tacrolimus and Colorectal-Neoplasms

Most common hepatobiliary manifestation of inflammatory bowel disease (IBD) are primary sclerosing cholangitis (PSC) and autoimmune hepatitis, ranking them as the main cause of liver transplantation (LT) in IBD setting. Course of pre-existing IBD after LT differs depending on many transplant related factors. Potential risk factors related to IBD deterioration after LT are tacrolimus-based immunosuppressive regimens, active IBD and cessation of 5-aminosalicylates at the time of LT. About 30% patients experience improvement of IBD after LT, while approximately the same percentage of patients worsens. Occurrence of

Topics: Algorithms; Anastomosis, Surgical; Cholangitis, Sclerosing; Colonoscopy; Colorectal Neoplasms; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Liver Failure; Liver Transplantation; Male; Mesalamine; Postoperative Period; Proctocolectomy, Restorative; Risk Factors; Tacrolimus; Treatment Outcome; Tumor Necrosis Factor-alpha

There was estimated a higher incidence of de novo inflammatory bowel disease (IBD) after solid organ transplantation than in the general population. The onset of IBD in the organ transplant recipient population is an important clinical situation which is associated to higher morbidity and difficulty in the medical therapeutic management because of possible interaction between anti-reject therapy and IBD therapy. IBD course after liver transplantation (LT) is variable, but about one third of patients may worsen, needing an increase in medical therapy or a colectomy. Active IBD at the time of LT, discontinuation of 5-aminosalicylic acid or azathioprine at the time of LT and use of tacrolimus-based immunosuppression may be associated with an unfavorable outcome of IBD after LT. Anti-tumor necrosis factor alpha (TNFα) therapy for refractory IBD may be an effective and safe therapeutic option after LT. The little experience of the use of biological therapy in transplanted patients, with concomitant anti-rejection therapy, suggests there be a higher more careful surveillance regarding the risk of infectious diseases, autoimmune diseases, and neoplasms. An increased risk of colorectal cancer (CRC) is present also after LT in IBD patients with primary sclerosing cholangitis (PSC). An annual program of endoscopic surveillance with serial biopsies for CRC is recommended. A prophylactic colectomy in selected IBD/PSC patients with CRC risk factors could be a good management strategy in the CRC prevention, but it is used infrequently in the majority of LT centers. About 30% of patients develop multiple IBD recurrence and 20% of patients require a colectomy after renal transplantation. Like in the liver transplantation, anti-TNFα therapy could be an effective treatment in IBD patients with conventional refractory therapy after renal or heart transplantation. A large number of patients are needed to confirm the preliminary observations. Regarding the higher clinical complexity of this subgroup of IBD patients, a close multidisciplinary approach between an IBD dedicated gastroenterologist and surgeon and an organ transplantation specialist is necessary in order to have the best clinical management of IBD after transplantation.

Topics: Azathioprine; Cholangitis, Sclerosing; Colectomy; Colorectal Neoplasms; End Stage Liver Disease; Graft Rejection; Heart Transplantation; Humans; Inflammatory Bowel Diseases; Kidney Transplantation; Liver Transplantation; Mesalamine; Risk Factors; Tacrolimus; Treatment Outcome; Tumor Necrosis Factor-alpha

Topics: Adalimumab; Antibodies, Monoclonal, Humanized; Colitis, Ulcerative; Colorectal Neoplasms; Humans; Probiotics; Remission Induction; Salicylates; Tacrolimus; Thiazolidines

Clinical trials addressing the acneiform rash associated with epidermal growth factor receptor inhibitors are lacking.. We evaluated the ability of topical pimecrolimus to reduce the severity of cetuximab-related facial rash.. In all, 24 patients with metastatic colorectal cancer with cetuximab facial rash received twice daily pimecrolimus application for 5 weeks to half of the face. At baseline, week 2, and week 5, a dermatologist performed facial lesion counts, patients reported perceived severity of rash-related symptoms, and standardized facial photographs were obtained for blinded evaluation of global rash severity.. Treatment sides had greater decrease in lesion counts than observation sides of face at weeks 2 (P < .001) and 5 (P = .02). However, there were no significant differences in patients' assessment of symptoms and in review of facial photographs for rash severity between treatment and observation sides.. This study was not placebo controlled.. Pimecrolimus application did not translate into clinically meaningful benefit for patients with cetuximab-related facial rash.

Topics: Acneiform Eruptions; Administration, Topical; Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Cetuximab; Colorectal Neoplasms; Dermatologic Agents; Drug Eruptions; Female; Humans; Male; Middle Aged; Prospective Studies; Tacrolimus; Treatment Failure; Young Adult

Chronic immunosuppression may increase the risk of post-transplant infection and medication-related injury and may also be responsible for the increased risk of gastrointestinal complications in kidney transplant recipients. Differentiating the various forms of post-transplant colitis is challenging, since most have similar clinical and histological features. This study evaluated the incidence of post-transplant gastrointestinal complications during screening colonoscopy. Kidney transplant recipients undergoing a colonoscopy for any reasons in the period 2014-2018 were included. Among the 134 patients completing the colonoscopy, 74 patients (56%) had an abnormal finding: an adenoma was found in 25 patients (18.6%), while 19 patients (14.1%) had colitis. Mycophenolic acid/related colitis was the most common colitis (6%), while 7 patients (5.2%) developed a

Topics: Adenoma; Age Distribution; Aged; Anemia; Colitis; Colonoscopy; Colorectal Neoplasms; Diarrhea; Diverticulosis, Colonic; Early Detection of Cancer; Female; Gastrointestinal Hemorrhage; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Inflammatory Bowel Diseases; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Tacrolimus; Time Factors

There is a lack of consensus regarding the treatment of inflammatory bowel disease (IBD) after liver transplantation (LT) forprimary sclerosing cholangitis (PSC).. To investigate the safety and effectiveness of anti-TNF therapy in patients with IBD after a LT for PSC.. We reviewed the medical files of all of the IBD patients who underwent a LT for PSC and who were treated with anti-TNF therapy at 23 French liver transplantation centers between 1989 and 2012.. Eighteen patients (12 with ulcerative colitis and 6 who had Crohn's disease) were recruited at 9 LT centers. All of these patients received infliximab or adalimumab following their LT, and the median duration of their anti-TNF treatment was 10.4 months. The most frequent concomitant immunosuppressive treatment comprised a combination of tacrolimus and corticosteroids. Following anti-TNF therapy induction, a clinical response was seen in 16/18 patients (89%) and clinical remission in 10 (56%). At the end of the anti-TNF treatment or at the last follow-up examination (the median follow-up was 20.9 months), a clinical response was achieved in 12 patients (67%) and clinical remission in 7 (39%). A significant endoscopic improvement was observed in 9 out of 14 patients and a complete mucosal healing in 3 out of 14 patients (21%). Six patients experienced a severe infection. These were due to cholangitis, cytomegalovirus (CMV) infection, Clostridium difficile, cryptosporidiosis, or Enterococcus faecalis. Three patients developed colorectal cancer after LT, and two patients died during the follow-up period.. Anti-TNF therapy proved to be effective for treating IBD after LT for PSC. However, as 17% of the patients developed colorectal cancer during the follow-up, colonoscopic annual surveillance is recommended after LT, as specified in the current guidelines.

Topics: Adalimumab; Adolescent; Adrenal Cortex Hormones; Adult; Cholangitis, Sclerosing; Colonoscopy; Colorectal Neoplasms; Disease Progression; Drug Therapy, Combination; Female; France; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Infliximab; Liver Transplantation; Male; Middle Aged; Remission Induction; Retrospective Studies; Tacrolimus; Tumor Necrosis Factor-alpha; Young Adult

Cancer stem cells (CSC) are capable of reconstructing cancer tissues, are involved in both recurrence and metastasis, and contribute to therapeutic resistance. Therefore, elucidating the molecular mechanism in CSCs is important to successfully treat unresectable cancers. Previously, we observed that colon cancer stem-like cells can be induced from human colon cancer cell lines by retrovirally introducing OCT3/4, SOX2, and KLF4, and we have designated such cells as induced cancer stem cells (iCSC). In the current study, we used iCSCs to evaluate the molecular mechanism of colon CSCs and developed new methods to control them. The spheres that were derived

Topics: Cell Line, Tumor; Colorectal Neoplasms; Gene Expression Regulation, Neoplastic; Glycogen Synthase Kinase 3; Human Umbilical Vein Endothelial Cells; Humans; Kruppel-Like Factor 4; Neoplastic Stem Cells; NFATC Transcription Factors; Pyridines; Pyrimidines; Spheroids, Cellular; Tacrolimus; Tumor Cells, Cultured; Valproic Acid

Colorectal cancer stem cells (CSCs) drive tumor growth and are suggested to initiate distant metastases. Moreover, colon CSCs are reportedly more resistant to conventional chemotherapy, which is in part due to upregulation of anti-apoptotic Bcl-2 family members. To determine whether we could circumvent this apoptotic blockade, we made use of an inducible active caspase-9 (iCasp9) construct to target CSCs. Dimerization of iCasp9 with AP20187 in HCT116 colorectal cancer cells resulted in massive and rapid induction of apoptosis. In contrast to fluorouracil (5-FU)-induced apoptosis, iCasp9-induced apoptosis was independent of the mitochondrial pathway as evidenced by Bax/Bak double deficient HCT116 cells. Dimerizer treatment of colon CSCs transduced with iCasp9 (CSC-iCasp9) also rapidly induced high levels of apoptosis, while these cells were unresponsive to 5-FU in vitro. More importantly, injection of the dimerizer into mice that developed a colon CSC-iCasp9-induced tumor resulted in a strong decrease in tumor size, an increase in tumor cell apoptosis and a clear loss of CD133(+) CSCs. Taken together, our data indicate that dimerization of iCasp9 circumvents the apoptosis block in CSCs, which results in effective tumor regression in vivo.

Topics: Animals; Antimetabolites, Antineoplastic; Apoptosis; Apoptosis Regulatory Proteins; Caspase 3; Caspase 9; Cell Proliferation; Colorectal Neoplasms; Enzyme Activation; Fluorouracil; Gene Expression Regulation; HCT116 Cells; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular Targeted Therapy; Neoplastic Stem Cells; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerases; Protein Multimerization; Recombinant Proteins; Spheroids, Cellular; Tacrolimus; Tumor Burden; Xenograft Model Antitumor Assays

The underlying mechanism regulating the expression of the cancer stem cell/tumor-initiating cell marker CD133/prominin-1 in cancer cells remains largely unclear, although knowledge of this mechanism would likely provide important biological information regarding cancer stem cells. Here, we found that the inhibition of mTOR signaling up-regulated CD133 expression at both the mRNA and protein levels in a CD133-overexpressing cancer cell line. This effect was canceled by a rapamycin-competitor, tacrolimus, and was not modified by conventional cytotoxic drugs. We hypothesized that hypoxia-inducible factor-1 alpha (HIF-1 alpha), a downstream molecule in the mTOR signaling pathway, might regulate CD133 expression; we therefore investigated the relation between CD133 and HIF-1 alpha. Hypoxic conditions up-regulated HIF-1 alpha expression and inversely down-regulated CD133 expression at both the mRNA and protein levels. Similarly, the HIF-1 alpha activator deferoxamine mesylate dose-dependently down-regulated CD133 expression, consistent with the effects of hypoxic conditions. Finally, the correlations between CD133 and the expressions of HIF-1 alpha and HIF-1 beta were examined using clinical gastric cancer samples. A strong inverse correlation (r = -0.68) was observed between CD133 and HIF-1 alpha, but not between CD133 and HIF-1 beta. In conclusion, these results indicate that HIF-1 alpha down-regulates CD133 expression and suggest that mTOR signaling is involved in the expression of CD133 in cancer cells. Our findings provide a novel insight into the regulatory mechanisms of CD133 expression via mTOR signaling and HIF-1 alpha in cancer cells and might lead to insights into the involvement of the mTOR signal and oxygen-sensitive intracellular pathways in the maintenance of stemness in cancer stem cells.

Topics: AC133 Antigen; Antigens, CD; Cell Line, Tumor; Chromones; Colorectal Neoplasms; Down-Regulation; Glycoproteins; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Lung Neoplasms; Morpholines; Neoplasms; Peptides; Protein Kinases; RNA, Messenger; Signal Transduction; Sirolimus; Stomach Neoplasms; Tacrolimus; TOR Serine-Threonine Kinases; Transcription, Genetic; Up-Regulation