Pancreatic adenocarcinoma is currently the fourth leading cause for cancer-related mortality. Stem cells have been implicated in pancreatic tumor growth, but the specific role of these cancer stem cells in tumor biology, including metastasis, is still uncertain. We found that human pancreatic cancer tissue contains cancer stem cells defined by CD133 expression that are exclusively tumorigenic and highly resistant to standard chemotherapy. In the invasive front of pancreatic tumors, a distinct subpopulation of CD133(+) CXCR4(+) cancer stem cells was identified that determines the metastatic phenotype of the individual tumor. Depletion of the cancer stem cell pool for these migrating cancer stem cells virtually abrogated the metastatic phenotype of pancreatic tumors without affecting their tumorigenic potential. In conclusion, we demonstrate that a subpopulation of migrating CD133(+) CXCR4(+) cancer stem cells is essential for tumor metastasis. Strategies aimed at modulating the SDF-1/CXCR4 axis may have important clinical applications to inhibit metastasis of cancer stem cells.

Conventional immunosuppressive drugs have been used effectively to prevent immunologic rejection in organ transplantation. Individuals taking these drugs are at risk, however, for the development and recurrence of cancer. In the present study we show that the new immunosuppressive drug rapamycin (RAPA) may reduce the risk of cancer development while simultaneously providing effective immunosuppression. Experimentally, RAPA inhibited metastatic tumor growth and angiogenesis in in vivo mouse models. In addition, normal immunosuppressive doses of RAPA effectively controlled the growth of established tumors. In contrast, the most widely recognized immunosuppressive drug, cyclosporine, promoted tumor growth. From a mechanistic perspective, RAPA showed antiangiogenic activities linked to a decrease in production of vascular endothelial growth factor (VEGF) and to a markedly inhibited response of vascular endothelial cells to stimulation by VEGF. Thus, the use of RAPA, instead of cyclosporine, may reduce the chance of recurrent or de novo cancer in high-risk transplant patients.

Cross-sectional imaging did not reliably stage patients with HCC for LTx. A protocol using a biopsy to exclude poorly differentiated tumors and aggressive bridging therapy achieved excellent survival rates with LTx for otherwise incurable advanced HCC, irrespective of tumor size and number.

Development of cancer is a feared, and increasingly apparent, complication of long-term immunosuppressive therapy in transplant recipients. In addition to the need to reduce cancer occurrence in these patients, therapeutic protocols are lacking to simultaneously attack the malignancy and protect the allograft when neoplasms do occur. In this overview, we present the current literature regarding the pro- and anti-neoplastic effects of immunosuppressive agents on cancer growth and development. Recent experimental findings are paving the way for new therapeutic strategies aimed at both protecting an allograft from immunologic rejection and addressing the problem of cancer in this high-risk population.

Objective To examine risk of malignancy and death in patients with kidney transplant who receive the immunosuppressive drug sirolimus.Design Systematic review and meta-analysis of individual patient data.Data sources Medline, Embase, and the Cochrane Central Register of Controlled Trials from inception to March 2013.Eligibility Randomized controlled trials comparing immunosuppressive regimens with and without sirolimus in recipients of kidney or combined pancreatic and renal transplant for which the author was willing to provide individual patient level data. Two reviewers independently screened titles/abstracts and full text reports of potentially eligible trials to identify studies for inclusion. All eligible trials reported data on malignancy or survival. Results The search yielded 2365 unique citations. Patient level data were available from 5876 patients from 21 randomized trials. Sirolimus was associated with a 40% reduction in the risk of malignancy (adjusted hazard ratio 0.60, 95% confidence interval 0.39 to 0.93) and a 56% reduction in the risk of non-melanoma skin cancer (0.44, 0.30 to 0.63) compared with controls. The most pronounced effect was seen in patients who converted to sirolimus from an established immunosuppressive regimen, resulting in a reduction in risk of malignancy (0.34, 0.28 to 0.41), non-melanoma skin cancer (0.32, 0.24 to 0.42), and other cancers (0.52, 0.38 to 0.69). Sirolimus was associated with an increased risk of death (1.43, 1.21 to 1.71) compared with controls.Conclusions Sirolimus was associated with a reduction in the risk of malignancy and non-melanoma skin cancer in transplant recipients. The benefit was most pronounced in patients who converted from an established immunosuppressive regimen to sirolimus. Given the risk of mortality, however, the use of this drug does not seem warranted for most patients with kidney transplant. Further research is needed to determine if different populations, such as those at high risk of cancer, might benefit from sirolimus.

Objective: The aim of this study was to evaluate peak serum alanine aminotransferase (ALT) and postoperative clinical outcomes after hypothermic oxygenated machine perfusion (HOPE) versus static cold storage (SCS) in extended criteria donation (ECD) liver transplantation (LT) from donation after brain death (DBD). Background: HOPE might improve outcomes in LT, particularly in high-risk settings such as ECD organs after DBD, but this hypothesis has not yet been tested in a randomized controlled clinical trial (RCT). Methods: Between September 2017 and September 2020, 46 patients undergoing ECD-DBD LT from four centers were randomly assigned to HOPE (n = 23) or SCS (n = 23). Peak-ALT levels within 7 days following LT constituted the primary endpoint. Secondary endpoints included incidence of postoperative complications [Clavien-Dindo classification (CD), Comprehensive Complication Index (CCI)], length of intensive care- (ICU) and hospital-stay, and incidence of early allograft dysfunction (EAD). Results: Demographics were equally distributed between both groups [donor age: 72 (IQR: 59–78) years, recipient age: 62 (IQR: 55–65) years, labMELD: 15 (IQR: 9–25), 38 male and 8 female recipients]. HOPE resulted in a 47% decrease in serum peak ALT [418 (IQR: 221–828) vs 796 (IQR: 477–1195) IU/L, P = 0.030], a significant reduction in 90-day complications [44% vs 74% CD grade ≥3, P = 0.036; 32 (IQR: 12–56) vs 52 (IQR: 35–98) CCI, P = 0.021], and shorter ICU- and hospital-stays [5 (IQR: 4–8) vs 8 (IQR: 5–18) days, P = 0.045; 20 (IQR: 16–27) vs 36 (IQR: 23–62) days, P = 0.002] compared to SCS. A trend toward reduced EAD was observed for HOPE (17% vs 35%; P = 0.314). Conclusion: This multicenter RCT demonstrates that HOPE, in comparison to SCS, significantly reduces early allograft injury and improves post-transplant outcomes in ECD-DBD liver transplantation.

After decades of successful organ transplantation clinicians continue to be troubled by the increasing incidence of cancers under maintenance immunosuppression. In this study, we examined rates of malignancies in 2419 renal transplant recipients transplanted in our institution between 1978 and 2005. In renal transplant recipients the cumulative incidence of cancer after 25 years was 49.3% for all tumors and 39.7% excluding non-melanoma skin cancers, compared with 21% for a normal sex- and age-matched population. The most frequent tumors observed were non-melanoma skin cancers (20.5%), kidney cancers (12.0%), and cancers of the pharynx, larynx, or oral cavity (8.2%). The general increase of cancer risk was 4.3-fold. Independent risk factors for the development of a tumor were male gender, older recipient age, the presence of preformed antibodies before transplantation, and the time on immunosuppression. Interestingly, the use of IL-2-receptor antagonists significantly reduced the tumor risk of transplant recipients. The tumor risk between immunosuppressive drugs typically used for maintenance immunosuppression was not significantly different. However, mammalian target of rapamycin (mTOR) inhibitor-based immunosuppressive protocols showed a clear tendency for lower malignancy rates. De novo malignancies following renal transplantation represent a serious problem endangering the prognosis of otherwise successfully transplanted patients. Future studies will have to address whether optimized immunosuppressive regimens including mTOR-inhibitors are capable of reducing the incidence or preventing the development of posttransplant malignancies.

Early conversion to a calcineurin inhibitor-free regimen with SRL in combination with mycophenolate mofetil may be a useful strategy to improve renal function. The identification of appropriate candidates and safe management of SRL-related adverse events will be a key to avoid the high rate of dropouts, which currently limit the broad applicability of this protocol.