Concurrent adjuvant chemotherapy and immediate breast reconstruction with skin expanders after mastectomy for breast cancer

Background. Immediate breast reconstruction (IBR) by means of skin expander is currently one of the most widely used methods of breast reconstruction in mastectomized patients. However, given that many breast cancer patients usually receive adjuvant chemotherapy, the adoption of IBR raises new questions concerning possible cumulative toxicity. The present study reports our experience in the use of concurrent adjuvant chemotherapy and immediate breast reconstruction with skin expander after mastectomy for breast cancer and the acute cumulative toxicity of the treatments. Methods. We evaluated a consecutive series of 52 breast cancer patients who have received IBR by skin expander after radical mastectomy and adjuvant chemotherapy concurrently during skin expansion between 1995 and 1998 (IBR/CT group). We identified two series of control patients treated during the same period: 51 consecutive patients undergoing radical mastectomy and IBR without adjuvant chemotherapy (IBR group) and 63 consecutive patients undergoing radical mastectomy and adjuvant chemotherapy without IBR (CT group). For each patient, we evaluated the incidence of surgical complications and chemotherapy's side effects and dose intensity. Results. The interval between surgery and the start of expander inflation was similar in IBR/CT (range 0–19, median 5 days) and IBR groups (range 0–40, median 5 days) and the timing of inflation was not influenced by chemotherapy. The overall incidence of surgical complications in patients undergoing IBR was low: seroma in eight cases, infection in one, skin necrosis in one, expander rupture in two and erythema in three. There were no statistically significant differences in the distribution of complications between the IBR/CT and IBR groups. The dose intensity of chemotherapy was similar between IBR/CT and CT groups, with a median dose intensity of 96% and 95% of the projected dose, respectively. The only statistically significant difference in terms of chemotherapy side effects (p=0.03) was that stomatitis was more frequent and intense in the CT than in the IBR/CT group. Conclusions. Concurrent treatment with IBR and adjuvant chemotherapy appears feasible and safe, it does not increase acute surgical complications or chemotherapy side effects, and does not require any changes in dose intensity or the timing of inflation.     

Wound healing of laparoscopic esophageal myotomy with or without an added gastric patch

Background: The purpose of this research is to compare the wound healing of the laparoscopic esophagomyotomy with and without a gastric patch. Methods: Twelve male pigs were distributed into two groups of six animals. Esophagomyotomy was performed in group A. A gastric patch was associated to the myotomy in group B. On the 21^st postoperative day, lumen molding was accomplished to determine the index of stenosis (IS) at the area of myotomy (AM). Macroscopic and microscopic aspects of wound healing were also studied at AM. Three microscopic morphologic patterns were defined for morphometric evaluation: leukocytes (constituted by polymorphonuclear and mononuclear cells), new endothelial cells, and collagen fibers. Results: There was a longer operative duration in group B (93.6 min) than in group A (45 min). At AM, IS was negative (lumen increased) and equivalent in both groups: −11.1% in group A and −12.7% in group B. Mesotelial epithelium covering RM was observed in group A. Inflammatory reaction was greater in group B in comparison with group A (leuCocytes: 22 cells versus 8.6; fibrosis: 25.5 fibers versus 15.6; granulation tissue: 18.7 vessels versus 9.7). Conclusion: Esophagomyotomy followed by gastric patch does not heal adequately and is worsened by the presence of foreign body granulomas around stitches. Myotomy without gastric patch is faster and causes lower inflammation. Myotomy alone or with gastric patch does not lead to esophageal stenosis at RM and does not lead to restoration of the esophageal musculature continuity.     

Quality of life and disability assessment in neuropathy: a multicentre study

Neuropathy can severely affect patients' quality of life (QoL), causing disability and decreased motor efficiency while modifying their perception of the external environment. We performed a large, multi-perspective, and multi-measurement assessment using validated clinical measurements of disability and QoL. With regard to general disability, more than 10% of patients needed assistance to walk. With regard to arm disability, about 10% of patients had severe disability defined as impairment in carrying out simple tasks. General disability was similar both in polyneuropathic and multi-neuropathic groups, but arm disability appeared more severe in multi-neuropathic patients. QoL profiles were highly deteriorated in our sample with respect to the Italian normative sample. All age brackets were highly impaired except for older patients for whom the QoL picture was only mildly impaired with respect to Italian norms. We believe that our study provides reliable data on QoL in patients with neuropathies and that it may represent a quantitative step forward in understanding the disability of patients with neuropathy.     

Intraventricular nerve growth factor infusion: a possible treatment for neurological deficits following hypoxic-ischemic brain injury in infants

OBJECTIVE AND IMPORTANCE: Hypoxic-ischemic brain injuries in childhood are associated with poor neurological outcome. Unfortunately, no new therapeutic approaches have been proposed. Recently, animal studies show that nerve growth factor (NGF) can reduce neurological deficits following hypoxic-ischemic brain injuries. The objective of this study is to demonstrate the therapeutic effects of intraventricular NGF infusion in severe post-ischemic damage. CLINICAL PRESENTATION: Two infants, aged 9 and 8 months, with hypoxic-ischemic brain damage, secondary to prolonged cardiorespiratory arrest and stabilized after the conventional treatment, were treated with intraventricular NGF infusion. Before the therapy both infants were comatose with asymmetrical tetraparesis; their Glasgow Coma Scale (GCS) was 4 and 5, respectively. One month after the treatment, their GCS was 8 and 9, respectively. EEG examinations performed after the NGF infusion showed an increased alpha/theta ratio. MRI showed a reduction of malacic areas in the brain. A SPECT study, performed only in one infant, demonstrated that the NGF treatment resulted in an improvement of regional cerebral perfusion in right temporal and occipital cortices. INTERVENTION: The drug utilized was 2.5S NGF purified and lyophilized from male mouse submaxillary glands. NGF infusion was started about 30 days after the hypoxic-ischemic brain injury. 0.1 mg NGF was administered via the external drainage catheter into the right cerebral ventricle once a day for 10 days consecutively. CONCLUSION: Our observations are interesting, but further studies are necessary to confirm the effects of NGF in hypoxic-ischemic brain injuries in infants.     

Antitumor agents. 3. Design, synthesis, and biological evaluation of new pyridoisoquinolindione and dihydrothienoquinolindione derivatives with potent cytotoxic activity

New antiproliferative compounds, the 1-aryl-3-ethoxycarbonyl-pyrido[2,3-g]isoquinolin-5,10-diones (PIQDs, 1-7), were designed on the basis of a molecular model obtained by aligning the common quinolinquinone substructure of 5H-pyrido[3,2-a]phenoxazin-5-one (PPH) and some known anticancer agents. A Diels-Alder reaction between quinolin-5,8-dione (QD) and a 2-azadiene, formed by demolition of 2-aryl-1,3-thiazolidine ethyl esters (T compounds), was used to produce 1-7 and the isomeric 1-aryl-3-ethoxycarbonylpyrido[3,2-g]isoquinolin-5,10-diones (8-14). Two other compounds, the 3-amino-3-ethoxycarbonyldihydrothieno[2,3-g]quinolin-4,9-dione (15) and the 3-amino-3-ethoxycarbonyldihydrothieno[3,2-g]quinolin-4,9-dione (16), arising from a 1,4 Michael reaction of QD with a thiolate species formed by opening of T compounds, were recovered from the reaction mixture. The antiproliferative activity of 1-16 was evaluated against representative human liquid and solid neoplastic cell lines. The IC(50) of these compounds had median values in the range 2.00-0.01 microM, with 2-4 and 15 exhibiting significantly higher in vitro cytotoxic activity. Compound 2, also evaluated against KB subclones (KB(MDR), KB(7D), and KB(V20C)), was shown to be scarcely subject to the MDR1/P-glycoprotein drug efflux pump responsible for drug resistance. The noncovalent DNA-binding properties of PIQDs were examined using UV-vis and (1)H NMR spectroscopy experiments. Accordingly, these compounds were confirmed to have an ability to intercalate into double-stranded DNA by topoisomerase I superhelix unwinding assay. Interesting structure-activity relationships were found. Three important features seem to contribute to the cytotoxic activity of these anticancer ligands: (i) the DNA intercalating capability of the three-cyclic quinonic system, typical of this class of compounds, (ii) the position of the pendant phenyl ring that, according to the superimposition model, must occupy the same area of the corresponding benzo-fused ring A of PPH, and (iii) the effect of electron-withdrawing substituents on the phenyl ring, which can contribute improving the pi-pi stacking interactions between ligand and DNA base pairs. Besides, a mechanism of action suspected to involve topoisomerases could be hypothesized to interpret the antiproliferative activity of the thienoquinolindione 15, which can be regarded as a cyclic cysteine derivative.     

Dexamethasone promotes toxicity in U937 cells exposed to otherwise nontoxic concentrations of peroxynitrite: pivotal role for lipocortin 1-mediated inhibition of cytosolic phospholipase A2

Pretreatment with dexamethasone (Dex) was not toxic for U937 cells but caused a rapid lethal response upon subsequent exposure to otherwise nontoxic concentrations of peroxynitrite. This effect was not associated with enhanced formation of hydrogen peroxide taking place after peroxynitrite and was shown previously to play a pivotal role in the ensuing lethal response. Further analyses revealed that although Dex did not affect cytosolic phospholipase A(2) (cPLA(2)) expression, it markedly reduced the extent of arachidonic acid (AA) release mediated by peroxynitrite-dependent stimulation of cPLA(2). This event, as well as the enhanced toxicity, was abolished by mifepristone, a glucocorticoid receptor antagonist. The outcome of various approaches, using phospholipase A(2) inhibitors, cPLA(2) antisense oligonucleotide-transfected cells, and supplementation with exogenous AA, led to the demonstration that inhibition of cPLA(2) activity is causally linked to the increased susceptibility to peroxynitrite caused by Dex. Finally, the effects of Dex were shown to be mediated by enhanced expression of lipocortin 1 (LC1), a cPLA(2) inhibitory protein. These results indicate that Dex promotes toxicity in U937 cells exposed to otherwise nontoxic concentrations of peroxynitrite and that this event is causally linked to enhanced expression of LC1 leading to inhibition of cPLA(2). Thus, the increased lethal response arises because of LC1-dependent impairment of the AA-induced cytoprotective mechanism triggered by peroxynitrite.