Regenerative therapy with mesenchymal stem cells at the site of malignant primary bone tumour resection: what are the risks of early or late local recurrence?

Purpose

There is concern that regenerative cell-based therapies at the site of malignant primary bone tumours could result in increased risk of local tumour recurrence. We therefore investigated the long-term risks for site-specific recurrences in patients who had received an autologous bone marrow derived mesenchymal stem cell suspension to improve healing at the host-to-allograft bone junction of the reconstruction after bone tumour resection.

Methods

A total of 92 patients were treated from 1993 to 2003 with bone marrow-derived mesenchymal stem cells after bone tumour resection. Patients were monitored for cancer incidence from the date of first operation (1993) until death, or until 31 December 2013. The mean follow-up time was 15.4 years (range ten to 20 years). The average number of MSCs returned to the patient was 234,000 MSCs?±?215,000. The primary outcome was to evaluate the risk of tumorigenesis recurrence at the cell therapy treatment sites with radiographs and/or MRIs. The relative risk of cancer recurrence was expressed as the ratio of observed and expected number of cases according to three different control populations.

Results

Thirteen recurrences were found at the treatment sites among the 92 patients. The expected number of recurrences based on incidence in the three cohort populations was between 15 and 20 for the same cancer, age and sex distribution. The standardized incidence ratio (equal to observed cancers divided by expected cancers) for the entire follow-up period and for all recurrences was between 0.65 and 0.86 (95 % CI 0.60–1.20).

Conclusion

This study found no increased cancer local recurrence risk in patients after application of autologous cell-based therapy using bone marrow-derived mesenchymal stem cells at the treatment site after an average follow-up period of 15.4 years, ranging from ten to 20 years.     

Supercharging irradiated allografts with mesenchymal stem cells improves acetabular bone grafting in revision arthroplasty

Purpose

The procedure of bone allografting associated with a reinforcement device is widely used for acetabulum revision. However in absence of biologic fixation of the allograft, failure of the reconstruction may occur. We made the hypothesis that it would be possible to load these grafts with bone marrow derived mesenchymal stem cells (MSC) to rescue the osteogenic capacity of an allogenic dead bone and therefore enhance incorporation of allografts with the host bone and decrease the number of failures related to the allograft.

Method

We identified 60 patients who had undergone acetabular component revision for aseptic failure of cemented implants associated with massive periacetabular osteolysis and Paprosky type 3A or 3B classification (without pelvic discontinuity) between 1996 and 2001. The study group of 30 patients received MSCs in the allograft and at the host graft junction. The average total number of MSCs received by each patient was 195,000 cells (range 86,000–254,000 cells). The control group of 30 patients had no MSCs in the allograft. Patients were matched for the size of periacetabular osteolysis (Paprosky type 3A or 3B). We compared the evolution of the allografts and evaluated cup migration and revision of the hips as end points at a minimum of 12 years or until failure.

Result

Better radiographic graft union rates and less allograft resorption were observed with allografts loaded with stem cells. Allograft resorption was significantly decreased in the group with allograft loaded with MSCs (1.2 cm² —range 0–2.3 cm²—of resorption on radiographs in the group with MSCs; versus 6 cm², range 2.1–8.5 cm² in the group without MSCs). The rate of mechanical failure was highest (p?=?0.01) among the 30 patients with allograft without stem cells (9/30; 30 %) compared with no failures for patients with allograft loaded with stem cells. Revision of the cup was necessary in nine patients in the control group. No revision was performed in the 30 patients of the study group with MSCs.

Conclusion

For acetabular defect reconstruction, loading the allograft with MSCs has resulted in a lower rate of failure as compared with allograft without MSCs.     

Efficient migration of dendritic cells toward lymph node chemokines and induction of T(H)1 responses require maturation stimulus and apoptotic cell interaction

Dendritic cells (DCs) have the unique ability to initiate primary immune responses, and they can be conditioned for vaccinal purposes to present antigens after the engulfment of apoptotic cells. To recruit the rare antigen-specific naive T cells, DCs require a maturation step and subsequent transport toward lymph node (LN). To date, prostaglandin E2 (PGE2) is the best-characterized compound inducing this LN-directed migration in vitro, but PGE2 may skew the immune responses in a T(H)2 direction. We demonstrate here that on incubation with apoptotic tumor cells and tumor necrosis factor-alpha (TNF-alpha) or lipopolysaccharide (LPS), human monocyte-derived DCs become fully mature and acquire high migratory capacities toward LN-directing chemokines. The migration of TNF-alpha-treated DCs occurs only after cotreatment with apoptotic cells but not with necrotic cells. DC migration requires CD36 expression and incubation with apoptotic cells in the presence of heat-labile serum components. Moreover, on treatment with apoptotic cells and LPS, the migrating DCs are able to recruit naive T cells to generate T(H)1 immune responses. Our results show that the cotreatment of DCs with apoptotic tumor cells and inflammatory signals is promising for the design of an antitumoral DC-based vaccine.     

Variation in the IGF1 gene and growth in foetal life and infancy. The Generation R Study

Objective The objective of this study was to examine whether variants of the IGF1 gene are associated with growth patterns from foetal life until infancy. Study design and measurements This study was embedded in the Generation R Study, a population‐based prospective cohort study of foetal life. Foetal growth (head circumference, abdominal circumference, femur length, estimated foetal weight) was assessed by ultrasound in early, mid‐ and late pregnancy. Growth in infancy was assessed at birth (weight) and at the ages of 6 weeks, 6 months and 14 months (head circumference, length, weight). The IGF1 promoter region genotype was determined in 738 children. Results Eight alleles of the IGF1 promoter region were identified. In total, 43% of the subjects were homozygous for the most common 192‐bp allele (wild‐type), 45% were heterozygous, and 12% were noncarriers of the 192‐bp allele. No differences were found in birthweight between the three groups. However, noncarriers had a lower estimated foetal weight in mid‐pregnancy (P = 0·040), followed by an increased growth rate until 6 months (P < 0·005) in comparison to the 192‐bp homozygotes. A similar difference in growth rate was found for length (P < 0·001). Conclusions Variants of the IGF1 promoter region are not associated with birthweight. However, noncarriers of the 192‐bp allele tend to have a smaller foetal size, followed by an increased growth rate from mid‐pregnancy to early infancy. Studies in larger cohorts are necessary to replicate our findings and to examine whether these effects persist throughout childhood.     

Non-hodgkin's lymphoma of the heart in patients infected with human immunodeficiency virus

A case of HIV-associated cardiac non-Hodgkin's lymphoma (NHL) is described, and the epidemiologic and clinicopathologic features of 21 cases previously reported in the literature are analyzed. All patients were homosexual males, and the cardiac NHL was the first acquired immune deficiency syndrome-defining condition in the majority. Patients were referred with nonspecific clinical findings including dyspnea and tachycardia, but rapid progression of cardiac dysfunction was frequent after symptoms appeared. Echocardiography constitutes the most useful noninvasive procedure in the diagnosis of cardiac NHL. Most of the patients had disseminated disease at initial presentation; pathologically, the lymphomas were of B lymphocyte origin and of high-grade subtypes. Prognosis of HIV-associated cardiac NHL is generally poor, although clinical remission has been observed with combination chemotherapy. Cardiac lymphomas in HIV-associated patients are typically high-grade and often disseminate early. Although the prognosis is poor, patients in whom dissemination has not occurred could have longer survival under systemic chemotherapy.