Prognostic significance of AMPK activation in advanced stage colorectal cancer treated with chemotherapy plus bevacizumab.

BACKGROUND: AMP-activated protein kinase (AMPK) has a central role in cellular energy sensing and is activated in preclinical tumour models following anti-vascular endothelial growth factor (VEGF) therapy. The possible predictive or prognostic role of AMPK status in cancer patients treated with anti-VEGF drugs has not been investigated so far. METHODS: Expression of components of the AMPK pathway including phosphorylated AMPK (pAMPK), phosphorylated acetyl-Coa carboxylase (pACC) and liver kinase B1 (LKB1) was investigated by immunohistochemistry in 48 colorectal cancers treated with FOLFIRI plus bevacizumab. Correlation between pAMPK and pACC and associations between the AMPK pathway scores and clinico-pathological characteristics were assessed. Overall survival (OS) was estimated through Kaplan-Meier method, whereas hazard ratios were computed to identify prognostic factors. RESULTS: Fourteen patients (29.2%) were included in the pAMPK-negative group (score ≤5), whereas 34 patients (70.8%) were included in the pAMPK-positive group (score >5). The Spearman's coefficient for the correlation between pAMPK and pACC scores in primary tumour samples was 0.514 (P=0.0002). Low pAMPK levels were associated with worse OS (P-value 0.0002) but not with PFS, whereas low pACC levels were associated both with worse OS and PFS (P-value 0.0007 and 0.01, respectively). CONCLUSIONS: Our findings suggest that high tissue AMPK activation is a prognostic biomarker in this cohort of metastatic colorectal cancer patients.

Primitive omental leiomyoma: a case report.

Primitive omental leiomyomas are very rare. The primitive omental location of the leiomyoma is quite difficult to determine, with the possible presence of "parasite" myomas and of omental metastasizing myomas. Moreover, omental masses may be primitive or secondary metastasis from neoplasms. In this case report a primitive omental leiomyoma is described, and their diagnosis and management are briefly discussed, in order to improve the knowledge of this very uncommon disease.

The pathogenesis of endometrial polyps: a systematic semi-quantitative review.

UNLABELLED: The pathogenesis and natural history of endometrial polyps are not very clear. The objective of this study was to assess the opinions of international medical literature regarding the factors involved in the pathogenesis of endometrial polyps and to organize the results consistently with what is known about endometrial physiology. MATERIALS AND METHODS: A systematic review was carried out with the following search engines: PubMed, OVID, Scopus, SCIELO, and AJOL. Two hundreds forty-six abstracts were selected from the literature; of these abstracts, 58 factors were extracted and set as causative, non-causative, unclear or protective link with endometrial polyps. This relation is described through a correspondence analysis and tested with a main effect hierarchical log-linear model. RESULTS: The log-linear model resulted significant for the correspondence found with the following factors: (i) causative link (ageing, bcl-2 protein, excess weight/obesity, tamoxifen regardless of timing, relationship between estrogen receptors and prog-estinics, unbalanced estrogen therapy, estrogen-like effect, and unbalance between estrogens and progestinics), (ii) protective link (progestinics, antiestrogenic action), (iii) unclear link (menopause, ki-67 protein, angiogenesis, tamoxifen for a short time, tamoxifen for a long time, hormone replacement therapy (HRT), endometritis/inflammation), and (iv) non-causative link (none of the factors specifically). DISCUSSION: Subsequently to a review of the physiology of the endometrium, the onsetting of endometrial polyps was suggested through estrogen-related and non-estrogen related ways; the two ways can overlap. The most implied factors in the development of endometrial polyps are linked with one of these or both ways.

Behaviour of lab parameters and neonatal weight loss in relation to neonatal breathing movements and cord clamping time.

BACKGROUND: To date, delaying cord clamping two to three minutes after birth is considered effective for newborn well-being. This time does not consider the newborn's breathing movements, which may also condition neonate well-being. AIM: To investigate the behaviour of neonatal weight loss and of some umbilical vein lab parameters, in relation to timing of newborn breathing and cord clamping. MATERIALS AND METHODS: Time from birth to cord clamping and time from birth to first cry of the newborn were collected in 87 full-term healthy women. First cry is a sign of effective breathing. Birth weight loss at the first, second, and third day from birth and lab parameters were assessed in relation to: time from birth to cord clamping, time from birth to first cry, and cord clamping before or after the first cry. RESULTS: Partial pressure of carbon dioxide (pCO2) decreased if cord clamping was performed after first cry and increased if first cry occurred after cord clamping, independently from the time elapsed from birth to first cry (p = 0.012). Calcium (Ca(2+)) concentration decreased if cord clamping was performed after the first cry and increased if first cry of the baby after birth was delayed (p = 0.021). Each second of delay from birth to cord clamping resulted in an increase in Cl- concentration (p <0.001). Each second of delay in cord clamping resulted in a reduction in the percentage of weight loss at the first day (p = 0.024), at the second day (p = 0.007), and at the third day (p = 0.028) after birth. CONCLUSIONS: Neonate breathing after birth should induce umbilical vein flow from placenta to lungs, conditioning the reduction of birth weight loss after birth and umbilical lab parameters modifications.

Experience of practitioners and delivery outcome.

BACKGROUND: It is commonly believed that the experience of practitioners (time spent in delivery ward) may be helpful in aiding the spontaneous vaginal birth. AIM: To check if this opinion is true. METHODS: In 995 low-risk, full-term, pregnancies resulting in spontaneous labour, multivariate logistic regression analysis was performed, which considered the age, the years of service of the obstetrician and of the midwife, and of both as independent variables. Results The longer the obstetrician (odds ratio 0.779, C.I. 95% 0.653-0.930, p = 0.006) or the midwife has been practising (odds ratio 0.609, C.I. 95% 0.408-0.909, p = 0.015) the less likely is the occurrence of a spontaneous vaginal birth. The combined years of service of the caring doctor/midwife pair appears to have no influence on the outcome of delivery. The chances of an operative vaginal birth increase with the age of the caring obstetrician (odds ratio 1.362, C.I. 95% 1.138-1.630, p = 0.001). CONCLUSION: The experience of the staff assisting women in labour definitely does not determine the success of deliveries. The skills of each professional category are based on theoretical knowledge that is possibly not being put to use during routine duties, especially by the 'more experienced' practitioners. Additionally, it appears that there is no team work, and decisions are not taken together.

Dynamic changes of live/apoptotic circulating tumour cells as predictive marker of response to sunitinib in metastatic renal cancer.

BACKGROUND: Recently, we developed an apoptotic assay for expanding the monitoring capabilities of the circulating tumour cells (CTC) test during therapy. An automated platform for computing CTCs was integrated with a mAb (M30) targeting a neoepitope disclosed by caspase cleavage at cytokeratin 18 in early apoptosis; we showed that live CTCs were associated with progression, consistent with enhanced cell migration and invasion. The test was first applied here to mRCC. METHODS: Live/apoptotic CTCs changes were measured in mRCC patients receiving first-line Sunitinib and compared with circulating endothelial cell (CEC) levels. RESULTS: The presence of EpCAM-positive, live CTCs predicts progression in individual mRCC patient, being associated with distant metastasis under first-line Sunitinib. Synchronous detection of CTCs and CEC levels discloses for the first time an association between their dynamic changes and outcome: a rapid increase of the CEC number as early as the first cycle of therapy is associated with CTC decrease in non-progressed patients, whereas a delayed response of CECs is related to higher CTC values in the progressed group indicating treatment failure. CONCLUSION: We demonstrated that a delayed response to antiangiogenic treatment indicated by persistent detection of CECs correlates with persistent live CTCs and more aggressive disease.

Could endometrial cytology be helpful in detecting endometrial malignancies?

This short communication assesses the concordance indexes between hysteroscopic biopsies and endometrial cytology for each endometrial pattern found in a sample of 37 women. Patients underwent endometrial cytology under sonographic guidance. The specimens were obtained with an endocervical brush and were fixed on slides (no liquid-based methods). After endometrial cytology, hysteroscopy with biopsy was performed. The best concordance index was found for endometrial malignancies, suggesting that endometrial cytology is able to detect cancers but not other endometrial diseases, as compared with endometrial hysteroscopic biopsies. Therefore, the overall concordance index suggests a fair concordance between histological and cytological findings. This leads us to conclude that usual endometrial cytology should not be recommended to screen endometrial diseases, but it may be used as an alternative diagnostic tool when hysteroscopic biopsies or other blinded procedures for endometrial sampling are unwanted, because it allows malignancies to be detected as well as hysteroscopic-guided biopsies.

Effect of epidural analgesia on labor times and mode of delivery: a prospective study.

PURPOSE: To assess changes in labor times and delivery outcome in low-risk women requesting pain relief and undergoing epidural analgesia, according to the epidural analgesia schemes. MATERIALS AND METHODS: Prospective observational study of 499 low-risk women with epidural analgesia. Speed of dilatation (SD) (centimeters of dilatation / hours), speed of lowering of the fetal head through maternal pelvis (SL) (centimeters in lowering / hours), time of active phase of labor (TA), cesarean section (CS), vacuum application (VA) were dependent variables in multivariable linear and logistic regressions. RESULTS: Dilution of ropivacain, fentanyl amount, and volume of the first dose of epidural analgesia did not seem to affect labor times. Epidural analgesia with schemes used in this study favored both the dilatation and the fetal head lowering through maternal pelvis. Every five minutes from the first dose of epidural to the last top-up, SD decreased by about 13% (p=0.002), SL decreased by about 14% (p<0.001), and TA increased by about 40% (p<0.001). Additionally, every five minutes from the first dose of epidural to the last top-up, the odds of an operative vaginal birth (vacuum) increased by 0.7% (p<0.001). Increasing of number of top-ups independently caused a reduction in odds of undergoing CS (odds ratio 0.434; C.I. 95% 0.219-0.859, p=0.017), without influencing labor times. CONCLUSION: Epidural analgesia in patients requesting pain relief favors normal course of labor if it is not discontinued or delayed.

Pain and breastfeeding: a prospective observational study.

OBJECTIVE: To demonstrate that pain affects the goodness of breastfeeding. MATERIALS AND METHODS: Seventy-nine patients were interviewed regarding satisfaction in breastfeeding, tiredness, uterine pain, nipple and other pain, and analgesic use at day three and at first, second, third, and fourth week after birth. Data regarding the mode of delivery were recorded from medical charts. Milk formula supplements, bottle use, pacifier use, and nipple shields use were considered as variables suggesting unsuccessful breastfeeding. RESULTS: At third day after delivery, it appeared that analgesic use was significantly associated with milk formula supplementing, bottle use, less satisfaction in breastfeeding, and more tiredness. At first week after delivery, the presence of pain differing from nipple and uterine pain, was more likely associated with milk formula supplementing, bottle use, pacifier use, less satisfaction in breastfeeding, and more tiredness. At third week after delivery, nipple pain was directly related to tiredness, while it increased the odds of adding milk formula and using a bottle. CONCLUSION: Pain affects the goodness of breastfeeding.

Effect of epidural analgesia on operative vaginal birth rate.

The aim of the study was to investigate if epidural analgesia may affect the operative vaginal birth rate. An observational study was carried out on 1,158 in low-risk patients who delivered vaginally; 46.9% of these patients underwent epidural analgesia using different doses and drugs. Overall, epidural analgesia enhanced the probability of vacuum delivery (OR 2.70 95% CI 1.88-3.89, p < 0.001). Vacuum application was increased about seven times by administration of fentanyl alone at the first dose, while it was reduced if ropivacaine was added to fentanyl. In patients undergoing epidural analgesia, increasing the amount of ropivacaine at the first dose reduced the probability of vacuum delivery (OR 0.82; 95% CI 0.67-1.00, p = 0.05). Moreover, increasing the number of top-ups reduced the probability of vacuum delivery (OR 0.49 95% CI 0.27-0.93, p = 0.029) and the time of the second stage of labor. On the other hand, increasing time from the first dose of epidural to the last top-up increased the risk of operative vaginal delivery (OR 1.33 95% CI 1.03-1.72, p = 0.031) and the time of the second stage of labor. Epidural analgesia seems to favor spontaneous delivery when it is properly carried on.

Druggable targets meet oncogenic drivers: opportunities and limitations of target-based classification of tumors and the role of Molecular Tumor Boards.

The therapeutic landscape of cancer is changing rapidly due to the growing number of approved drugs capable of targeting specific genetic alterations. This aspect, together with the development of noninvasive methods for the assessment of somatic mutations in the peripheral blood of patients, generated a growing interest toward a new tumor-agnostic classification system based on 'predictive' biomarkers. The current review article discusses this emerging alternative approach to the classification of cancer and its implications for the selection of treatments. It is suggested that different types of cancers sharing the same molecular profiles could benefit from the same targeted drugs. Although recent clinical trials have demonstrated that this approach cannot be generalized, there are also specific examples that demonstrate the clinical utility of this alternative vision. In this rapidly evolving scenario, a multidisciplinary approach managed by institutional Molecular Tumor Boards is fundamental to interpret the biological and clinical relevance of genetic alterations and the complexity of their relationship with treatment response.

Lymphoproliferative disease in human peripheral blood mononuclear cell-injected SCID mice. I. T lymphocyte requirement for B cell tumor generation.

Mechanisms of tumor development were studied in SCID mice injected with human lymphoid cells from Epstein-Barr virus-positive (EBV+) donors. About 80% of peripheral blood mononuclear cell (PBMC)-injected animals developed a lymphoproliferative disease associated with oligoclonal EBV+ tumors of human B cell origin. No change in tumor development rate occurred when monocyte-depleted PBMC were inoculated. No tumors developed when purified B cells were injected. B cell lymphoproliferative disease was also prevented in most cases when PBMC-injected animals were treated with agents that prevent T cell activation, such as cyclosporin A. Both CD4+ and CD8+ T cell subpopulations were able to provide putative factor(s) necessary for EBV+ B cell expansion and progression to tumors. These data suggest that the transfer alone of potentially tumorigenic human cells into an immunodeficient environment, such as the SCID mouse, might not be sufficient for cell progression to tumor, and raise the possibility that chronic activation events could play a major role in the pathogenesis of some EBV+ lymphomas in the immunocompromised host.

Impact of the medicalization of labor on mode of delivery.

AIMS: To evaluate whether routine medical interventions during labor (oxytocin augmentation, induction, amniotomy, epidural analgesia) condition the outcome of delivery independently of each other and of obstetric risk (calculated in an objective manner). Moreover, to evaluate whether there is an ideal window for initiating such interventions. METHODS: Prospective, observational study with 1,047 patients enrolled. RESULTS: Medical interventions were high, whether in low-, medium- or high-risk pregnancies. Oxytocin augmentation (odds ratio 4.678) labour induction (odds ratio 1.717) amniotomy (odds ratio 1.403) and obstetric risk (intermediate-risk odds ratio 1.889, high-risk odds ratio 2.008) increase the probability of an operative delivery. Oxytocin augmentation increases both the probability of a Cesarean delivery and vacuum extraction. Epidural analgesia reduces the probability of cesarean delivery and increases the probability of vacuum extraction. The greater the cervical dilation when oxytocin infusion is initiated, the lower the probability of an operative delivery. The more advanced the cervical dilation and the lower the station when amniotomy or epidural analgesia are carried out, the lower the probability of an operative delivery. Obstetric risk and oxytocin augmentation appear to increase the probability of operative delivery in patients who have undergone amniotomy or epidural analgesia. In addition, labor induction in patients who undergo epidural analgesia increases the risk of operative delivery. CONCLUSIONS: Medical interventions during labor are high and cause a rise in operative delivery. Therefore, practitioners should defer it as much as possible. The exception is epidural analgesia because it seems to reduce the number of cesarean sections.

Malignant transformation of uterine leiomyomata.

The malignant transformation of a uterine leiomyoma is still debated and, if it occurs, it is very rare. The case of a patient affected by three small leiomyomas, monitored by the same gynecologist over the years is described. Two of these leiomyomas were transformed into leiomyosarcoma after menopause and the patient died despite receiving therapy. The case reported here is meant to underline the need to keep all uterine myomas in check since the transition into leiomyosarcomas may occur with an evolution over a time period which has not been established so far.

LKB1 loss is associated with glutathione deficiency under oxidative stress and sensitivity of cancer cells to cytotoxic drugs and γ-irradiation.

The liver kinase B1 (LKB1) gene is a tumor suppressor associated with the hereditary Peutz-Jeghers syndrome and frequently mutated in non-small cell lung cancer and in cervical cancer. Previous studies showed that the LKB1/AMPK axis is involved in regulation of cell death and survival under metabolic stress. By using isogenic pairs of cancer cell lines, we report here that the genetic loss of LKB1 was associated with increased intracellular levels of total choline containing metabolites and, under oxidative stress, it impaired maintenance of glutathione (GSH) levels. This resulted in markedly increased intracellular reactive oxygen species (ROS) levels and sensitivity to ROS-induced cell death. These effects were rescued by re-expression of LKB1 or pre-treatment with the anti-oxidant and GSH replenisher N-acetyl cysteine. This role of LKB1 in response to ROS-inducing agents was largely AMPK-dependent. Finally, we observed that LKB1 defective cells are highly sensitive to cisplatin and γ-irradiation in vitro, suggesting that LKB1 mutated tumors could be targeted by oxidative stress-inducing therapies.

Biochemical determinations of arylsulphatase A activity and sulphatide concentrations in decidua of women at 41 and 42 weeks of gestation.

OBJECTIVE: To evaluate arylsulphatase A activity and sulphatide concentrations in decidua of women at 41 and 42 weeks of gestation. STUDY DESIGN: Enzyme activity and sulphatide concentrations were determined by biochemical procedures on samples of women at 41 and 42 weeks of gestation; thin-layer chromatography was also prepared to separate and visualize sulphatides and other lipid fractions. RESULTS: The spectrophotometric values of arylsulphatase A showed very low values at 41 weeks, which reduced to a half at 42 weeks of gestation, while values of sulphatide concentrations increased in 42 weeks. CONCLUSIONS: The behavior of two parameters examined could be due to the amount of placental estriol reduction, because of sudden placental aging.

Bilateral Brenner tumor with endometrial adenocarcinoma in a postmenopausal woman.

Brenner tumor is a rare ovarian neoplasm which is generally monolateral, more rarely bilateral, and often associated with endometrial disorders related to oestrogenic production. However, there is no considerable evidence that the possible oestrogenic production of this tumor may be the cause of endometrial disorders. A case of bilateral Brenner tumor with endometrial adenocarcinoma in a postmenopausal woman is presented and the features are briefly discussed, with the conclusion that hormone-producing Brenner tumors may exert their promoter effect on the development of endometrial carcinoma causing an imbalance in the oestrogen and progesterone ratio rather than producing a large amount of oestrogen.

Effects of angiostatin gene transfer on functional properties and in vivo growth of Kaposi's sarcoma cells.

Gene transfer delivery of endogenous angiogenesis inhibitors such as angiostatin would circumvent problems associated with long-term administration of proteins. Kaposi's sarcoma (KS), a highly vascular neoplasm, is an excellent model for studying tumor angiogenesis and antiangiogenic agent efficacy. We investigated the effects of angiostatin gene transfer in in vitro and in vivo models of KS-induced neovascularization and tumor growth. A eukaryotic expression plasmid and a Moloney leukemia virus-based retroviral vector for expression of murine angiostatin were generated harboring the angiostatin cDNA with cleavable leader signals under the control of either the strong cytomegalovirus promoter/enhancer or the Moloney leukemia virus long terminal repeat. Angiostatin secretion was confirmed by radioimmunoprecipitation and Western blot analysis. Supernatants of angiostatin-transfected cells inhibited endothelial cell migration in vitro. Stable gene transfer of the angiostatin cDNA by retroviral vectors in KS-IMM cells resulted in sustained angiostatin expression and delayed tumor growth in nude mice, which was associated with reduced vascularization. These findings suggest that gene therapy with angiostatin might be useful for treatment of KS and possibly other highly angiogenic tumors.

Calcineurin and GSK-3 inhibition sensitizes T-cell acute lymphoblastic leukemia cells to apoptosis through X-linked inhibitor of apoptosis protein degradation.

The calcineurin (Cn)-nuclear factor of activated T cells signaling pathway is critically involved in many aspects of normal T-cell physiology; however, its direct implication in leukemogenesis is still ill-defined. Glycogen synthase kinase-3ß (GSK-3ß) has recently been reported to interact with Cn in neuronal cells and is implicated in MLL leukemia. Our biochemical studies clearly demonstrated that Cn was able to interact with GSK-3ß in T-cell acute lymphoblastic leukemia (T-ALL) cells, and that this interaction was direct, leading to an increased catalytic activity of GSK-3ß, possibly through autophosphorylation of Y216. Sensitivity to GSK-3 inhibitor treatment correlated with altered GSK-3ß phosphorylation and was more prominent in T-ALL with Pre/Pro immunophenotype. In addition, dual Cn and GSK-3 inhibitor treatment in T-ALL cells promoted sensitization to apoptosis through proteasomal degradation of X-linked inhibitor of apoptosis protein (XIAP). Consistently, resistance to drug treatments in primary samples was strongly associated with higher XIAP protein levels. Finally, we showed that dual Cn and GSK-3 inhibitor treatment in vitro and in vivo is effective against available models of T-ALL, indicating an insofar untapped therapeutic opportunity.