Impact of the Multidisciplinary Cancer Team on the Diagnostic and Therapeutic Care Pathway of Early Breast Cancer Patients and Perception of Team Members: The Experience of a Cancer Centre in Italy.

Literature on the role of multidisciplinary team (MDT) in cancer is still controversial. We aimed to investigate MDT impact on a panel of indicators in breast cancer care in a single-center retrospective study performed in a Cancer Reference Center in Italy. We analysed the diagnostic and therapeutic care pathway (DTCP) of 266 early breast cancer patients managed by our MDT during 2019-2020. Process indicators reflecting the change of the diagnostic and therapeutic care pathways occurred after the MDT discussion were computed. Further, the performance of some quality care indicators in breast cancer care since the establishment of the MDT activity and the breast cancer MDT members' perceptions were also investigated. According to our study, the MDT approach improves breast cancer management by increasing the completion of staging and by encouraging neo-adjuvant treatment and an appropriate and faster surgery. In MDT members' perspective it also improves decision-making and training and creates a positive work environment. Globally, our study encourages MDT rollout in breast cancer care. However, to enhance the reliability and comparability of the results of studies investigating MDT effectiveness in clinical practice, shared guidelines on its operationalisation are strongly desirable.

Third whole-brain radiation therapy for multiple brain metastases. Should it be considered in selected patients?

Whole brain reirradiation for the treatment of multiple brain metastases has shown promising results. However, concerns remain over the possible neurotoxic effects of the cumulative dose as well as the questionable radiosensitivity of recurrent metastases. A second reirradiation of the whole brain is ordinarily performed in our department for palliative purposes in patients presenting with multiple metastatic brain progression. For this study, an investigational third whole brain reirradiation has been administered to highly selected patients to obtain disease control and delay progression. Clinical outcomes and neurological toxicity were also evaluated.

DIAGNOSIS OF ENDOCRINE DISEASE: Primary empty sella: a comprehensive review.

Primary empty sella (PES) is characterized by the herniation of the subarachnoid space within the sella, which is often associated with variable degrees of flattening of the pituitary gland in patients without previous pituitary pathologies. PES pathogenetic mechanisms are not well known but seem to be due to a sellar diaphragm incompetence, associated to the occurrence of upper sellar or pituitary factors, as intracranial hypertension and change of pituitary volume. As PES represents in a majority of cases, a neuroradiological findings without any clinical implication, the occurrence of endocrine, neurological and opthalmological symptoms, due to the above describes anatomical alteration, which delineates from the so called PES syndrome. Headache, irregular menses, overweight/obesity and visual disturbances compose the typical picture of PES syndrome and can be the manifestation of an intracranial hypertension, often associated with PES. Although hyperprolactinemia and growth hormone deficit represent the most common endocrine abnormalities, PES syndrome is characterized by heterogeneity both in clinical manifestation and hormonal alterations and can sometime reach severe extremes, as occurrence of papilledema, cerebrospinal fluid rhinorrhea and worsening of visual acuity. Consequently, a multidisciplinary approach, with the integration of endocrine, neurologic and ophthalmologic expertise, is strongly advocated and recommended for a properly diagnosis, management, treatment and follow-up of PES syndrome and all of the related abnormalities.

Inhibition of WNT signaling attenuates self-renewal of SHH-subgroup medulloblastoma.

The SMOOTHENED inhibitor vismodegib is FDA approved for advanced basal cell carcinoma (BCC), and shows promise in clinical trials for SONIC HEDGEHOG (SHH)-subgroup medulloblastoma (MB) patients. Clinical experience with BCC patients shows that continuous exposure to vismodegib is necessary to prevent tumor recurrence, suggesting the existence of a vismodegib-resistant reservoir of tumor-propagating cells. We isolated such tumor-propagating cells from a mouse model of SHH-subgroup MB and grew them as sphere cultures. These cultures were enriched for the MB progenitor marker SOX2 and formed tumors in vivo. Moreover, while their ability to self-renew was resistant to SHH inhibitors, as has been previously suggested, this self-renewal was instead WNT-dependent. We show here that loss of Trp53 activates canonical WNT signaling in these SOX2-enriched cultures. Importantly, a small molecule WNT inhibitor was able to reduce the propagation and growth of SHH-subgroup MB in vivo, in an on-target manner, leading to increased survival. Our results imply that the tumor-propagating cells driving the growth of bulk SHH-dependent MB are themselves WNT dependent. Further, our data suggest combination therapy with WNT and SHH inhibitors as a therapeutic strategy in patients with SHH-subgroup MB, in order to decrease the tumor recurrence commonly observed in patients treated with vismodegib.

The Notch signaling pathway in esophageal adenocarcinoma.

The Notch signaling pathway plays a critical role in embryonic development, self-renewal of stem cells, and carcinogenesis. Aberrant Notch signaling has been linked to a wide variety of cancers, and can either suppress or promote tumors depending on the cell type and the context. Increasingly it is being realized that Notch signaling not only involves in the pathogenesis and development of esophageal adenocarcinoma (EAC), it also promotes the growth of EAC cells and also involved in the maintenance of EAC cancer stem cells. The efficacy of gamma-secretase inhibitor (GSI) in EAC treatment could have a major impact on easing the burden of this devastating disease. Therefore, it appears that inhibition of Notch sensitizes EAC cells to chemotherapeutic agents, which should lead to a better and more durable response to neoadjuvant chemotherapy (NAC). In this review, we bring to highlight how Notch plays a role in the development, tumorigenicity, and stemness of EAC cells, and how Notch signaling pathway could be a promising therapeutic target for the treatment of human EAC.

The hedgehog processing pathway is required for NSCLC growth and survival.

Considerable interest has been generated from the results of recent clinical trials using smoothened (SMO) antagonists to inhibit the growth of hedgehog (HH) signaling-dependent tumors. This interest is tempered by the discovery of SMO mutations mediating resistance, underscoring the rationale for developing therapeutic strategies that interrupt HH signaling at levels distinct from those inhibiting SMO function. Here, we demonstrate that HH-dependent non-small cell lung carcinoma (NSCLC) growth is sensitive to blockade of the HH pathway upstream of SMO, at the level of HH ligand processing. Individually, the use of different lentivirally delivered shRNA constructs targeting two functionally distinct HH-processing proteins, skinny hedgehog (SKN) or dispatched-1 (DISP-1), in NSCLC cell lines produced similar decreases in cell proliferation and increased cell death. Further, providing either an exogenous source of processed HH or a SMO agonist reverses these effects. The attenuation of HH processing, by knocking down either of these gene products, also abrogated tumor growth in mouse xenografts. Finally, we extended these findings to primary clinical specimens, showing that SKN is frequently overexpressed in NSCLC and that higher DISP-1 expression is associated with an unfavorable clinical outcome. Our results show a critical role for HH processing in HH-dependent tumors, identifies two potential druggable targets in the HH pathway, and suggest that similar therapeutic strategies could be explored to treat patients harboring HH ligand-dependent cancers.

Synthesis of picosecond pulses by spectral compression and shaping of femtosecond pulses in engineered quadratic nonlinear media.

Narrow-bandwidth picosecond pulses of predetermined spectral and temporal shapes are generated with high efficiency by frequency conversion of femtosecond pulses in lithium tantalate crystals with engineered quasi-phase-matching structures. We give examples of the synthesis of Gaussian and super-Gaussian picosecond pulses and also of a pair of synchronized phase-coherent picosecond pulses with a predetermined carrier-frequency difference.

It's T-ALL about Notch.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive subset of ALL with poor clinical outcome compared to B-ALL. Therefore, to improve treatment, it is imperative to delineate the molecular blueprint of this disease. This review describes the central role that the Notch pathway plays in T-ALL development. We also discuss the interactions between Notch and the tumor suppressors Ikaros and p53. Loss of Ikaros, a direct repressor of Notch target genes, and suppression of p53-mediated apoptosis are essential for development of this neoplasm. In addition to the activating mutations of Notch previously described, this review will outline combinations of mutations in pathways that contribute to Notch signaling and appear to drive T-ALL development by 'mimicking' Notch effects on cell cycle and apoptosis.

Penetrating keratoplasty in a newborn: case report and analysis of current surgical trends in Italy.

PURPOSE: The aims of this study were to describe bilateral penetrating keratoplasty (PK) in a newborn and to analyze the data of PKs performed in Italy during the 5-year period 1999-2003 in children under 4 years of age. METHODS: A male newborn had PK at age 3 months and 5 months for near-blindness secondary to severe congenital corneal clouding in both eyes. The infant''s explanted corneas were subjected to histochemical and ultrastructural analyses. Data regarding the number of PKs performed in Italy on 0-4-year-olds were obtained from the Web site of the Italian Ministry of Health. RESULTS: The postoperative courses were uncomplicated, and 42 months of follow-up data show bilateral graft transparency and substantial improvement in visual acuity despite high-grade myopia and nystagmus. At the ultrastructural level, the main alterations involved the endothelial cells and Descemet membrane. A total of 45 PKs were performed in Italy on patients 0-4 years old from 1999 through 2003; only nine involved babies under 1 year of age. CONCLUSIONS: In babies with congenital corneal opacities, early PK can reduce severe amblyopia. However, the risk of intra- and postoperative complications in PK is high. Based on the 42-month follow-up, the anatomic and functional results achieved in the current patient are satisfactory despite the presence of nystagmus and postoperative high-grade myopia. This study shows that PKs are rarely performed, in Italy, in children aged 0-4 years, and very few are done during the first year of life.

Narrow-bandwidth picosecond pulses by spectral compression of femtosecond pulses in second-order nonlinear crystals.

We introduce a simple approach for the efficient generation of tunable narrow-bandwidth picosecond pulses synchronized to broadband femtosecond ones. Second harmonic generation in the presence of large group velocity mismatch between the interacting pulses transfers a large fraction of the energy of a broadband fundamental frequency pulse into a narrowband second harmonic one. Using a periodically poled stoichiometric lithium tantalate crystal coupled to an infrared optical parametric amplifier, we generated 200-nJ pulses with spectral width lower than 8.5 cm(-1) and tunability from 720 to 890 nm. Energy scaling and extension of the tuning range are straightforward.

Expression of JAGGED1 in T-lymphocytes results in thymic involution by inducing apoptosis of thymic stromal epithelial cells.

Proper development of the thymus and differentiation of T-lymphocytes requires cell-cell interactions between the developing T-lymphocytes and the thymic epithelia. The Delta/Serrate/Lag-2 (DSL)/Notch signal-transduction pathway is known to govern cell fate decisions required for proper development through direct cell-cell interactions. The functional consequences of specific DSL/Notch interactions during the development of a complex organ, such as the thymus, have not been thoroughly elucidated, however. In order to examine the role of DSL proteins during thymus development and T-lymphocyte differentiation, we targeted expression of JAGGED1 in T-lymphocyte progenitors via the control of the proximal lck promoter. Here, we report that expression of JAGGED1 in T cells causes premature involution of the thymus by directing thymic epithelial cells to undergo an apoptotic program. Adoptive transfer of JAGGED1 transgenic bone marrow into non-transgenic mice revealed that JAGGED1 expression on T cells does not alter T-cell differentiation, but is directly responsible for involution of the thymus. We propose that the phenotype of the lck-JAGGED1 transgenic mice is a direct result of specific DSL/Notch interactions and improper cell-to-cell signaling.

[The Currarino syndrome: two case reports]. / La sindrome di Currarino: due casi clinici.

The association of congenital anal stenosis, or other anal and rectal malformation, sacral defect and a presacral mass is known as the Currarino syndrome described for the first time in 1981. Currarino et al. proposed that abnormal endoectodermal adhesions and notochordal defects in early fetal life may result in a fistula between the gut and the spinal canal with enteric elements ventrally and neural elements dorsally. This abnormality appears to be a variant of the split notochord syndrome. The occurrence of Currarino's triad of anomalies is familial in more than 50% of cases. The most important suggested hypothesis of transmission is an X-linked dominant pattern, but most of the other reports are consistent with an autosomal dominant mode of inheritance. The medical therapy is poorly successful and, therefore, the surgical treatment is recommended for Currarino's syndrome.

Foker's technique in oesophageal atresia with double fistula: a case report.

The authors' starting point is a new surgical approach described by Foker and performed by them on a newborn with long-gap oesophageal atresia. We discuss the possibility of obtaining rapid growth of the atretic oesophagus and performing a primary anastomosis in the case of long-gap oesophageal atresia. With this procedure, primary oesophageal repair could be performed without myotomies, without flaps and with the gastrooesophageal junction below the diaphragm. The need for gastrostomy would be also eliminated if the patient underwent the operation as a neonate.

Segmental dilatation of the ileum presenting with acute intestinal bleeding.

The authors report a case of acute intestinal bleeding caused by ulcerated segmental ileal dilatation occurring in a 5-month-old infant. The profuse emission of dark red blood per rectum caused acute anemia (Hb 5.3 g/dL). Because of absence of any other sign and symptom and normal plain x-ray, a bleeding Meckel's diverticulum was suspected. Laparoscopy was performed showing the ileal dilatation, and through an enlarged port incision the bowel was exteriorized and resected. Histology results showed an ulcer caused by heterotopic gastric mucosa. The etiopathogenesis and clinical manifestations of segmental intestinal dilatation are discussed.

Nitric oxide produced by non-motoneuron cells enhances rat embryonic motoneuron sensitivity to excitotoxins: comparison in mixed neuron/glia or purified cultures.

The present study compares the sensitivity to chronic exposure to glutamate agonists of SMI-32-positive rat-derived embryonic motoneurons under both mixed neuron/glia and purified cultures. We found that in spite of a trophic role of glia on cultured motoneurons, SMI-32-positive cells are more sensitive to excitotoxicity in the presence of glia than in purified culture, very likely through nitric oxide released by non-neuronal cells. The rank order of potency for inducing toxicity after 48 h incubation was AMPA>kainate>NMDA, with EC(50): 0.43, 4.9 and 49 microM, respectively, in mixed neuron/glia culture and 14, 32 and 135 microM in purified cultures. The effect of NMDA was dose-dependently potentiated by glycine, with similar potency in the two culture conditions. The effect of agonists was completely antagonized by the specific antagonists CNQX, BNQX and MK801 in both culture conditions. Motoneurons were similarly immunoreactive to NR1 and GluR2 antibodies under both mixed neuron/glia and purified cultures, thus confirming the presence of the calcium-impermeant AMPA receptor subtypes and of the obligatory subunit for NMDA receptors. The effect of kainate in mixed neuron/glia culture was reduced by the addition of 40 microM N-nitro-L-arginine or L-NAME, which shifted the EC(50) to 9 microM. By contrast, L-NAME did not modify the effect of kainic acid in purified cultures. These results suggest that the release of nitric oxide by non-neuronal cells in culture enhances glutamate excitotoxicity in SMI-32-positive cells, and that direct activation of ionotropic glutamate receptors is not enough to explain the mechanism of chronic motoneuron degeneration occurring in vivo in amyotrophic lateral sclerosis (ALS).

[Biliary atresia syndrome and splenic malformation. A case report]. / Sindrome da atresia delle vie biliari e malformazione splenica. Caso clinico.

Biliary atresia is a severe neonatal malformation in which the entire extrahepatic biliary tract or part of it is absent and replaced by fibrosclerotic tissue. Having been described for the first time by Thomson in 1891, biliary atresia has an incidence of 1:10,000-15,000 live neonates with a slight predominance in the female sex; it is associated with other malformations in 25% of cases. In 1993 Davenport et al. identified a subgroup of patients with biliary atresia who presented a splenic malformation. This condition was known as biliary atresia and splenic malformation syndrome (BASM). The cases of biliary atresia and BASM are still not clear and a number of etiopathogenetic hypotheses have been put forward. The treatment is surgical and includes a first stage of hepatic-porto-enteroanastomosis using a defunctionalised Roux loop (Kasal), followed by the definitive operation comprising liver transplant. We report the case of a boy who was brought to our attention with jaundice, polypnea and hepatosplenomegalia; instrumental tests allowed the diagnosis of biliary atresia, median liver, stomach and spleen on the right, polysplenia, atresia of the intrahepatic tract of the inferior vena cava, presence of a superior vena cava to the left that drained into the upper left portion of the common atrium. Moreover, the cardiac apex was present on the right, extensive DIA of the common atrium type, extensive DIV and right aortic arch.

Induction of cyclin D1 transcription and CDK2 activity by Notch(ic): implication for cell cycle disruption in transformation by Notch(ic).

Notch genes encode a family of transmembrane proteins that are involved in many cellular processes such as differentiation, proliferation, and apoptosis. Although it is well established that all four Notch genes can act as oncogenes, the mechanism by which Notch proteins transform cells remains unknown. Previously, we have shown that transformation of RKE cells can be conditionally induced by hormone activation of Notch(ic)-estrogen receptor (ER) chimeras. Using this inducible system, we show that Notch(ic) activates transcription of the cyclin D1 gene with rapid kinetics. Transcriptional activation of cyclin D1 is independent from serum-derived growth factors and de novo synthesis of secondary transcriptional activators. Moreover, hormone activation of Notch(ic)-ER proteins induces CDK2 activity in the absence of serum. Upregulation of cyclin D1 and activation of CDK2 by Notch(ic) result in the promotion of S-phase entry. These data demonstrate the first evidence that Notch(ic) proteins can directly regulate factors involved in cell cycle control and affect cellular proliferation. Furthermore, nontransforming Notch(ic) proteins do not induce cyclin D1 expression, indicating that the mechanism of transformation involves cell cycle deregulation through constitutive expression of cyclin D1. Finally, we have identified a CSL [stands for CBF1, Su(H), and Lag-1] binding site within the human and rat cyclin D1 promoters, suggesting that Notch(ic) proteins activate cyclin D1 transcription through a CSL-dependent pathway.

The effect of paracetamol on nociception and dynorphin A levels in the rat brain.

Male Wistar rats were administered with naloxone (1 mg/kg i.p.) or MR 2266 (5 mg/kg i.p) 15 min before paracetamol (400 mg/kg i.p.) treatment and the pain threshold was evaluated. Rats were subjected to the hot-plate and formalin tests and immunoreactive dynorphin A (ir-dynorphin A) levels were measured in the hypothalamus, hippocampus, striatum, brainstem, frontal and parietal-temporal cortex by radioimmunoassay. Pretreatment with naloxone abolished paracetamol antinociceptive activity both in hot-plate and in the first phase, but not in the second phase of the formalin test, while MR 2266 pretreatment was able to antagonise paracetamol effect either in the hot-plate test or in both phases of the formalin test. Among different brain areas investigated paracetamol significantly decreased ir-dynorphin A levels only in the frontal cortex. MR 2266 but not naloxone reversed the decrease in ir-dynorphin A levels elicited by paracetamol. Paracetamol seems to exert its antinociceptive effect also through the opioidergic system modulating dynorphin release in the central nervous system (CNS) of the rat, as suggested by the decrease in the peptide levels.

The effect of a paracetamol and morphine combination on dynorphin A levels in the rat brain.

The purpose of this study was to find out whether the combination of inactive doses of paracetamol (PARA) and morphine was able to change dynorphin (DYN) A levels, evaluated by radioimmunoassay, and whether naloxone or [(-)-2-(3 furylmethyl)-normetazocine] (MR 2266), a kappa-opioid antagonist, modifies or prevents the activity of this combination on nociception and on DYN levels. The work was suggested by our previous findings which demonstrated that inactive doses of PARA and morphine, when given in combination, share an antinociceptive effect, and that PARA, at antinociceptive doses, decreases DYN levels in the frontal cortex, thus indicating a selective action within the CNS. Our present results demonstrate that the combination of inactive doses of PARA (100 mg/kg) and morphine (3 mg/kg) is just as effective in decreasing the levels of DYN A as full antinociceptive doses of PARA or morphine alone in the frontal cortex of the rat. The values, expressed in pmol/g tissue, were: control = 2.83 +/- 0.20; paracetamol (100) = 2.60 +/- 0.23; morphine (3) = 2.73 +/- 0.24; paracetamol + morphine = 1.34 + 0.16 (P < 0.05). The decrease was partially antagonised by MR 2266, but not by naloxone, suggesting that the activity of PARA and morphine in combination on DYN A levels could be mediated, at least in part, through kappa-receptors, although other systems may be involved. On the other hand, both naloxone and MR 2266 prevented the antinociceptive effect of the combination in the hot plate test. All our experimental data suggest that PARA and morphine in combination exert their antinociceptive effect through the opioidergic system, which in turn may cause a decrease in DYN levels in the CNS of the rat.

Erythropoietin prevents neuronal apoptosis after cerebral ischemia and metabolic stress.

Erythropoietin (EPO) promotes neuronal survival after hypoxia and other metabolic insults by largely unknown mechanisms. Apoptosis and necrosis have been proposed as mechanisms of cellular demise, and either could be the target of actions of EPO. This study evaluates whether antiapoptotic mechanisms can account for the neuroprotective actions of EPO. Systemic administration of EPO (5,000 units/kg of body weight, i.p.) after middle-cerebral artery occlusion in rats dramatically reduces the volume of infarction 24 h later, in concert with an almost complete reduction in the number of terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling of neurons within the ischemic penumbra. In both pure and mixed neuronal cultures, EPO (0.1--10 units/ml) also inhibits apoptosis induced by serum deprivation or kainic acid exposure. Protection requires pretreatment, consistent with the induction of a gene expression program, and is sustained for 3 days without the continued presence of EPO. EPO (0.3 units/ml) also protects hippocampal neurons against hypoxia-induced neuronal death through activation of extracellular signal-regulated kinases and protein kinase Akt-1/protein kinase B. The action of EPO is not limited to directly promoting cell survival, as EPO is trophic but not mitogenic in cultured neuronal cells. These data suggest that inhibition of neuronal apoptosis underlies short latency protective effects of EPO after cerebral ischemia and other brain injuries. The neurotrophic actions suggest there may be longer-latency effects as well. Evaluation of EPO, a compound established as clinically safe, as neuroprotective therapy in acute brain injury is further supported.