Intratumoral gene therapy versus intravenous gene therapy for distant metastasis control with 2-diethylaminoethyl-dextran methyl methacrylate copolymer non-viral vector-p53.

Lung cancer still remains to be challenged by novel treatment modalities. Novel locally targeted routes of administration are a methodology to enhance treatment and reduce side effects. Intratumoral gene therapy is a method for local treatment and could be used either in early-stage lung cancer before surgery or at advanced stages as palliative care. Novel non-viral vectors are also in demand for efficient gene transfection to target local cancer tissue and at the same time protect the normal tissue. In the current study, C57BL/6 mice were divided into three groups: (a) control, (b) intravenous and (c) intatumoral gene therapy. The novel 2-Diethylaminoethyl-Dextran Methyl Methacrylate Copolymer Non-Viral Vector (Ryujyu Science Corporation) was conjugated with plasmid pSicop53 from the company Addgene for the first time. The aim of the study was to evaluate the safety and efficacy of targeted gene therapy in a Lewis lung cancer model. Indeed, although the pharmacokinetics of the different administration modalities differs, the intratumoral administration presented increased survival and decreased distant metastasis. Intratumoral gene therapy could be considered as an efficient local therapy for lung cancer.

CT-guided percutaneous chemoablation using an ethanol-ethiodol-doxorubicin emulsion for the treatment of metastatic lymph node carcinoma: a comparative study.

Current therapies for metastatic lymph node (LN) are a major burden on health-care systems. Alternative such as percutaneous chemoablation using interstitial injection of ethanol or ethanol-ethiodol-drug(s) mixture (EEM) has been successfully applied to solid tumor ablation of the liver, adrenal glands, lymph nodes and others. However, EEM chemoablation efficacy on two most frequent clinical lymph node presentation, isolated or confluent, has not yet been determined. This study was designed to compare the therapeutic effects of CT-guided percutaneous EEM injection (PEEMI) on patients presenting with single or multiple confluent metastatic LN localizations from various carcinoma. Thirty six patients with metastatic LN carcinoma at various anatomical regions were enrolled from 2009 to 2010 over a nine month period. They were separated into two groups: group A includes 24 single isolated metastatic lymph nodes and group B includes 12 multiple and confluent nodes. The primary end point was the ablative efficacy of PEEMI. The intratumoral (IT) EEM distribution and the occurrence of reflux were recorded. Adjuvant systemic chemotherapy was administered after the procedure. Contrast-enhanced CT scans were performed during procedure and follow-up. Six patients were tested for Fluorodeoxyglucose (FDG) fixation before and after the procedure. For group A the EEM IT distribution-to-tumor ratio was 100% vs. 50% to 80% for group B (t = 11.5, p < 0.05). The reflux frequency was 80% for group A versus 30% for group B. For group A, a complete response (CR) rates of 45.8%, 70.8%, 91.7% and a partial response (PR) rates of 54.2%, 29.2%, 8.3% were obtained at 3, 6 and 12 months after therapy. Regarding group B, a CR rate of 0%, 0%, 0% and PR rate of 16.7%, 50%, 58.3% were observed at similar period of time. Standardized rate by direct method was performed and the CR rate (74.5%) for group A was higher than for group B. The tumor FDG uptake was lower 6 months after PEEMII compared with the preoperative images. Five patients presenting with concomitant lung metastasis, had a good local response-node size reduction on postoperative CT scanning, but no response on lung nodules that were progressing. No serious adverse events were observed. A few patients had mild pain during the procedure, which resolved with peritumor injection of local anesthetic. No needle tract seeding or infection occurred. CT-guided PEEMI treatment is a simple, fast and predictable procedure that has better effectiveness on single, well circumscribed metastatic lymph node than on multiple and confluent ones. Technical improvements are expected to bring better results on large nodes that should be confirmed on larger group of patients.

Percutaneous tumor ablation: microencapsulated echo-guided interstitial chemotherapy combined with cryosurgery increases necrosis in prostate cancer.

This study aimed at confirming the increased growth inhibition (GI) of human prostate tumors produced by a intentionally palliative combination treatment of cryochemotherapy, i.e., partial cryoablation (CA) followed by intratumor partial chemotherapy with injection of microencapsulated 5-fluorouracil (MCC/5FU) at the ice ball (IB) periphery. We report the local effectiveness of cryochemotherapy compared to chemotherapy only with using multiple injections of MCC/5FU spaced out to maximize cumulative effect of sustained release of 5-fluorouracil (5FU) during a 21-day period. Prostate bioluminescent tumor cells - DU145 Luc+ - were implanted sub-cutaneously and bilaterally in each flank of nude mice. Tumors were treated with: (i) cryoablation alone (CA), causing necrosis in approximately 45% of the tumor volume; (ii) cryo-chemotherapy (CA+MCC/5FU), a combined regimen consisting of partial CA followed immediately and on day 14 by ultrasound assisted, intra-tumor injections (40 mul) of MCC/5FU( 0.81 ng/mm3 of tumor) containing Ethiodol (IPO) an imaging contrast agent, on two opposite sides of the unfrozen part of tumor; (iii) intratumor chemotherapy (MCC/5FU), consisting of three successive intra-tumor injections of microencapsulated 5FU on two opposite sides on Day 0, 4, and 11, and (iv) control series (MM), consisting of a single injection of echogenic microcapsules (mucaps) containing IPO but no 5FU. Tumor growth and viability were followed during a 21-day period with using biometric measurements, bioluminescent imaging (BLI) and ultrasonography (US), and then animals were sacrificed. CA, spared 54.4% of the tumor volume and the IB kill ratio was 0.4 +/-0.9. The maximum tumor volume reduction observed by Day 3 was short-lived as re-growth became significant by Day 6. CA+ MCC/5FU spared 55.6% of the tumor volume and the IB kill ratio was 0.54 +/- 0.12. The viable tumor cells, as measured by BLI remained at preoperative levels. After 11 days CA+ MCC/5FU limited the growth of the partially ablated tumors to only 10.6% of the growth of CA treated tumors (p=0.04). By Day 18 the CA+MCC/5FU had inhibited tumor growth by 78% compared to the CA treated tumors (p=0.05) and after 21 days the growth was inhibited by 71% (p=0.04) compared to more than 650% growth in the MM group and 600% growth in the CA treated group. The two injections of MCC/5FU produced a visible focal necrosis in 55% of the tumors. MCC/5FU proved effective by themselves and reduced the growth of prostate tumor volumes by 51% (p=0.025) compared to MM controls during the 21 days. Focal necrosis was macroscopically visible at the site of 66% of the tumors injected only with MCC/5FU. The BLI clearly showed zones of reduced tumor cell viability at the injection sites. The mean number of bioluminescent (viable) tumor cells, remained below preoperative levels for the first 6 days and then increased at a rate approximately 20% that of the growth of control tumor cells. The chemoablative effects of intentionally limited doses of MCC/5FU injected within the IB margin augment the effects of incomplete cryoablation in this prostate tumor model, with dramatic tumor GI and directionally increased necrosis dimensions compared to CA alone, confirming the results of a previous study. Our results indicate the potential advantages of our combination cryochemotherapy that utilizes different mechanisms to kill tumor cells and retard tumor growth in the region surrounding the IB where tumor cells escape the lethal effects of cryosurgery. The study suggests that cryochemotherapy may become a more predictable technique that could be indicated as an adjuvant or an alternative to palliative therapy of hormone refractory prostate cancer (HRPC).

[Controlled cryosurgery of varices of the lower extremities. A new therapeutic approach. Apropos of 350 cases]. / Cryochirurgie contrôlée des varices des membres inférieurs. Une approche thérapeutique nouvelle. A propos de 350 cas.

The idea of applying cryosurgery to the treatment of lower extremities varicose veins originated in 1978 from three developments: The increasing abundance of experimental and clinical observations of the vascular effect of low temperatures. The development of a more suitable, flexible instrumentation, in collaboration with the Atomic Energy Commissary. The intrinsic advantages of cryosurgery, a painless and less aggressive method, which may be applied to fragile or elderly patients, without general anesthesia. In a first phase (1979-1981) fifty, fragile, elderly or obese patients were treated. All presented a long saphenous reflux. The method demonstrates its feasibility and validity. Two obstacles limit a broader application to the ambulatory treatment of surgical varicose veins: The absence of a strict per-operative control of the ice ball forme at the tip of the cooling device. The conditions of surgery, painful for the patient and un for the physician, because of a bulky, rigid or flexible, instrumentation, which is not very adapted to venous catheterization and does not permit treatment above the knee fold. A second phase of clinical applications started in 1982. Vascular cryoprobes were developed. Because of a better adaptation, they permit the catheterization of most saphenous trunks, in their entirety, and also the control of tissues freezing by measuring the low frequency bioelectric impedance. This study describes: The biological and experimental bases on which rest the venous applications. Cryosurgical instrumentation that we have created and developed. An endoluminal controlled cryosurgical technique of the saphenous trunks. This technique was applied since 1982 to three hundred patients suffering from reflux with ostial incontinence. The results are analyzed in view of clinical and histological findings. The correlation between the absence of venous repermeation and the elevation of per-operative low frequency impedance values, and a follow-up beyond five years for the first patients seem sufficient to justify the present publication, the presentation of this material and to co-ordinate the start of a multicentric study.

[Cryosclerosis of the saphenous veins in varicose reflux in the obese and elderly]. / Cryosclérose des troncs saphéniens dans les reflux variqueux de l'obèse et du viellard.

We have developed an outpatient technique for high-risk varicose patients, using local anesthesia and cryo-sclerosis of the vein wall. A flexible cryo-probe is introduced in the vessel lumen, and its tip refrigerated to --89 degrees C. Thrombosis is thus induced with a limited inflammatory reaction and no pain. The vein then undergoes a progressive fibrosis, and recanalisation was not observed. Clinical results have been excellent on 44 patients who could not be submitted to standard surgical techniques, due to age and obesity.

[The treatment of villous tumors of the rectum by cryosurgery. A report of 10 cases (author's transl)]. / Le traitement des tumeurs villeuses du rectum par la cryochirurgie. A propos de 10 observations.

A study of 10 cases of villous tumors treated by cryosurgery shows that this is a simple, benign, and conservative method which can be repeated if need be. It is possible to associate this method with other methods, in particular radiotherapy. The first results obtained suggest that cryosurgery can take its place amongst all the other non-invasive methods but requires, like them, a careful and continuous surveillance of the result which involves repeated endoscopy. The follow up time and the number of patients involved is not large enough to state definitely its long term efficacy but the results of this series are encouraging and optimistic for the future use of this method.

[The effect of a mixture of bacterial ribosomes and membrane fractions of Klebsiella pneumoniae on the development of a transplanted epithelial cancer in rats]. / Effet d'un mélange de ribosomes bactériens et d'une fraction membranaire de Klebsiella pneumoniae sur le développement d'un cancer épithélial greffé chez le rat.

An association of bacterial ribosomes and cell-wall of Klebsiella pneumoniae was shown to reduce the incidence of an epidermoid carcinoma in Sprague-Dawley rats when administered subcutaneously prior the tumoral graft. Mononuclear cells accumulate around the tumor. This association was considered as a non specific adjuvant stimulating the host's intrinsic immunity to tumor antigens.

["In situ" anesthetics and experimental cryotumorectomy]. / Anesthesiques "in situ" et cryotumorectomies experimentales.

Some similarities have been found between the actions of anesthetics and freezing on biological membranes. Therefore, it has been thought that these agents could potentiate the destructive effect of cryosurgery. Experiments on cryopreservation of HeLa cells in vitro using three anesthetics--thiopental sodium, lignocaïne and CT 1341--indicate enhancement of "cryosensitivity". When using in vivo the same anesthetics injected in an experimental carcinoma (KDMC) of the Sprague-Dawley rat, cryosurgically treated, the results are: --no tumoricidal effect nor antitumoral activity of these agents when used alone,--the simultaneous use of anesthetics and cryosurgery gives better (but no significant results than cryosurgery alone,--the best agent in regard to this possible adjuvant effect seems to be thiopental sodium, it also facilitates tumoral dissemination. The authors conclude from these preliminary results that they need further experiments to assess this findings with smaller tumors, more numerous animals, same and others anesthetics at different concentrations. They attempt to define some caracteristics of potentiative agents during physical phase of cryodestruction.

[Study of the arterial vascularisation of the esophagus of micro-angiography]. / Etude de la vascularisation artérielle de l'oesophage par micro-angiographie.

Study of the intrinsic vascularization of the oesophagus in eleven organs. A technic of microangiography was used. The thoracic portion of the oesophagus was carefully studied. The way of penetration of the nutrient arteries and the intraparietal vascular pattern were precised. The vascularization is rather poor, especially 4-5 cms above the oesophagal hiatus.

[Use of bioelectric impedance measurements as a control in the cryodestruction of normal or pathological tissue in vivo].

Using an original device including cryoprobes and a measurement apparatus to evaluate bioelectrical impedances, the authors have accurately determined the zone of irreversible cellular injury after cryotherapy.