TNFR2 blockade of regulatory T cells unleashes an antitumor immune response after hematopoietic stem-cell transplantation.

BACKGROUND: Targeting immune checkpoints that inhibit antitumor immune responses has emerged as a powerful new approach to treat cancer. We recently showed that blocking the tumor necrosis factor receptor-type 2 (TNFR2) pathway induces the complete loss of the protective function of regulatory T cells (Tregs) in a model of graft-versus-host disease (GVHD) prevention that relies on Treg-based cell therapy. Here, we tested the possibility of amplifying the antitumor response by targeting TNFR2 in a model of tumor relapse following hematopoietic stem-cell transplantation, a clinical situation for which the need for efficient therapeutic options is still unmet. METHOD: We developed appropriate experimental conditions that mimic patients that relapsed from their initial hematological malignancy after hematopoietic stem-cell transplantation. This consisted of defining in allogeneic bone marrow transplantation models developed in mice, the maximum number of required tumor cells and T cells to infuse into recipient mice to develop a model of tumor relapse without inducing GVHD. We next evaluated whether anti-TNFR2 treatment could trigger alloreactivity and consequently antitumor immune response. In parallel, we also studied the differential expression of TNFR2 on T cells including Treg from patients in post-transplant leukemia relapse and in patients developing GVHD. RESULTS: Using experimental conditions in which neither donor T cells nor TNFR2-blocking antibody per se have any effect on tumor relapse, we observed that the coadministration of a suboptimal number of T cells and an anti-TNFR2 treatment can trigger alloreactivity and subsequently induce a significant antitumor effect. This was associated with a reduced percentage of activated CD4+ and CD8+ Tregs. Importantly, human Tregs over-expressed TNFR2 relative to conventional T cells in healthy donors and in patients experiencing leukemia relapse or cortico-resistant GVHD after hematopoietic stem cell transplantation. CONCLUSIONS: These results highlight TNFR2 as a new target molecule for the development of immunotherapies to treat blood malignancy relapse, used either directly in grafted patients or to enhance donor lymphocyte infusion strategies. More widely, they open the door for new perspectives to amplify antitumor responses against solid cancers by directly targeting Tregs through their TNFR2 expression.

Intraoperative chemotherapy with cisplatin and epinephrine after cytoreductive surgery in patients with recurrent ovarian cancer: a phase I study.

BACKGROUND: Intraperitoneal (i.p.) epinephrine was shown to increase the accumulation of i.p. cisplatin in tumours, and thus its antitumour effect in a model of peritoneal carcinomatosis in rats. METHODS: To determine the tolerance to i.p. epinephrine with cisplatin, 18 patients with recurrent ovarian carcinoma were intraoperatively treated in this phase 1 study. After maximal cytoreductive surgery, the peritoneal cavity was filled twice for 1 h with 30 mg/l of cisplatin and increasing concentrations of epinephrine (0, 1, 2, 3 mg/l) in 3 l of saline solution at 37 degrees C. RESULTS: No deaths occurred. Three patients were treated at each of the 0, 1 and 2 mg/l epinephrine levels without adverse events. Two of the three patients who received 3 mg/l epinephrine experienced cardiac intolerance. Six additional patients received 2 mg/l of epinephrine without toxicity. A relationship between the serum concentration of epinephrine and occurrence of cardiac toxicity was established. A 60% decrease in serum area under the curve of platinum was calculated in patients receiving i.p. epinephrine compared with i.p. cisplatin alone. Renal toxicity from cisplatin was not increased by epinephrine. No haematological or neurological toxicity was recorded. The other grade 3-4 adverse events [thromboembolism (5), peritonitis (1), abdominal bleeding (1), bowel fistula (1)] occurred as often as usually reported for this heavy surgical procedure. CONCLUSION: The combination of i.p. epinephrine with cisplatin as intraoperative chemotherapy after optimal cytoreductive surgery is feasible. The recommended concentration for further studies is 2 mg/l for i.p. epinephrine.

Comparison of the biomechanical behavior of the liver during frontal and lateral deceleration.

BACKGROUND: The trunk of a car occupant can be injured by a frontal or lateral impact. Lesions can be either intrusion injuries or due to the effects of deceleration alone. The aim of this study conducted with human cadavers was to explore the effects of deceleration on the liver during frontal or lateral deceleration. METHODS: Trunks previously instrumented with accelerometers in three sites, the left and right lobes of the liver and the retrohepatic inferior vena cava, were subjected to substantial deceleration in three orientations: frontal, left, and right lateral. The anatomic consequences and deceleration data were measured. A deceleration ratio was defined as a peak deceleration measured in the liver divided by peak deceleration imposed on the trunk. RESULTS: Peak deceleration imposed on the trunks was up to 60 g, which caused peak deceleration up to 26 g in the liver. No anatomic injury was observed. For each orientation, deceleration ratios were not significantly different among the three sites (p = 0.64) or between left and right lateral decelerations (p = 0.12). Deceleration ratios were significantly different (p = 0.001) between frontal (3 sites combined) and lateral (3 sites of left and right lateral orientations combined) decelerations: 39.4% (+/-6) versus 48.4% (+/-11). CONCLUSIONS: In conclusion, at tested decelerations, under the hepatic injury threshold, cadaveric liver seemed to be subjected to higher deceleration when the trunk was decelerated in lateral than in frontal direction, without terminal impact.

Closed hyperthermic intraperitoneal chemotherapy with open abdomen: a novel technique to reduce exposure of the surgical team to chemotherapy drugs.

BACKGROUND: Exposure of the surgical team to toxic drugs during hyperthermic intraperitoneal chemotherapy (HIPEC) remains a matter of great concern. During closed-abdomen HIPEC, operating room staff are not exposed to drugs, but the distribution of the heated liquid within the abdomen is not optimal. With open-abdomen HIPEC, the opposite is true. Although the open-abdomen method is potentially more effective, it has not become a standard procedure because of the risk of exposure of members of the team to drugs. METHODS: We present a new technique (closed HIPEC with open abdomen) which ensures protection against potentially contaminating exposure to liquids, vapours and aerosols, and allows permanent access to the whole abdominal cavity. Its principle is to extend the abdominal surgical wound upwards with a sort of "glove-box". The cutaneous edges of the laparotomy are stapled to a latex "wall expander". The expander is draped over a special L-section metal frame placed above the abdomen. A transparent cover containing a "hand-access" port, like those used in laparoscopic surgery, is fixed inside the frame. RESULTS: In 10 patients, this device proved to be hermetic for both liquids and vapours. Intra-abdominal temperature was maintained between 42 and 43 degrees C during most of the procedure. The whole abdominal cavity was accessible to the surgeon, allowing optimal exposure of all peritoneal surfaces. CONCLUSION: This technique allows optimal HIPEC, while limiting the potential toxic effects for the surgical, medical and paramedical teams.

Attempts to improve locoregional chemotherapy for the prevention of colonic cancer liver metastasis in the rat.

AIM OF THE STUDY: To improve prophylactic local treatment of hepatic metastasis from colonic cancer cells in the rat. METHODS: The in vitro anticancer activity of 30 mn exposure to different drugs was first evaluated by dimethyl-thiazol-diphenyl-tetrazolium-bromide assay on confluent DHD/K12/PROb rat and HT29 human colonic cancer cells. Hepatic metastasis was induced by portal vein infusion of 12 x 106 PROb colonic cancer cells in syngenic BDIX rats. Hepatic and general tolerance to epirubicin was studied. Rats were treated with epirubicin delivered by either intravenous (IV), intraperitoneal (IP) or intraportal (Ipo) administration to compare their antitumoral effects. Hepatic distribution of epirubicin was assessed by fluorescence microscopy after IV, IP, Ipo, and combined administration. High pressure liquid chromatography was used to measure hepatic concentrations of epirubicin. RESULTS: Only pirarubicin was fully cytotoxic in vitro against the two types of tumor cells. No general or hepatic toxicity was observed. The preventive effect on hepatic metastasis was similar for IV, IP, and Ipo pirarubicin treatments. Hepatic pirarubicin concentrations obtained by Ipo administration were 4.1-fold higher than those obtained after IV administration (P=0.013). Three hours after IP and Ipo administration, hepatic remnants of pirarubicin were similar and significantly higher that those obtained after IV administration (P=0.074). Clamping the hepatic vein doubled hepatic pirarubicin concentrations after Ipo administration (P=0.048). Combined hepatic and intraportal administration was necessary to achieve diffuse, intense and homogeneous fluorescence throughout the entire liver. CONCLUSION: Homogeneous hepatic diffusion of pirarubicin was successfully achieved with combined hepatic vein and intraportal administration but systemic, intraperitoneal or intraportal administration had no preventive effect on hepatic metastasis. Other drugs could be tested using this approach to evaluate their efficacy and toxicity.

Rationale supporting the use of vasoconstrictors for intraperitoneal chemotherapy with platinum derivatives.

By decreasing drug drainage through the peritoneal and tumoral vascular networks, epinephrine increases the penetration of cisplatin and oxaliplatin into the metastatic peritoneal tumor nodules. This improved drug penetration increases their antitumor efficacy, allowing the cure of millimetric-sized peritoneal tumor nodules that could not be obtained with cisplatin or oxaliplatin used alone. However, limited drug diffusion into supramillimetric nodules did not result in curing advanced peritoneal carcinomatosis, unless complete resection of macroscopic localized tumor nodules is performed before intraperitoneal chemotherapy. In our opinion, the intraperitoneal epinephrine-cisplatin combination should be clinically assessed in completely or almost completely surgically resected peritoneal carcinomatosis with the objective of preventing recurrent tumors. Due to its reduced toxicity, repeated courses of intraperitoneal oxaliplatin associated with epinephrine could be an interesting alternative to cisplatin for the unresectable disease.

Young children's mapping between arrays, number words, and digits.

This study investigates when young children develop the ability to map between three numerical representations: arrays, spoken number words, and digits. Children (3, 4, and 5 years old) had to map between the two directions (e.g., array-to-digit vs. digit-to-array) of each of these three representation pairs, with small (1-3) and large numbers (4-6). Five-year-olds were at ceiling in all tasks. Three-year-olds succeeded when mapping between arrays and number words for small numbers (but not large numbers), and failed when mapping between arrays and digits and between number words and digits. The main finding was that four-year-olds performed equally well when mapping between arrays and number words and when mapping between arrays and digits. However, they performed more poorly when mapping between number words and digits. Taken together, these results suggest that children first learn to map number words to arrays, then learn to map digits to arrays and finally map number words to digits. These findings highlight the importance of directly exploring when children acquire digits rather than assuming that they acquire digits directly from number words.

Trends in frequency and management of obstructing colorectal cancers in a well-defined population.

BACKGROUND: Few population-based studies investigate obstructing colorectal cancers. This study was designed to describe trends in their frequency and management. METHODS: Data were obtained for 13,331 colorectal cancers registered by the population-based cancer registry of Burgundy, France, between the years 1976 and 2000. RESULTS: Obstructing cancers represented 8.3 percent of all colorectal cancers. This proportion was stable throughout the study. Resection for cure increased from 54.9 percent (1976-1980) to 71.4 percent (1996-2000; P = 0.011). Using multivariate analysis, site of cancer and period of diagnosis were the only factors significantly associated to a curative resection. Postoperative mortality for obstructing colorectal cancers decreased from 32.6 percent (1976-80) to 15.2 percent (1996-2000; P < 0.001). The presence of obstruction was significantly associated with a higher postoperative mortality, independent of age and tumor stage (odds ratio = 2.55; 95 percent confidence interval = 2.13-3.5). CONCLUSION: The frequency of obstructing colorectal cancers has remained unchanged for 25 years. Operative mortality is still high, although some improvements have occurred. Efforts must be made to diagnose colorectal cancers before obstruction occurs. Mass screening represents a promising approach.

3' Mutation of the APC gene and family history of FAP in a patient with apparently sporadic desmoid tumors.

Desmoid tumors may occur sporadically or as part of the extraintestinal manifestations of familial adenomatous polyposis. Different phenotypes have been described and some genotype-phenotype correlations have been raised, associated with different sites of germline mutations in the adenomatous polyposis coli (APC) gene. We report on a 42-year-old woman ascertained for a large desmoid tumor of the anterior chest wall with pleural involvement, which persistently recurred despite a decade of treatment including hormone therapy, chemotherapy, and surgery. Spontaneous disappearance of the tumor was later noted after 1 year without any treatment and confirmed after 4 years of regular follow-up. Repeated colonoscopies were normal in the proband and DNA sequencing showed a frameshift mutation due to a single adenosine deletion at position 5772 (codon 1924). This mutation, located in the exon 15 at the 3' end of the APC gene, leads to an unusual and late onset phenotype. The pedigree revealed other isolated or familial adenomatous polyposis-associated cases of desmoid tumors. This family report shows that a molecular analysis of the APC gene should be performed in familial desmoid tumors for accurate genetic counseling and follow-up.

Biomechanic study of the human liver during a frontal deceleration.

BACKGROUND: Mechanisms of hepatic injury remain poorly understood. Surgical literature reports some speculative theories that have never been proved. The aim of this study was to examine the behavior of the liver during brutal frontal deceleration. METHODS: Six trunks, removed from human cadavers, underwent free falls at 4, 6, and 8 meters per second (mps). Accelerometers were positioned in the two lobes of the liver, in front of the vertebra L2, and in the retro hepatic inferior vena cava. Relative motions of the lobes of the liver and of the two other anatomic marks were observed. In parallel, numerical simulations of this experiment have been performed using a finite element model. RESULTS: In the direction of impact, the vertebra L2 had no considerable displacement with the inferior vena cava. There was a noteworthy displacement between the two hepatic lobes. The left hepatic lobe had a large relative displacement with the vertebra L2 and the inferior vena cava. The right hepatic lobe was more stable with the vertebra L2 and the inferior vena cava. Numerical simulation of the same protocol underlined a rotation effect of the liver to the left around the axis of the inferior vena cava. CONCLUSIONS: These results support the surgical data. They highlight a crucial zone and explain how dramatic lacerations between the two lobes of the liver can occur.

High intra-abdominal pressure enhances the penetration and antitumor effect of intraperitoneal cisplatin on experimental peritoneal carcinomatosis.

OBJECTIVE: To investigate the role of increased intra-abdominal pressure (IAP) on the intratumoral accumulation and the antitumor effect of intraperitoneal cisplatin in rats with advanced peritoneal carcinomatosis. To evaluate the tolerance of IAP in pigs, as it is a large animal with a body size equivalent to humans. SUMMARY BACKGROUND DATA: To investigate if an active convection, driven by a positive IAP, increases cisplatin penetration and antitumor effectiveness in a model of advanced peritoneal carcinomatosis in rats. EXPERIMENTAL DESIGN: BDIX rats with macroscopic peritoneal tumors received cisplatin administered as intravenous injection (IV), conventional intraperitoneal injection (IP), or sustained intraperitoneal injection of cisplatin given in a large volume of solvent for maintaining IAP for 1 hour. Platinum tissue concentration was measured by atomic absorption spectroscopy (AAS), and platinum distribution into the tumor nodules was assessed by the particular-induced x-ray emission (PIXE) method. The antitumor effect was assessed in a survival experiment. The hemodynamic, local, and systemic tolerance of IAP, with or without cisplatin, was evaluated in Large White pigs. RESULTS: The maximum tolerated IAP was 22 mm Hg for 1 hour in nonventilated rats. IAP, in comparison with IV or conventional IP injections, resulted in the increased concentration and depth of diffusion of platinum into diaphragm and peritoneal tumor nodules. Consequently, IAP treatment induced an extended survival of rats treated at an advanced stage of carcinomatosis. In 7 50- to 70-kg ventilated pigs, a 40-mm Hg IAP was well tolerated when maintained stable for 2 hours. Renal failure occurred in pigs receiving a total dose of 200 and 400 mg of cisplatin with IAP, but a dose of 100 mg was well tolerated. CONCLUSIONS: Intraperitoneal chemotherapy with increased IAP, in comparison with conventional IP or IV chemotherapy, improved the tumor accumulation and the antitumor effect of cisplatin in rats bearing advanced peritoneal carcinomatosis. In preclinical conditions, the tolerance of sustained IAP was manageable in ventilated pigs.

Feasibility of using intraperitoneal epinephrine and cisplatin in patients with advanced peritoneal carcinomatosis.

Intraperitoneal epinephrine above 1 mg/l concentration has been shown to enhance the intratumoral accumulation and antitumor activity of intraperitoneal cisplatin in rats with advanced peritoneal carcinomatosis. The aim of this study was to determine the tolerance of intraperitoneal epinephrine combined with intraperitoneal cisplatin in patients with advanced peritoneal carcinomatosis (17 ovarian cancers, one peritoneal mesothelioma). Intraperitoneal epinephrine (1-5 mg/l) and cisplatin (50 mg/l; 100 mg total dose) were infused in 2 l of saline solution over 2 h. The maximal tolerated concentration of intraperitoneal epinephrine was not reached at 5 mg/l. Cardiovascular symptoms were infrequent and not strictly related to the epinephrine concentration. Tumor responses were obtained in some patients with disease resistant to intravenous platinum compounds. This work demonstrates for the first time that intraperitoneal epinephrine at sufficient concentration enhances the cisplatin effect and can be safely infused into the peritoneal cavity of patients with peritoneal carcinomatosis. The greatest limitation was abdominal pain and limited intraperitoneal distribution of the peritoneal fluid in this closed-abdomen procedure.

Classification for predicting mediastinal lymph node metastases in patients with T1 or T2 lung cancer.

The aim of this study is to classify patients into risk groups for mediastinal lymph node metastases. Three hundred and thirty-seven patients underwent lung resection for lung cancer. The nodal status was pN0 in 181 patients, pN1 in 62 and pN2 in 94. The presence of the involvement of one mediastinal compartment (superior or inferior) or two mediastinal compartments (superior and inferior) was considered to be the main end point. One mediastinal compartment was involved in 65 patients and two mediastinal compartments in 29 patients. Two variables (visceral pleural invasion and the primary tumor location) were retained in the model. The regression tree analysis categorized patients into 3 risk groups for the involvement of two mediastinal compartments. The low-risk group included 118 patients with a tumor located in the left side and no visceral pleural invasion. The intermediate-risk group included 160 patients with a tumor located in the right side and no visceral pleural invasion. The high-risk group included 59 patients with visceral pleural invasion and a tumor located in the right side or left lower lobe. A practical, easy-to-use risk grouping system is proposed to aid the decision making and to simplify mediastinal lymphadenectomy procedure.

Preventing lymphedema and morbidity with an omentum flap after ilioinguinal lymph node dissection.

BACKGROUND: Pedicled omentoplasty has been advocated to prevent the formation of lymphocysts and lymphedema after pelvic lymph node dissection, We evaluated the possible benefit of a pediculated omentoplasty placed in the groin for preventing complications after ilioinguinal lymph node dissection. METHODS: In this pilot study, we report a series of four women and three men with inguinal metastatic lymph nodes. Each was treated with a pediculated omentoplasty after groin dissection. We examined complications such as lymphedema, lymphorrhea, wound breakdown, skin necrosis, and lymphocysts. RESULTS: Only one wound breakdown with skin necrosis was observed, and it healed satisfactorily in 10 days without exposing the femoral vessels. No lymphocele or infectious complications occurred, even though no antibiotic prophylaxis was used. Midthigh circumference increase ranged from 1.5 to 7 cm in four cases but remained asymptomatic. Furthermore, lymphedema of the lower limb decreased in the three remaining patients, who previously had an enlargement of the thigh. No evidence of peritoneal carcinomatosis was noted during the 4-month follow-up. CONCLUSIONS: Pedicled omentoplasty seemed to facilitate the absorption or transport of lymph fluids and resulted in less lymphedema in the lower limb even after radiotherapy. Pedicled omentoplasty reduces both short-term and long-term postoperative complications without affecting treatment outcome and could even be considered as a safe and effective therapy for lymphedema of the lower extremity.

Prevention of peritoneal carcinomatosis from colon cancer cell seeding using a pirarubicin solution in rats and nude mice.

Free malignant cells, which are frequently detected in the washing liquid from the peritoneal cavity before and after resection of human colorectal cancer, are suspected to cause recurrent peritoneal cancer. We carried out an experimental study to compare the prophylactic efficacy of washing the peritoneum with several anticancer drugs and the antiseptic povidone-iodine against the development of peritoneal carcinomatosis from colonic origin in rats and nude mice. The in vitro anticancer activity of a short, 15-minute exposure of pirarubicin, doxorubicin, 5-fluorouracil, cisplatin, mitomycin C, and 1% povidone-iodine was first evaluated by an MTT assay on DHD/K12/PROb rat and LS174T human colon cancer cells. For the in vivo experiments, BDIX rats were inoculated intraperitoneally (i.p.) with 1 x 10(6) DHD/K12/PROb cells followed by peritoneal scarring and a colocolic anastomosis. A 15-minute peritoneal washing with the anticancer drugs or povidone-iodine was then performed. Nude mice were i.p.-inoculated with 1 x 10(7) LS174T human cells and treated 2 hours later with i.p. pirarubicin. Only pirarubicin, mitomycin C, and povidone-iodine were fully cytotoxic in vitro against DHD/K12/PROb rat colon cancer cells. In contrast to pirarubicin and povidone-iodine, mitomycin C was not completely active against LS174Tcells. In vivo, pirarubicin cured DHD/K12/PROb-inoculated rats, even at the site of the peritoneal scarring and intestinal anastomosis. i.p. pirarubicin prevented the development of peritoneal carcinomatosis and liver metastasis in LS174T-inoculated mice. i.p. washing with pirarubicin cured 2-day-old, but not 7-day-old, peritoneal carcinomatosis in rats. Short exposure to i.p. pirarubicin is nontoxic and more active than povidone-iodine and other anticancer drugs in preventing the development of peritoneal carcinomatosis from colonic origin in rats and mice. The prophylactic effect of preoperative peritoneal washing with pirarubicin on the development of recurrent peritoneal cancer should be evaluated in a randomized clinical trial.