Defibrotide for Sinusoidal Obstruction Syndrome/Veno-Occlusive Disease Prophylaxis in High-Risk Adult Patients: A Single-Center Experience Study

Sinusoidal obstruction syndrome (SOS), also known as hepatic veno-occlusive disease (VOD), is a serious complication after hematopoietic stem cell transplantation (HSCT). SOS/VOD usually occurs within 3 weeks of HSCT, but the 2016 European Society for Blood and Marrow Transplantation diagnosis criteria have been revised to include late forms. Prophylactic use of defibrotide is recommended in the pediatric setting, but its value remains uncertain in the adult population. We report here a single-center series of 63 adult patients considered at high risk for SOS/VOD who received defibrotide prophylaxis in combination with ursodeoxycholic acid between May 2012 and August 2016. The median duration of defibrotide therapy was 23 days. Bleeding occurred in 14 patients (21.5%). Defibrotide prophylaxis was discontinued in 7 patients (10.8%): 4 cases (6.3%) due to bleeding and 3 cases (4.6%) because of the need for antithrombotic therapy. Overall, SOS/VOD occurred in 4 cases (6.3%) within 21 days after HSCT (days 13 and 14) in 2 cases and late-onset SOS/VOD (days 57 and 58) in the other 2 cases. SOS/VOD was moderate in 1 case, very severe in 3 cases, with 2 deaths related to SOS/VOD. Cumulative incidence of grades II to IV acute graft-versus-host disease and transplant-associated thrombotic microangiopathy were 22.2% and 3.2%, respectively. With a median follow-up of 31 months (range, 10.7 to 60.3), the rates of 2-year overall survival, progression-free survival, incidence of relapse, and nonrelapse mortality were 56.5%, 49%, 28.7%, and 22.3%, respectively. In our experience defibrotide prophylaxis is associated with a low incidence of SOS/VOD after allogeneic HSCT in a high-risk adult population with an acceptable safety profile.     

The use of external mesh reinforcement to reduce intimal hyperplasia and preserve the structure of human saphenous veins

The saphenous vein is the conduit of choice in bypass graft procedures. Haemodynamic factors play a major role in the development of intimal hyperplasia (IH), and subsequent bypass failure. To evaluate the potential protective effect of external reinforcement on such a failure, we developed an ex vivo model for the perfusion of segments of human saphenous veins under arterial shear stress. In veins submitted to pulsatile high pressure (mean pressure at 100 mmHg) for 3 or 7 days, the use of an external macroporous polyester mesh 1) prevented the dilatation of the vessel, 2) decreased the development of IH, 3) reduced the apoptosis of smooth muscle cells, and the subsequent fibrosis of the media layer, 4) prevented the remodelling of extracellular matrix through the up-regulation of matrix metalloproteinases (MMP-2, MMP-9) and plasminogen activator type I. The data show that, in an experimental ex vivo setting, an external scaffold decreases IH and maintains the integrity of veins exposed to arterial pressure, via increase in shear stress and decrease wall tension, that likely contribute to trigger selective molecular and cellular changes.     

Outcome of common iliac arteries after aortoaortic graft placement during elective repair of infrarenal abdominal aortic aneurysms

HYPOTHESIS: Supplemental oxygen can reduce intimal hyperplasia (IH) after stent deployment in a rabbit model. BACKGROUND: Endovascular stent placement is technically feasible, but long-term durability in vessels outside the aortoiliac system is compromised with postinterventional IH, which causes restenosis and failure of the arterial conduit. METHODS: Groups (n = 4 to 6) of female New Zealand white rabbits underwent placement of a 3-mm intraaortic stent with laparotomy and were placed in either normoxic (21% inspired oxygen concentration) or supplemental-oxygen (40% inspired oxygen concentration) environments for 0, 7, 14, and 28 days. The transarterial wall oxygen gradient was measured at 0, 7, and 28 days with an oxygen microelectrode. 5-Bromo-2'deoxyuridine (BrdU) was injected into the peritoneum before death to assess cellular proliferation. Aortic specimens were harvested en bloc and sectioned for analysis of cellular proliferation and intimal thickness. RESULTS: Intraaortic stent placement significantly decreased the transarterial wall oxygen gradient in the outer 70% of the vessel wall and was easily reversed at 7, 14, and 28 days with application of supplemental oxygen. Cellular proliferation was significantly decreased at 14 days (0.5% +/- 0.001% versus 2.3% +/- 0.002%; P <.001) and 28 days (0.4% +/- 0.001% versus 1.0% +/- 0.001%; P <.025) as measured with count of nuclei staining for 5-Bromo-2'deoxyuridine in the intima and media. Intimal thickness was significantly decreased at 28 days in oxygen-supplemented rabbits (intimal area/medial area = 0.50 +/- 0.07) as compared with controls (intimal area/medial area = 0.89 +/- 0.11; P <.025). CONCLUSION: This study shows the ability of supplemental oxygen to reverse arterial wall hypoxia, decrease cellular proliferation, and control IH at the deployment site of an intraarterial stent in a rabbit model. Forty-percent supplemental oxygen suppresses IH by 44% at 28 days as compared with normoxic control values. Cellular proliferation is reduced four-fold at 14 days and two-fold at 28 days in oxygen-supplemented rabbits as compared with control media after deployment. The clinical implications of these findings are significant, especially as the role of endovascular interventions continues to expand.     

Strategies for the prevention of hip fracture

Hip fractures are associated with 10% to 20% excess mortality in the first year and cause functional disability in most survivors. An estimated 17% of white women in the United States will sustain a hip fracture after the age of 50 years. Despite the availability of evidence-based guidelines for hip fracture prevention, routine screening and preventive measures have not been incorporated into standard primary care practice. Many physicians lack adequate knowledge to initiate bone mineral density testing and treatment with preventive medications to decrease the incidence of osteoporosis and fractures. Furthermore, patients are less likely to request information about bone health than about diseases for which systematic screening and prevention protocols have been established. This review describes preventive measures to decrease hip fracture in postmenopausal women, including screening by bone mineral density testing, risk factor assessment, and chemoprevention. Existing guidelines are summarized, and dilemmas regarding their implementation are discussed.     

Reversible skeletal abnormalities in gamma-glutamyl transpeptidase-deficient mice

Gamma-glutamyl transpeptidase (GGT) is a widely distributed ectopeptidase responsible for the degradation of glutathione in the gamma-glutamyl cycle. This cycle is implicated in the metabolism of cysteine, and absence of GGT causes a severe intracellular decrease in this amino acid. GGT-deficient (GGT-/-) mice have multiple metabolic abnormalities and are dwarf. We show here that this latter phenotype is due to a decreased of the growth plate cartilage total height resulting from a proliferative defect of chondrocytes. In addition, analysis of vertebrae and tibiae of GGT-/- mice revealed a severe osteopenia. Histomorphometric studies showed that this low bone mass phenotype results from an increased osteoclast number and activity as well as from a marked decrease in osteoblast activity. Interestingly, neither osteoblasts, osteoclasts, nor chondrocytes express GGT, suggesting that the observed defects are secondary to other abnormalities. N-acetylcysteine supplementation has been shown to reverse the metabolic abnormalities of the GGT-/- mice and in particular to restore the level of IGF-1 and sex steroids in these mice. Consistent with these previous observations, N-acetylcysteine treatment of GGT-/- mice ameliorates their skeletal abnormalities by normalizing chondrocytes proliferation and osteoblastic function. In contrast, resorbtion parameters are only partially normalized in GGT-/- N-acetylcysteine-treated mice, suggesting that GGT regulates osteoclast biology at least partly independently of these hormones. These results establish the importance of cysteine metabolism for the regulation of bone remodeling and longitudinal growth.     

Radiation dose,chemotherapy and risk of lung cancer after breast cancer treatment

It is of particular concern to evaluate the risk of lung cancer occurrence after breast cancer treatment as women with breast cancer quite often undergo radiation therapy as part of their initial treatment and their life expectancy remains long. From a roster of 7711 women initially treated for breast cancer between 1954 and 1984, a cohort-study was performed among 4171 1-year survivors followed during the period 1975-1995. The relationship between the radiation dose received by the lung and the risk of lung cancer was then evaluated in a nested case-control study of 11 breast-cancer patients who developed lung cancer and 22 controls matched for age at diagnosis of breast cancer, period of initial treatment and length of follow-up. Among the 4171 women, six developed lung cancer during the entire follow-up as compared to 5.4 cases expected (SIR = 1.1, 95% CI: 0.4-2.3). When considering only the women initially treated by radiotherapy with or without adjunction of chemotherapy and excluding the 10 first years of follow-up, the SIR was significantly increased (SIR = 3.2, 95%CI: 1.0-7.4). In the case-control study, nine of the 11 lung cancers occurred in the ipsilateral lung and two in the trachea. The overall odds ratio (OR) of lung cancer associated with initial radiotherapy was 1.4 (95% CI: 0.2-11.1) and an excess in the OR of 7% (90% CI: ? to 41%, p = 0.10) per gray delivered to the site of lung cancer was evidenced. Our results agree with previous studies in favor of an increased risk of lung cancer after radiation therapy for breast cancer.     

Increased risk of second cancers following breast cancer: Role of the initial treatment

Objectives and methods.The risk of second primary malignancies (SMN) was studied in a cohort of 4,416 one-year survivors of a breast cancer. The role of the menopausal status and of the initial treatment modalities (surgery, radiotherapy, and chemotherapy) was investigated. Results.Excluding second primary breast cancer and non-melanoma skin cancer, a total of 193 (4.4%) patients developed a SMN between 1973 and 1992, compared with 136 expected (Standardised Incidence Ratio, SIR=1.4, 95% CI (1.2–1.6)). No trend towards either an increase or a decrease was noted in the SIR with time after treatment (p=0.2). The greatest increase in the relative risk concerned soft tissue cancers (SIR=13.0, 95% CI: 6.8–22.3), followed by leukaemia (SIR=3.1, 95% CI: 1.7–5.0), melanoma (SIR = 2.7, 95% CI: 1.4–4.8), kidney (SIR=2.5, 95% CI: 1.2–4.5), ovary (SIR=2.0, 95% CI: 1.2–3.1) and uterine tumours (SIR=1.9, 95% CI: 1.4–2.5). The SIR was 3.0 (95% CI 1.8–4.7) in women under 40 at the time of the breast cancer, 1.9 (95% CI : 1.4 – 2.4) in those aged 40–49 and 1.2 (95% CI 1.0–1.4) in those aged 50 or more. In the 2,514 women who had received radiotherapy as initial treatment without chemotherapy, the SIR for all SMN was 1.6 (95% CI: 1.1–2.3) fold higher than in those who had not received radiotherapy as initial treatment. Conclusion.In conclusion, this study confirms the increased risk of second malignancies in women treated for a breast cancer, and particularly in those who were younger at the time of treatment for breast cancer. Our results also suggest that radiotherapy may play a role in the onset of these second lesions.