The two-faces of NK cells in oncolytic virotherapy.

Oncolytic viruses (OVs) are immunotherapeutics capable of directly killing cancer cells and with potent immunostimulatory properties. OVs exert their antitumor effect, at least partially, by activating the antitumor immune response, of which NK cells are an important component. However, if on the one hand increasing evidence revealed that NK cells are important mediators of oncolytic virotherapy, on the other hand, NK cells have evolved to fight viral infections, and therefore they can have a detrimental effect for the efficacy of OVs. In this review, we will discuss the dichotomy between the antitumor and antiviral functions of NK cells related to oncolytic virotherapy. We will also review NK cell-based and OV-based therapies, engineered OVs aimed at enhancing immune stimulation, and combination therapies involving OVs and NK cells currently used in cancer immunotherapy.

TLR9 re-expression in cancer cells extends the S-phase and stabilizes p16(INK4a) protein expression.

Toll-like receptor 9 (TLR9) recognizes bacterial, viral or cell damage-associated DNA, which initiates innate immune responses. We have previously shown that TLR9 expression is downregulated in several viral induced cancers including HPV16-induced cervical neoplasia. Findings supported that downregulation of TLR9 expression is involved in loss of anti-viral innate immunity allowing an efficient viral replication. Here we investigated the role of TLR9 in altering the growth of transformed epithelial cells. Re-introducing TLR9 under the control of an exogenous promoter in cervical or head and neck cancer patient-derived cells reduced cell proliferation, colony formation and prevented independent growth of cells under soft agar. Neither TLR3, 7, nor the TLR adapter protein MyD88 expression had any effect on cell proliferation, indicating that TLR9 has a unique role in controlling cell growth. The reduction of cell growth was not due to apoptosis or necrosis, yet we observed that cells expressing TLR9 were slower in entering the S-phase of the cell cycle. Microarray-based gene expression profiling analysis highlighted a strong interferon (IFN) signature in TLR9-expressing head and neck cancer cells, with an increase in IFN-type I and IL-29 expression (IFN-type III), yet neither IFN-type I nor IL-29 production was responsible for the block in cell growth. We observed that the protein half-life of p16(INK4a) was increased in TLR9-expressing cells. Taken together, these data show for the first time that TLR9 affects the cell cycle by regulating p16(INK4a) post-translational modifications and highlights the role of TLR9 in the events that lead to carcinogenesis.

[Lymphedema of the lower limbs: CT staging]. / Lymphoedème des membres inférieurs: apport du scanner.

Routinely performed, CT is useful and reliable for staging lower limb lymphedema. We describe methods we utilized. We found in frequency order: skin thickening, subcutaneous tissues area increase in regard the safe limb, perimuscular aponevrosis thickening, fat infiltration: lines parallel to the skin, edematous areas along perimuscular aponevrosis, lines perpendicular to the skin. The lowest fat density is increased on the pathologic side. Subfascial compartment is slightly fattened. We found huge differences between primary and secondary lymphedema for the thigh. Same images may be generated by old or young lymphedema. Rarely useful for positive diagnosis, CT is indispensable for secondary lymphedema staging (initial staging or after a recent increase). It seems us indispensable for any pretherapeutic staging (whole objectively disorders, exact upper limit, infraclinic bilaterality).

[Computerized tomography of 150 cases of lymphedema of the leg]. / Tomodensitométrie de 150 cas de lymphoedèmes des membres inférieurs.

The aim of this work was to evaluate the usefulness of CT imaging to stage lower limb lymphedemas. Between 1992 and 1997, we studied 150 cases of lymphedema, half idiopathic and half secondary. Methods used are described. In decreasing order of frequency, we found: skin thickening, increased subcutaneous tissue surface area compared with the healthy limb, thickening of the perimuscular aponevrosis, fat infiltration: lines parallel to the skin (parallel), edematous areas along the perimuscular aponevrosis, lines perpendicular to the skin (perpendicular). The lowest fat density was increased on the diseased side. The subfascial tissue showed some fat accumulation. These results were compared with findings reported in the literature. There were very major differences between idiopathic lymphedema and secondary lymphedema of the thigh. Similar images were generally generated by new and long-standing lymphedema. Rarely useful for positive diagnosis, CT is indispensable for establishing stage initially or after recent increase and, in our opinion, is essential for pretherapeutic assessment. The CT-scan gives objective evidence of overall disorders, the exact upper limit of the lymphedema, and sometimes reveals infraclinical bilateral involvement.

Transaxial computer tomography of lower extremity lymphedema.

We examined retrospectively 11 patients with isolated unilateral lower limb lymphedema (clinical criteria confirmed by isotope lymphography) using computer tomography. In conjunction with earlier observations, the findings of soft tissue stranding, skin thickening, fat deposition in the epifascial compartment and perimuscular fascial thickening and edema relate to lymph stasis. This noninvasive and relatively simple imaging technique allows analysis of soft tissue changes in leg lymphedema and can be used to evaluate lymphatic insufficiency and its extent as well as document the response to treatment.

[Modern imaging of atheromatous aneurysms of the abdominal aorta]. / Imagerie moderne des anévrismes athéromateux de l'aorte abdominale.

Radiologic imaging advances, during the last decade, deeply modified diagnosis, follow up and preoperative staging of aortic abdominal atheromatous aneurysms. When congenital, infectious and inflammatory aneurysms are rare, atheroma is the most frequent etiology of aneurysms. Ultrasonography is actually very reliable for aneurysms diagnosis. Inexpensive, it is the best exam for early screening in a risk population (arterial hypertension). If ultrasonography is adequate for diagnosis and follow up, two tests are necessary for pretherapeutic staging: arteriography and computed tomography (CT). CT is more accurate than ultrasonography. It is realized just after arteriography without any other contrast media injection. Angiography of aorta and limbs vessels shows the whole arterial system and allows the adaptation of surgical procedure. IRM is more expansive and less accessible, it has not proved it superiority versus CT. It is realized only when CT is unwise (allergy, renal failure). Helicoidal CT will be in the future the best exam to study the whole vascular system and will probably take the place of arteriography and CT.

[Proximal tubal obstruction. Treatment by recanalization and transcervical dilatation]. / Obturations tubaires proximales. Traitement par recanalisation et dilatation transcervicale.

Forty-three fluoroscopic transcervical fallopian tube recanalizations were performed in 30 consecutive patients whose infertility was due to proximal tubal obstruction demonstrated by hysterosalpingography and laparoscopy. All had been recommended tubal microsurgery or in vitro fertilization. Thirty fallopian tubes (81 percent) were successfully recanalized, with balloon dilatation in 20 (57 percent). Six intrauterine and one ectopic pregnancies resulted from successful tuboplasty. Six women who did not conceive underwent follow-up hysterosalpingography 6 months on average after tuboplasty; 2 were found to have tubal reocclusion. There was no difference in our results between patients simply recanalized and those in whom recanalization was combined with balloon dilatation. We conclude that transcervical balloon tuboplasty is an effective treatment of infertility caused by proximal tubal obstruction.

[Peroperative echography in 14 cases of pancreatic insulinoma and gastrinoma]. / Echographie per-opératoire au cours de 14 cas d'insulinomes et de gastrinomes pancréatiques.

Fourteen cases of endocrine tumors (10 insulinomas and 4 gastrinomas) were to studied by intraoperative ultrasonography (IOU). Localization was established by preoperative ultrasonography in 1/14, by CT scan in 1/11, by arteriography in 6/12 and by pancreatic venous sampling in 7/8. Tumor size ranged from 0.5 cm to 2.5 cm. Manual palpation was positive in 10/14. The tumor was accurately and completely localized by IOU in 9/10 insulinomas: the one false negative was probably due to micro-adenoma. The intrapancreatic tumor was localized only in 1/14 gastrinomas. Intraoperative sonography localized lymph nodes in all cases. One distal pancreatectomy was improperly performed because of an accessory spleen. After reviewing 59 other cases in the literature, we propose: a) to abandon venous sampling in insulinomas because of adequate performance of IOU; b) to use IOU as a complementary investigative method along with other preoperative methods of localization in gastrinoma.

[Contribution of microradiography in search of calcifications of valvular bioprostheses]. / Apport de la microradiographie dans la recherche des calcifications des bioprothèses valvulaires.

Implantation of a valvular bioprosthesis is one of the best treatments for valvular disease, particularly in children. Unfortunately, their use is limited as calcifications develop over time. Prevention of these calcifications is still an unresolved problem that is under study by Professor Carpentier and coworkers. These investigators have developed an experimental model in which accelerated development of calcifications occurs: fragments of porcine valves implanted under the skin of rats become calcified in a few days. Prior to implantation, the fragments are pretreated in an attempt to delay or prevent the development of calcifications. Two, four, six and eight months after implantation, the fragments are removed and calcifications are looked for using microradiography. Two hundred fragments have been studied. The material and technique used in our study are described. Results are semi-quantitative, based on the volume of calcifications. We conclude that microradiography is faster and more reliable than histology (the only technique used up till now) as it allows to study the entire fragments.