with diffuse IP fibrosis, which in this study caused an intra-abdominal mass that was indistinguishable from recurrent malignancy in one patient and encasement of the bowel in the other.

Topics: Adenocarcinoma; Adult; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Female; Fibrosis; Floxuridine; Humans; Infusions, Parenteral; Leucovorin; Middle Aged; Peritoneum

We report two patients with large-cell non-Hodgkin's lymphomas who were treated with intensive chemotherapy (MACOP-B), and in whom large isolated intraparenchymal masses (splenic in one case, renal in the other) were found with computed tomography after clinical remission. It was found at surgery that both masses were constituted by acellular necrotic material, without tumoral infiltration and limited by fibrous tissue. The finding of these residual masses in patients in remission raises problems of approach, as they may be nontumoral and not require new therapy. At present, until new radiological or biochemical markers are available, a judicious clinical attitude should be taken, with radiological control of the evolution of the masses and reserving surgery only for those cases with progression, diagnostic doubts, or patient's decision to know his real status.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Cyclophosphamide; Doxorubicin; Fibrosis; Humans; Kidney; Leucovorin; Lymphoma, Non-Hodgkin; Male; Methotrexate; Middle Aged; Necrosis; Prednisone; Spleen; Vincristine