Acute ATP loss during irreversible electroporation mediates caspase independent cell death.

Irreversible electroporation (IRE) has been reported to variably cause apoptosis, necrosis, oncosis or pyroptosis. Intracellular ATP is a key substrate for apoptosis which is rapidly depleted during IRE, we sought to understand whether intracellular ATP levels is a determinant of the mode of cell death following IRE. A mouse bladder cancer cell line (MB49) was treated with electric fields while increasing the number of pulses at a fixed electric field strength, and pulse width. Cell proliferation and viability and ATP levels were measured at different timepoints post-treatment. Cell death was quantified with Annexin-V/Propidium Iodide staining. Caspase activity was measure with a fluorometric kit and western blotting. A pan-caspase (Z-VAD-FMK) inhibitor was used to assess the impact of signal inhibition. We found cell death following IRE was insensitive to caspase inhibition and was correlated with ATP loss. These findings were confirmed by cell death assays and measurement of changes in caspase expression on immunoblotting. This effect could not be rescued by ATP supplementation. Rapid and acute ATP loss during IRE interferes with caspase signaling, promoting necrosis. Cell necrosis from IRE is expected to be immunostimulatory and may be effective in cancer cells that carry mutated or defective apoptosis genes.

[Management of epithelial ovarian cancer. Short text drafted from the French joint recommendations of FRANCOGYN, CNGOF, SFOG, GINECO-ARCAGY and endorsed by INCa]. / Texte court rédigé à partir de la recommandation nationale de bonnes pratiques cliniques « Conduites à tenir initiales devant des patientes atteintes d'un cancer épithélial de l'ovaire ¼ élaborée par FRANCOGYN, CNGOF, SFOG, GINECO-ARCAGY et labélisée par l'INCa ¼.

Faced to an undetermined ovarian mass on ultrasound, an MRI is recommended and the ROMA score (combining CA125 and HE4) can be proposed (grade A). In case of suspected early stage ovarian or fallopian tube cancer, omentectomy (at least infracolonic), appendectomy, multiple peritoneal biopsies, peritoneal cytology (grade C) and pelvic and para-aortic lymphadenectomy are recommended (grade B) for all histological types, except for the expansive mucinous subtype where lymphadenectomy may be omitted (grade C). Minimally invasive surgery is recommended for early stage ovarian cancer, if there is no risk of tumor rupture (grade B). Adjuvant chemotherapy with carboplatin and paclitaxel is recommended for all high-grade ovarian or Fallopian tube cancers, stage FIGO I-IIA (grade A). In case of ovarian, Fallopian tube or primitive peritoneal cancer of FIGO III-IV stages, thoraco-abdomino-pelvic CT scan with injection (grade B) is recommended. Laparoscopic exploration for multiple biopsies (grade A) and to evaluate carcinomatosis score (at least using the Fagotti score) (grade C) are recommended to estimate the possibility of a complete surgery (i.e. no macroscopic residue). Complete medial laparotomy surgery is recommended for advanced cancers (grade B). It is recommended in advanced cancers to perform para-aortic and pelvic lymphadenectomy in case of clinical or radiological suspicion of metastatic lymph node (grade B). In the absence of clinical or radiological lymphadenopathy and in case of complete peritoneal surgery during an initial surgery for advanced cancer, it is possible not to perform a lymphadenectomy because it does not modify the medical treatment and the overall survival (grade B). Primary surgery is recommended when no tumor residue is possible (grade B). After a complete first surgery, it is recommended to deliver 6 cycles of intravenous (grade A) or to propose intraperitoneal (grade B) chemotherapy, to be discussed with patient, according to the benefit/risk ratio. After a complete interval surgery for a FIGO III stage, the hyperthermic intra peritoneal chemotherapy (HIPEC) can be proposed in the same conditions of the OV-HIPEC trial (grade B). In case of tumor residue after surgery or FIGO stage IV, chemotherapy associated with bevacizumab is recommended (grade A).

Contribution of Computed Tomography Enema and Magnetic Resonance Imaging to Diagnose Multifocal and Multicentric Bowel Lesions in Patients With Colorectal Endometriosis.

STUDY OBJECTIVE: To evaluate the diagnostic contribution of the computed tomography (CT) enema and magnetic resonance imaging (MRI) for multifocal (multiple lesions affecting the same segment) and multicentric (multiple lesions affecting several digestive segments) bowel endometriosis. DESIGN: Prospective cohort study (Canadian Task Force classification II-2). PATIENTS: Eighty-five patients. SETTING: Tenon University Hospital, Paris, France. INTERVENTION: All patients received a preoperative CT enema and underwent MRI interpreted by 2 radiologists. MEASUREMENTS AND MAIN RESULTS: Patients underwent colorectal resection for colorectal endometriosis from February 2009 to November 2012. Nineteen patients (22%) had multifocal lesions, and 11 patients (13%) had multicentric lesions. Six patients (7%) had both multifocal and multicentric lesions. The sensitivity, specificity, and positive and negative likelihood ratios (LRs) of MRI for the diagnosis of multifocal lesions were 0.58, 0.84, 3.55, and 0.5, respectively. The sensitivity, specificity, and positive and negative LRs of the CT enema for the diagnosis of multifocal lesions were 0.64, 0.86, 4.56, and 0.4, respectively. The sensitivity, specificity, and positive LR of MRI for the diagnosis of multicentric lesions were 1, 0.88, and 8.4, respectively. The sensitivity, specificity, and positive and negative LRs of MRI for the diagnosis of multicentric lesions were 0.46, 0.92, 5.6, and 0.59, respectively. No difference was observed between MRI and the CT enema for the diagnosis of multifocal and multicentric colorectal endometriosis. The interobserver agreement was good for MRI and the CT enema (κ = 0.45 and 0.45) for multifocality, and it was poor for both MRI and the CT enema (κ = 0.32 and 0.34) for multicentricity. CONCLUSIONS: Both MRI and the CT enema were able to diagnose multifocal and multicentric bowel endometriosis with similar accuracy.