Lymphatic complications are common side effects of mammalian target of rapamycin (mTOR) inhibitor-based immunosuppression in kidney transplantation. Therefore, we investigated whether the mTOR inhibitor rapamycin, besides its known antihemangiogenic effect, also impedes regenerative lymphangiogenesis. In a murine skin flap model, rapamycin impaired recovery of lymphatic flow across surgical incisions resulting in prolonged wound edema in these animals. Importantly, the antilymphangiogenic effect of rapamycin was not related to a general inhibition of wound healing as demonstrated an in vivo Matrigeltrade mark lymphangiogenesis assay and a model of lymphangioma. Rapamycin concentrations as low as 1 ng/ml potently inhibited vascular endothelial growth factor (VEGF)-C driven proliferation and migration, respectively, of isolated human lymphatic endothelial cells (LECs) in vitro. Mechanistically, mTOR inhibition impairs downstream signaling of VEGF-A as well as VEGF-C via mTOR to the p70S6 kinase in LECs. In conclusion, we provide extensive experimental evidence for an antilymphangiogenic activity of mTOR inhibition suggesting that the early use of mTOR inhibitor following tissue injury should be avoided. Conversely, the antilymphangiogenic properties of rapamycin and its derivates may provide therapeutic value for the prevention and treatment of malignancies, respectively.

The active homing of MSCs into primary pancreatic tumor stroma and activation of the CCL5 promoter was verified using eGFP- and RFP-reporter genes. In the presence of ganciclovir, HSV-Tk transfected MSCs led to a significant reduction of primary pancreatic tumor growth and incidence of metastases.

Background Surgery is the main modality of cure for solid cancers and was prioritised to continue during COVID-19 outbreaks. This study aimed to identify immediate areas for system strengthening by comparing the delivery of elective cancer surgery during the COVID-19 pandemic in periods of lockdown versus light restriction. Methods This international, prospective, cohort study enrolled 20 006 adult (≥18 years) patients from 466 hospitals in 61 countries with 15 cancer types, who had a decision for curative surgery during the COVID-19 pandemic and were followed up until the point of surgery or cessation of follow-up (Aug 31, 2020). Average national Oxford COVID-19 Stringency Index scores were calculated to define the government response to COVID-19 for each patient for the period they awaited surgery, and classified into light restrictions (index <20), moderate lockdowns (20–60), and full lockdowns (>60). The primary outcome was the non-operation rate (defined as the proportion of patients who did not undergo planned surgery). Cox proportional-hazards regression models were used to explore the associations between lockdowns and non-operation. Intervals from diagnosis to surgery were compared across COVID-19 government response index groups. This study was registered at ClinicalTrials.gov , NCT04384926 . Findings Of eligible patients awaiting surgery, 2003 (10·0%) of 20 006 did not receive surgery after a median follow-up of 23 weeks (IQR 16–30), all of whom had a COVID-19-related reason given for non-operation. Light restrictions were associated with a 0·6% non-operation rate (26 of 4521), moderate lockdowns with a 5·5% rate (201 of 3646; adjusted hazard ratio [HR] 0·81, 95% CI 0·77–0·84; p<0·0001), and full lockdowns with a 15·0% rate (1775 of 11 827; HR 0·51, 0·50–0·53; p<0·0001). In sensitivity analyses, including adjustment for SARS-CoV-2 case notification rates, moderate lockdowns (HR 0·84, 95% CI 0·80–0·88; p<0·001), and full lockdowns (0·57, 0·54–0·60; p<0·001), remained independently associated with non-operation. Surgery beyond 12 weeks from diagnosis in patients without neoadjuvant therapy increased during lockdowns (374 [9·1%] of 4521 in light restrictions, 317 [10·4%] of 3646 in moderate lockdowns, 2001 [23·8%] of 11 827 in full lockdowns), although there were no differences in resectability rates observed with longer delays. Interpretation Cancer surgery systems worldwide were fragile to lockdowns, with one in seven patients who were in regions with full lockdowns not undergoing planned surgery and experiencing longer preoperative delays. Although short-term oncological outcomes were not compromised in those selected for surgery, delays and non-operations might lead to long-term reductions in survival. During current and future periods of societal restriction, the resilience of elective surgery systems requires strengthening, which might include...

Background-The importance and therapeutic value of stem cells in lymphangiogenesis are poorly understood. We evaluated the potential of human and murine mesenchymal stem cells (MSCs) to acquire a lymphatic phenotype in vitro and to enhance lymphatic regeneration in vivo. Methods and Results-We assessed the lymphendothelial differentiation of human and murine MSCs after induction with supernatant derived from human dermal microvascular endothelial cells, isolated lymphatic endothelial cells, and purified vascular endothelial growth factor (VEGF)-C in vitro. We used human or murine progenitor MSC lines and then characterized the lymphatic phenotype by morphology, migratory capacity, and the expression of lymphatic markers such as Prox-1, podoplanin, Lyve-1, VEGF receptor-2, and VEGF receptor-3. Using a murine lymphatic edema model, we assessed the potential of these cells to form a functional lymphatic vasculature in vivo after injection of syngeneic MSCs. Incubation with supernatant from lymphatic endothelial cells induced an endothelium-like morphology and the expression of lymphendothelial markers in both human and murine MSCs in vitro. MSCs showed migratory activity along a VEGF-C gradient, which was enhanced by VEGF-C conditioning. In vivo, the local application of MSCs resulted in a significant decrease in edema formation (Ϫ20.1%; PϽ0.01 versus untreated tails) after 3 weekly cell injections and restored the drainage of intradermally injected methylene blue after 7 weekly injections. Conclusions-MSCs

Exogenously added MSCs are recruited to growing HCC xenografts with concomitant activation of the CCL5 or Tie2 promoters within the MSCs. Stem cell-mediated introduction of suicide genes into the tumor followed by prodrug administration was effective for treatment of experimental HCC and thus may help fill the existing gap in bridging therapies for patients suffering from advanced HCCs.