Peritoneal carcinomatosis from gastric cancer: a multi-institutional study of 159 patients treated by cytoreductive surgery combined with perioperative intraperitoneal chemotherapy

BACKGROUND: Peritoneal carcinomatosis (PC) from gastric cancer has long been regarded a terminal disease with a short median survival. New locoregional therapeutic approaches combining cytoreductive surgery with perioperative intraperitoneal chemotherapy (PIC) have evolved and suggest improved survival. MATERIALS AND METHODS: A retrospective multicentric study was performed in French-speaking centers to evaluate the toxicity and the principal prognostic factors in order to identify the best indications. All patients had cytoreductive surgery and PIC: hyperthermic intraperitoneal chemotherapy (HIPEC) and/or early postoperative intraperitoneal chemotherapy (EPIC). RESULTS: The study included 159 patients from 15 institutions between February 1989 and August 2007. The median follow-up was 20.4 months. HIPEC was the PIC used for 150 procedures. Postoperative mortality and grade 3-4 morbidity rates were 6.5 and 27.8%, respectively. By multivariate analysis, the institution had a significant influence on toxicity. The overall median survival was 9.2 months and 1-, 3-, and 5-year survival rates were 43, 18, and 13%, respectively. The only independent prognostic indicator by multivariate analysis was the completeness of cytoreductive surgery. For patients treated by complete cytoreductive surgery, the median survival was 15 months with a 1-, 3-, and 5-year survival rate of 61, 30, and 23%, respectively. CONCLUSIONS: The therapeutic approach combining cytoreductive surgery with PIC for patients with gastric carcinomatosis may achieve long-term survival in a selected group of patients (limited and resectable PC). The high mortality rate underlines this necessarily strict selection that should be reserved to experienced institutions involved in the management of PC and gastric surgery

Use of FDG-PET/CT for peritoneal carcinomatosis before hyperthermic intraperitoneal chemotherapy

BACKGROUND: Peritoneal carcinomatosis (PC) is associated with a very poor prognosis. Complete cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy has been shown to improve survival rates of PC. However, this treatment is beneficial for patients if the complete cytoreductive surgery is macroscopically completed before implementing hyperthermic intraperitoneal chemotherapy. Even so, a strict selection of patients is of fundamental importance because of the invasive nature of the intervention. The aim of this study was to assess the performance of FDG-PET/CT examinations for the diagnosis and evaluation of the extent of PC. METHODS: A retrospective analysis was conducted on 28 consecutive patients with suspected PC, scheduled for a complete cytoreductive surgery and hyperthermic intraperitoneal chemotherapy, and who underwent an FDG-PET/CT examination. We compared the results of PET examinations with histological and intraoperative findings. The extent of PC was assessed precisely using a simplified \u27peritoneal cancer index\u27, within the three modalities (PET, surgery and histology). RESULTS: Of 28 patients, 23 had histological PC. The sensitivity and specificity of the PET examination for the diagnosis of PC were, respectively, 82 and 100%. Even if the extent of PC was underestimated by PET, there was a good correlation when compared with histology and intraoperative results. CONCLUSION: PET presented a good performance level in the diagnosis and evaluation of the extent of PC. PET/CT examinations could be useful to avoid unnecessary surgery

Impact of 18F-fluoro-deoxy-glucose positron emission tomography (FDG-PET) in recurrent colorectal cancer

Purpose: The aim of the study was to evaluate the diagnostic performance, the prognosis factors and the therapeutic impact of 18F-FDG positron emission tomography (FDG-PET) in the detection of recurrent colorectal cancers. Methods: Sixty PET/CT with 18F-FDG and CT were performed in 52 patients, at the Paul Papin cancer center between 2003 and 2005, following suspicion of colorectal cancer relapse. The FDG-PET impact on the clinical management was studied by examination of multidisciplinary concertations results. Survival analysis were realized with a mean follow up of 2.2 years. Results: Recurrence was confirmed for 50 explorations by histologic (n = 32), radiologic (n = 14) or clinical (n = 4) findings. Twenty patients died during the time of the study. On a patient based analysis, FDG-PET sensitivity, specificity and overall accuracy were 90, 90, 90% respectively compared with 74, 50 and 70% for CT. FDG-PET changed the clinical management in 18 cases (30%). A positive FDG-PET signal, more than one hepatic lesion, more than two lymph node lesions detected on FDG-PET and more than two hepatic lesions on CT were characterized as bad prognostic factors for survival. Multivariate analysis showed that the only independent bad prognostic factor was the FDG-PET detection of more than two liver lesions. Conclusion: These results confirmed the important impact of FDG-PET in the clinical management of patients with a suspected recurrence of colorectal cancer

Has the liver and other visceral organs migrated to its normal position in children with giant omphalocele? A follow-up study with ultrasonography

Contains fulltext : 88428.pdf (publisher's version ) (Closed access)This study evaluates whether, on the long run, in patients born with a giant omphalocele, the liver and other solid organs reach their normal position, shape, and size. Seventeen former patients with a giant omphalocele, treated between 1970 and 2004, were included. Physical examination was supplemented with ultrasonography for ventral hernia and precise description of the liver, spleen, and kidneys. The findings were compared with 17 controls matched for age, gender, and body mass index. We found an abnormal position of the liver, spleen, left kidney, and right kidney in eight, six, five, and four patients, respectively. An unprotected liver was present in all 17 patients and in 11 controls, the difference being statistically significant (p = 0.04). In ten of the 11 patients with an incisional hernia, the liver was located underneath the abdominal defect. CONCLUSION: In all former patients with a giant omphalocele, an abnormal position of the liver and in the majority of them, an incisional hernia was also found. The liver and sometimes also the spleen and the kidneys do not migrate to their normal position. Exact documentation and good information are important for both the patient and their caretakers in order to avoid liver trauma.1 mei 201

Biphasic pulses enhance bleomycin efficacy in a spontaneous canine genital tumor model of chemoresistance: Sticker sarcoma

Sticker's sarcoma (also known as transmissible venereal tumor) is a horizontally transmitted neoplasm of the dog, that is passed with coitus. It is a locally aggressive tumor with a low tendency to metastatic spread. The most common locations are the genitals, the nose, the perianal area. Standard treatment consists with chemotherapy with vincristine, however other therapies such as, cryotherapy, immunotherapy or, in selected cases, radiation therapy, have been reported. In this article we describe the outcome of a small cohort of canine patients, with chemotherapy resistant transmissible venereal tumor (TVT), treated with bleomycin selectively driven by trains of biphasic pulses (electrochemotherapy). Three canine patients, with refractory TVT, entered the study and received two sessions of ECT under sedation. The pets had local injection of bleomycin at the concentration of 1.5 mg/ml and five minutes after the chemotherapy, trains of 8 biphasic electric pulses lasting 50 + 50 μs each, with 1 ms interpulse intervals, were delivered by means of modified caliper or, for difficult districts, through paired needle electrode. All the patients responded to the treatment and are still in remission at different times. Electrochemotherapy appears as a safe and efficacious modality for the treatment of TVT and warrants further investigations

Programmable Ligand Detection System in Plants through a Synthetic Signal Transduction Pathway

There is an unmet need to monitor human and natural environments for substances that are intentionally or unintentionally introduced. A long-sought goal is to adapt plants to sense and respond to specific substances for use as environmental monitors. Computationally re-designed periplasmic binding proteins (PBPs) provide a means to design highly sensitive and specific ligand sensing capabilities in receptors. Input from these proteins can be linked to gene expression through histidine kinase (HK) mediated signaling. Components of HK signaling systems are evolutionarily conserved between bacteria and plants. We previously reported that in response to cytokinin-mediated HK activation in plants, the bacterial response regulator PhoB translocates to the nucleus and activates transcription. Also, we previously described a plant visual response system, the de-greening circuit, a threshold sensitive reporter system that produces a visual response which is remotely detectable and quantifiable.We describe assembly and function of a complete synthetic signal transduction pathway in plants that links input from computationally re-designed PBPs to a visual response. To sense extracellular ligands, we targeted the computational re-designed PBPs to the apoplast. PBPs bind the ligand and develop affinity for the extracellular domain of a chemotactic protein, Trg. We experimentally developed Trg fusions proteins, which bind the ligand-PBP complex, and activate intracellular PhoR, the HK cognate of PhoB. We then adapted Trg-PhoR fusions for function in plants showing that in the presence of an external ligand PhoB translocates to the nucleus and activates transcription. We linked this input to the de-greening circuit creating a detector plant.Our system is modular and PBPs can theoretically be designed to bind most small molecules. Hence our system, with improvements, may allow plants to serve as a simple and inexpensive means to monitor human surroundings for substances such as pollutants, explosives, or chemical agents

Hydrogen bond networks determine emergent mechanical and thermodynamic properties across a protein family

<p>Abstract</p> <p>Background</p> <p>Gram-negative bacteria use periplasmic-binding proteins (bPBP) to transport nutrients through the periplasm. Despite immense diversity within the recognized substrates, all members of the family share a common fold that includes two domains that are separated by a conserved hinge. The hinge allows the protein to cycle between open (apo) and closed (ligated) conformations. Conformational changes within the proteins depend on a complex interplay of mechanical and thermodynamic response, which is manifested as an increase in thermal stability and decrease of flexibility upon ligand binding.</p> <p>Results</p> <p>We use a distance constraint model (DCM) to quantify the give and take between thermodynamic stability and mechanical flexibility across the bPBP family. Quantitative stability/flexibility relationships (QSFR) are readily evaluated because the DCM links mechanical and thermodynamic properties. We have previously demonstrated that QSFR is moderately conserved across a mesophilic/thermophilic RNase H pair, whereas the observed variance indicated that different enthalpy-entropy mechanisms allow similar mechanical response at their respective melting temperatures. Our predictions of heat capacity and free energy show marked diversity across the bPBP family. While backbone flexibility metrics are mostly conserved, cooperativity correlation (long-range couplings) also demonstrate considerable amount of variation. Upon ligand removal, heat capacity, melting point, and mechanical rigidity are, as expected, lowered. Nevertheless, significant differences are found in molecular cooperativity correlations that can be explained by the detailed nature of the hydrogen bond network.</p> <p>Conclusion</p> <p>Non-trivial mechanical and thermodynamic variation across the family is explained by differences within the underlying H-bond networks. The mechanism is simple; variation within the H-bond networks result in altered mechanical linkage properties that directly affect intrinsic flexibility. Moreover, varying numbers of H-bonds and their strengths control the likelihood for energetic fluctuations as H-bonds break and reform, thus directly affecting thermodynamic properties. Consequently, these results demonstrate how unexpected large differences, especially within cooperativity correlation, emerge from subtle differences within the underlying H-bond network. This inference is consistent with well-known results that show allosteric response within a family generally varies significantly. Identifying the hydrogen bond network as a critical determining factor for these large variances may lead to new methods that can predict such effects.</p

Synthetic biology approaches in drug discovery and pharmaceutical biotechnology

Synthetic biology is the attempt to apply the concepts of engineering to biological systems with the aim to create organisms with new emergent properties. These organisms might have desirable novel biosynthetic capabilities, act as biosensors or help us to understand the intricacies of living systems. This approach has the potential to assist the discovery and production of pharmaceutical compounds at various stages. New sources of bioactive compounds can be created in the form of genetically encoded small molecule libraries. The recombination of individual parts has been employed to design proteins that act as biosensors, which could be used to identify and quantify molecules of interest. New biosynthetic pathways may be designed by stitching together enzymes with desired activities, and genetic code expansion can be used to introduce new functionalities into peptides and proteins to increase their chemical scope and biological stability. This review aims to give an insight into recently developed individual components and modules that might serve as parts in a synthetic biology approach to pharmaceutical biotechnology