Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) with Low-Dose Cisplatin and Doxorubicin in Gastric Peritoneal Metastasis

Background

Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a novel technique of intraperitoneal chemotherapy. First results obtained with PIPAC in patients with advanced peritoneal metastasis (PM) from gastric cancer (GC) are presented.

Methods

Retrospective analysis: Sixty PIPAC were applied in 24 consecutive patients with PM from GC. 67 % patients had previous surgery, and 79 % previous platinum-based systemic chemotherapy. Mean Peritoneal Carcinomatosis Index (PCI) of 16?±?10 and 18/24 patients had signet-ring GC. Cisplatin 7.5 mg/m² and doxorubicin 1.5 mg/m² were given for 30 min at 37 °C and 12 mmHg at 6 week intervals. Outcome criteria were survival, adverse events, and histological tumor response.

Results

Median follow-up was 248 days (range 105–748), and median survival time was 15.4 months. Seventeen patients had repeated PIPAC, and objective tumor response was observed in 12 (12/24?=?50 %): no vital tumor cells?=?6, major pathological response?=?6, minor response?=?3. Postoperative adverse events?>?CTCAE 2 were observed in 9 patients (9/24, 37.5 %). In 3/17 patients, a later PIPAC could not be performed due to non-access. Two patients (ECOG 3 and 4) died in the hospital due to disease progression.

Conclusion

PIPAC with low-dose cisplatin and doxorubicin was safe and induced objective tumor regression in selected patients with PM from recurrent, platinum-resistant GC. First survival data are encouraging and justify further clinical studies in this indication.

     

Juvenile dermatomyositis: A report of three cases

Juvenile dermatomyositis (JDM), an autoimmune idiopathic myositis, is characterized by rash and proximal muscle weakness. Immunohistopathology typically shows perivascular inflammatory infiltrate with predominance of CD4+ T lymphocytes, perifascicular atrophy, and upregulation of major histocompatibility complex class I. JDM has been attributed to a humoral-driven muscle microangiopathy probably implicating the type I interferon pathway. Tubulo-reticular inclusions present in endothelial cell of muscle are biomarkers of interferon exposure, and so may be an indirect data of this myopathy especially in the absence of rash and inflammatory infiltrate. We report on three patients in which electron microscopy solves the differential diagnosis among infantile myositis showing peculiar inclusions.     

Molecular dissection of the rDNA array and of the 5S rDNA gene in Meloidogyne artiellia: phylogenetic and diagnostic implications

The sequence of a 13.423 nucleotide genomic fragment has been determined for the plant parasitic nematode Meloidogyne artiellia. It contains an entire rDNA cluster, the bordering intergenic regions and portions of the flanking coding regions. The sequence analysis of the rDNA repeats suggests homogeneity in M. artiellia, thus providing a further indication of the usefulness of these genes for the diagnostic identification of this species. The comparison of the secondary structures of the internal transcribed spacer 2 region in several Meloidogyne species indicates that RNA folding predictions can be used as a tool of potential diagnostic relevance. The other ribosomal gene, 5S rDNA, has been demonstrated to be functional and located near the trans-spliced leader sequences, in the same arrangement found in the distantly related nematode Caenorhabditis elegans but never in other Meloidogyne thus providing species-specific markers for the identification of several Thylenchida parasitic nematodes.     

Results of primary angioplasty for acute myocardial infarction in patients with multivessel coronary artery disease

The influence of multivessel coronary artery disease on the outcome of reperfusion therapy for myocardial infarction has not been fully characterized. Direct coronary angioplasty without antecedent thrombolytic therapy was performed during evolving myocardial infarction in 285 patients with multivessel coronary artery disease at 5.2 +/- 4.2 h after the onset of chest pain. Two vessel disease was present in 163 patients (57%) and three vessel disease in 122 (43%). An anterior infarct was present in 123 patients (43%), cardiogenic shock in 33 (12%) and age greater than or equal to 70 years in 59 (21%). Angioplasty of the infarct-related vessel was successful in 256 patients (90%), including 92% with two vessel and 88% with three vessel disease (p = NS). Emergency bypass surgery was needed in six patients (2%). In-hospital death occurred in 33 patients (12%), including 13 with two vessel and 20 with three vessel disease (p less than 0.05). The mortality rate was only 4% in the subgroup of 101 patients who met entry criteria for thrombolytic trials. The in-hospital mortality rate was 45% in patients in shock and 7% in patients not in shock (p less than 0.01). Logistic regression analysis identified shock and age greater than or equal to 70 years as independently associated with in-hospital death. In 135 patients who underwent predischarge left ventriculography, global ejection fraction increased from 50% to 57% (p less than 0.001) and regional wall motion in the infarct zone improved in 59% of patients. Follow-up data were available in 251 patients (99%) at a mean of 35 +/- 19 months.(ABSTRACT TRUNCATED AT 250 WORDS)     

Molecular determinants of response to PI3K/akt/mTOR and KRAS pathways inhibitors in NSCLC cell lines

Despite the impressive results obtained in the preclinical setting, all the inhibitors targeting two central cascades in cancer, the PI3K/akt/mTOR and the KRAS/MEK/ERK pathways, have shown, apart from very few exceptions, disappointing efficacy when translated to the clinic. One of the main reasons of their clinical failure seems to be the lack of a clear molecular determinant of response to these drugs. In this study, we tried to address this point by evaluating the cytotoxic activity of different inhibitors targeting the two pathways at different levels in a panel of ten NSCLC cell lines harboring alterations in PI3K, KRAS or both. We were not able to highlight a correlation between the presence of KRAS and PI3K mutations and a specific sensitivity to the different drugs used. Molecular analyses performed after equimolar treatments showed that, independently from the entity of the response, the drugs are able to modulate the activation of their targets. Interestingly, we found that p53 mutational status separates the cell lines according to their sensitivity to PI3K pathway inhibitors treatments. The alterations considered in the PI3K/akt/mTOR and in the KRAS/MEK/ERK pathways in the different NSCLC cell lines are not sufficient to drive treatment choice but rather p53 status is a potential biomarker for the activity of this class of drugs.     

Sulfated Progesterone Metabolites That Enhance Insulin Secretion via TRPM3 Are Reduced in Serum From Women With Gestational Diabetes Mellitus

Serum progesterone sulfates were evaluated in the etiology of gestational diabetes mellitus (GDM). Serum progesterone sulfates were measured using ultra-performance liquid chromatography–tandem mass spectrometry in four patient cohorts: 1) the Hyperglycemia and Adverse Pregnancy Outcomes study; 2) London-based women of mixed ancestry and 3) U.K.-based women of European ancestry with or without GDM; and 4) 11–13 weeks pregnant women with BMI ≤25 or BMI ≥35 kg/m² with subsequent uncomplicated pregnancies or GDM. Glucose-stimulated insulin secretion (GSIS) was evaluated in response to progesterone sulfates in mouse islets and human islets. Calcium fluorescence was measured in HEK293 cells expressing transient receptor potential cation channel subfamily M member 3 (TRPM3). Computer modeling using Molecular Operating Environment generated three-dimensional structures of TRPM3. Epiallopregnanolone sulfate (PM5S) concentrations were reduced in GDM (P < 0.05), in women with higher fasting plasma glucose (P < 0.010), and in early pregnancy samples from women who subsequently developed GDM with BMI ≥35 kg/m² (P < 0.05). In islets, 50 µmol/L PM5S increased GSIS by at least twofold (P < 0.001); isosakuranetin (TRPM3 inhibitor) abolished this effect. PM5S increased calcium influx in TRPM3-expressing HEK293 cells. Computer modeling and docking showed identical positioning of PM5S to the natural ligand in TRPM3. PM5S increases GSIS and is reduced in GDM serum. The activation of GSIS by PM5S is mediated by TRPM3 in both mouse and human islets.