Lidocaine inhibits cytoskeletal remodelling and human breast cancer cell migration.

BACKGROUND: The metastatic potential of breast cancer cells has been strongly associated with overexpression of the chemokine CXCL12 and the activity of its receptor CXCR4. Lidocaine, a local anaesthetic that can be used during breast cancer excision, inhibits the growth, invasion, and migration of cancer cells. We therefore investigated, in a breast cancer cell line, whether lidocaine can modulate CXCL12-induced responses. METHODS: Intracellular calcium, cytoskeleton remodelling, and cell migration were assessed in vitro in MDA-MB-231 cells, a human breast cancer epithelial cell line, after exposure to lidocaine (10 µM or 100 µM). RESULTS: Lidocaine (10 or 100 µM) significantly inhibited CXCR4 signalling, resulting in reduced calcium release (Fluo 340 nm/380 nm, 0.76 mean difference, p<0.0001), impaired cytoskeleton remodelling (F-Actin fluorescence mean intensity, 21 mean difference, P=0.002), and decreased motility of cancer cells, both in the scratch wound assay (wound area at 21 h, -19%, P<0.0001), and in chemotaxis experiments (fluorescence mean intensity, 0.16, P=0.0047). The effect of lidocaine was not associated with modulation of the CD44 adhesion molecule. CONCLUSIONS: At clinical concentrations, lidocaine significantly inhibits CXCR4 signalling. The results presented shed new insights on the molecular mechanisms governing the inhibitory effect of lidocaine on cell migration.

Radical hypo-fractionated radiotherapy with volumetric modulated arc therapy in lung cancer : A retrospective study of elderly patients with stage III disease.

BACKGROUND: This study aimed to analyse the feasibility and acute toxicity of radical hypo-fractionated radiotherapy (RT) for elderly patients with non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: We conducted a retrospective evaluation of treatment with volumetric modulated arc therapy (VMAT) of elderly patients affected by stage III inoperable NSCLC. The dose prescription was 56 Gy in 20 fractions, 55 Gy in 22 fractions, or 50 Gy in 20 fractions. Target volume included only the primary lesion and the infiltrated lymph nodes. The primary end point was acute and late toxicity, while secondary end points were progression-free survival (PFS), and overall survival (OS). RESULTS: In all, 41 patients were included in this analysis. The mean age of the patients was 78.6 years, and 22 patients had staged IIIA while 19 patients had stage IIIB disease. All but one patient had pathological nodal involvement; 15 patients received chemotherapy before RT. Acute grade 1-2 toxicity was recorded in 25 (61%) patients. Late toxicity was recorded in 13 (32%) patients. No cases of G3 or G4 toxicity were recorded. Complete response was obtained in two (5%) patients, 26 (63%) showed a partial response, and two (5%) experience disease progression. At a mean follow-up of 9.9 months (range, 1.1-25.4), 17 patients had died from disease progression, one died from other causes, and 23 were alive. Median OS was 13.7 ± 1.5 months (95% CI: 10.7-16.7), OS at 12 and 18 months was 51.3 ± 9.5% and 35.1 ± 10.1%, respectively. Median PFS was 13.7 ± 2.3 months (95% CI: 9.1-18.2), and PFS at 12 and 18 months was 50.1 ± 9.9% and 38.9 ± 10.4%, respectively. CONCLUSION: Radical hypo-fractionated VMAT is a promising treatment for locally advanced NSCLC in the elderly. The use of hypo-fractionated radiotherapy for lung cancer in older patients can be considered a valuable approach, particularly for patients with poor performance status or refusing other treatment approaches.

Lymph-node relapsed prostate cancer management and PET-driven external beam radiotherapy: salvage or palliative treatment?

New imaging modalities such as choline- positron emission tomography (PET) or PET/computed tomography (CT) may be useful to identify prostate cancer patients with small volume, limited nodal relapse ("oligo-recurrent"), potentially amenable to metastasis directed treatment (e.g. radiotherapy,) with the aim of long-term control of the disease, even in a setting traditionally considered prognostically unfavorable, so usually gone to palliative treatment. This report reviews the diagnostic tools and the main published data about the role of PET or PET/CT driven radiation therapy, (not only for the diagnosis, but also for the planning) in relapsed node prostate carcinoma, as an alternative therapeutic strategy than surgery or androgen deprivation therapy.

Low-dose fractionated radiotherapy and concomitant chemotherapy for recurrent or progressive glioblastoma: final report of a pilot study.

BACKGROUND: Evaluated in this study were the feasibility and the efficacy of concurrent low dose fractionated radiotherapy (LD-FRT) and chemotherapy as palliative treatment for recurrent/progressive glioblastoma multiforme (GBM). PATIENTS AND METHODS: Eligible patients had recurrent or progressive GBM, Karnofsky performance status ≥ 70, prior surgery, and standard radiochemotherapy treatment. Recurrence/progression disease during temozolomide (TMZ) received cisplatin (CDDP; 30 mg/m(2) on days 1, 8, 15), fotemustine (FTM; 40 mg/m(2) on days 2, 9, 16), and concurrent LD-FRT (0.3 Gy twice daily); recurrence/progression after 4 months from the end of adjuvant TMZ were treated by TMZ (150/200 mg/m(2) on days 1-5) concomitant with LD-FRT (0.4 Gy twice daily). Primary endpoints were safety and toxicity. RESULTS: A total of 32 patients were enrolled. Hematologic toxicity G1-2 was observed in 18.7 % of patients and G3-4 in 9.4 %. One patient (3.1 %) had complete response, 3 (9.4 %) had partial response, 8 (25 %) had stable disease for at least 8 weeks, while 20 patients (62.5 %) experienced progressive disease. The clinical benefit was 37.5 %. Median progression-free survival (PFS) and overall survival (OS) were 5 and 8 months, respectively. Survival rate at 12 months was of 27.8 %. CONCLUSION: LD-FRT and chemotherapy for recurrent/progressive GBM have a good toxicity profile and clinical outcomes, even though further investigation of this novel palliative treatment approach is warranted.

Is HE4 a useful endometrioma marker?

PURPOSE OF INVESTIGATION: By the comparison between most used tumor marker trend (cancer antigen 125: CA 125 and human epididymal secretory protein E4: HE4) before and after laparoscopic surgery, the aim of the present study was to assess HE4 usefulness in ovarian benign cyst and endometrioma diagnosis. MATERIALS AND METHODS: Thirty-eight patients were enrolled in this prospective study: 25 women underwent unilateral endometriosis ovarian cyst excision, 13 underwent benign ovarian cyst incision, and 26 were healthy controls. CA 125 and HE4 serum levels were estimated before surgery (in the early proliferative phase of the cycle) and one month after surgery. RESULTS: A statistically significant decrease of CA 125 serum level was found after an endometrioma surgical excision but no decreases in HE4 serum level. CONCLUSION: In patients with endometrioma, no alteration was found in HE4 serum levels before and after surgery, while CA125 serum levels decreased after surgery. HE4 may better distinguish a malign cyst from benign one, but it is not useful in the diagnosis of low risk endometrioma.

Concurrent and adjuvant temozolomide-based chemoradiotherapy schedules for glioblastoma. Hypotheses based on two prospective phase II trials.

AIM: To investigate the impact of nonstandard concomitant temozolomide (TMZ) administration in two prospective phase II studies for glioblastoma (GBM). PATIENTS AND METHODS: From October 2000 to June 2008, 104 patients were enrolled in two studies: 25 in RT-TMZ-10.00 and 79 in RT-TMZ-01.04. Adjuvant radiotherapy (RT) was used with a total dose of 59.4 Gy (1.8 Gy/day). Patients received concomitant TMZ (75 mg/m(2)/day) from Monday to Friday during the first and last weeks of RT in the RT-TMZ-10.00 study and from Monday to Friday during all weeks of RT in the RT-TMZ-01.04 trial. Adjuvant TMZ (200 mg/m(2)) was administered for 5 days every 28 days. RESULTS: Median progression-free (PFS) and overall survival (OS) were 9 and 16 months, respectively, with no significant difference between the two groups (p = 0.5 and 0.14, respectively). The 2- and 5-year OS rates were 32 and 3 %, respectively, and similar to those observed with standard treatment regimens. CONCLUSION: Our data support the hypothesis that adjuvant TMZ is more important than concomitant chemotherapy (CH) and that RT is the more important element of the concomitant treatment schedule.

Voltammetric platform for detection of 2,4,6-trinitrotoluene based on a molecularly imprinted polymer.

New methods for determination of explosive substances as, for example, 2,4,6-trinitrotoluene (TNT), in a rapid way and at low cost are highly required. An electrochemical platform has been here developed with good characteristics of low dimension, fast response, low cost, and high selectivity. It is based on a commercially available screen printed cell with graphite ink working and auxiliary electrodes and a silver ink quasi-reference electrode. The whole cell is covered with a thick layer of cation exchanging acrylic polymer molecularly imprinted with 2,4,6-trinitrotoluene. The polymeric layer acts at the same time as electrolytic medium and selective receptor. It has been demonstrated that, in this medium, 2,4,6-trinitrotoluene is electroactive at graphite electrode, being reduced by a non-reversible reaction. The peak current (differential pulse voltammogram) is proportional to TNT concentration with limit of detection for TNT around 5 × 10(-7) M and linearity range up to 2 × 10(-5) M. The selectivity for TNT relative to other reducible compounds as, for example, nitroaromatic derivatives, and to other possible interfering substances, as negatively charged ions, is good. Measurements can be performed in not de-aerated solution and in small volumes (20 µl), so that the proposed platform is very promising for in situ determinations.

Palmitoylethanolamide is a disease-modifying agent in peripheral neuropathy: pain relief and neuroprotection share a PPAR-alpha-mediated mechanism.

Neuropathic syndromes which are evoked by lesions to the peripheral or central nervous system are extremely difficult to treat, and available drugs rarely joint an antihyperalgesic with a neurorestorative effect. N-Palmitoylethanolamine (PEA) exerts antinociceptive effects in several animal models and inhibits peripheral inflammation in rodents. Aimed to evaluate the antineuropathic properties of PEA, a damage of the sciatic nerve was induced in mice by chronic constriction injury (CCI) and a subcutaneous daily treatment with 30 mg kg(-1) PEA was performed. On the day 14, PEA prevented pain threshold alterations. Histological studies highlighted that CCI induced oedema and an important infiltrate of CD86 positive cells in the sciatic nerve. Moreover, osmicated preparations revealed a decrease in axon diameter and myelin thickness. Repeated treatments with PEA reduced the presence of oedema and macrophage infiltrate, and a significant higher myelin sheath, axonal diameter, and a number of fibers were observable. In PPAR- α null mice PEA treatment failed to induce pain relief as well as to rescue the peripheral nerve from inflammation and structural derangement. These results strongly suggest that PEA, via a PPAR- α -mediated mechanism, can directly intervene in the nervous tissue alterations responsible for pain, starting to prevent macrophage infiltration.

Morular endometrial metaplasia: review of the literature and proposal of the management.

PURPOSE OF INVESTIGATION: Morular endometrial metaplasia is a rare condition that can be often misdiagnosed and overtreated, because it can be mistaken for a malignant disease. The aim of this review was to update the current opinion on the significance of this pathology and its risk for potential malignancies. MATERIALS AND METHODS: The authors report their experience of two cases of morular metaplasia involving very young women managed conservatively with hysteroscopic resection of the affected areas. RESULTS: Hysteroscopic resection of these lesions can be an adequate and fertility-sparing treatment of morular metaplasia in women of childbearing age. CONCLUSIONS: Morular metaplasia has indeed a mutational origin but it is a benign and hormonally inert condition. The risk to develop cancer is closely associated with premalignant or malignant endometrioid glandular proliferations that are often associated with hysthological finding of morules rather than with morules themselves. Management of this condition requires trained pathologists and gynecologists and should be adapted to the age of the patient.

Percutaneous radiofrequency ablation versus surgical radiofrequency-assisted nodulectomy in treatment of small single nodes of hepatocellular carcinoma: our experience.

AIM: Surgical resection usually represents the treatment of choice for solitary hepatocellular carcinoma (HCC) in cirrhotic patients, with well preserved liver function; local ablative strategies are the best treatment option for patients with small tumors who are not candidates for surgical resection or liver transplantation. Several studies showed that percutaneous radiofrequency ablation (RFA) has similar efficacy to surgical nodulectomy in the treatment of early-stage HCC, and is associated with lower complication rates and costs than resection. The aim of this study was to compare the effectiveness of these treatments, in terms of morbidity, overall survival, tumor recurrence and causes of death. METHODS: Between January 2006 and January 2012 we observed 176 patients affected by HCC, 84 underwent curative treatment. The 40 patients presenting single HCC nodes smaller than 3 cm in diameter have been treated with radiofrequency-assisted surgical nodulectomy (N.=20) or with percutaneous radiofrequency (N.=20). RESULTS: No perioperative mortality occurred in the two groups. Perioperative morbidity was 5% in group A (1 case of peritoneal bleeding) and 5% in group B (1 case of hepatic abscess). Disease-free survival was slightly higher in surgically treated patients, but not statistically significative differences have been demonstrated (P<0.06); no local recurrences were observed in surgically treated patients. CONCLUSION: RF and surgical nodulectomy can be either used in treatment of early stage hepatocellular carcinoma; no differences in terms of morbidity, overall and disease free survival were observed; nodulectomy seems to prevent from tumor local recurrence.

Experimental characterization of gaseous ion beams produced with the advanced ion source for hadrontherapy (AISHa) at 18 GHz.

The Advanced Ion Source for Hadrontherapy (AISHa) is an electron cyclotron resonance ion source operating at 18 GHz, developed at the Istituto Nazionale di Fisica Nucleare-Laboratori Nazionali del Sud, with the aim of producing high intensity and low emittance highly charged ion beams for hadrontherapy purposes. Moreover, thanks to its unique peculiarities, AISHa is a suitable choice for industrial and scientific applications. In the framework of the INSpIRIT and IRPT projects, in collaboration with the Centro Nazionale di Adroterapia Oncologica, new candidates for cancer treatment are being developed. In particular, the paper presents the results of the commissioning of four ion beams of interest for hadrontherapy: H+, C4+, He2+, and O6+. Their charge state distribution in the best experimental conditions, their emittance, and brightness will be critically discussed, along with the role of ion source tuning and space charge effects in beam transport. Perspectives for further developments will also be presented.

Production and characterization of 111Ag radioisotope for medical use in a TRIGA Mark II nuclear research reactor.

Radio Pharmaceutical Therapy (RPT) comes forth as a promising technique to treat a wide range of tumors while ensuring low collateral damage to nearby healthy tissues. This kind of cancer therapy exploits the radiation following the decay of a specific radionuclide to deliver a lethal dose to tumor tissues. In the framework of the ISOLPHARM project of INFN, 111Ag was recently proposed as a promising core of a therapeutic radiopharmaceutical. In this paper, the production of 111Ag via neutron activation of 110Pd-enriched samples inside a TRIGA Mark II nuclear research reactor is studied. The radioisotope production is modeled using two different Monte Carlo codes (MCNPX and PHITS) and a stand-alone inventory calculation code FISPACT-II, with different cross section data libraries. The whole process is simulated starting from an MCNP6-based reactor model producing the neutron spectrum and flux in the selected irradiation facility. Moreover, a cost-effective, robust and easy-to-use spectroscopic system, based on a Lanthanum Bromo-Chloride (LBC) inorganic scintillator, is designed and characterized, with the aim of using it, in the future, for the quality control of the ISOLPHARM irradiated targets at the SPES facility of the Legnaro National Laboratories of INFN. natPd and 110Pd-enriched samples are irradiated in the reactor main irradiation facility and spectroscopically characterized using the LBC-based setup and a multiple-fit analysis procedure. Experimental results are compared with theoretical predictions of the developed models, showing that inaccuracies in the available cross section libraries prevent an accurate reproduction of the generated radioisotope activities. Nevertheless, models are normalized to our experimental data allowing for a reliable planning of the 111Ag production in a TRIGA Mark II reactor.

Solid-phase microextraction of 2,4,6-trinitrotoluene using a molecularly imprinted-based fiber.

A molecularly imprinted polymer with trinitrotoluene as the template molecule was synthesized and used as the novel coating for solid-phase microextraction of the nitroaromatic explosive 2,4,6-trinitrotoluene for its selective determination. The fiber was characterized in terms of coating thickness, morphology, intra- and inter-batch repeatability and extraction efficiency. An average thickness of 50 ± 4 µm with a uniform distribution of the coating was obtained. Good performances of the developed procedure in term of both intra-batch and inter-batch repeatability with relative standard deviations <8% were obtained. Finally, detection and quantitation limits in the low nanogram per kilogram levels were achieved proving the superior extraction capability of the developed coating, obtaining gas chromatography-mass spectrometry responses about two times higher than those achieved using commercial devices.

Risk-group Classification by Recursive Partitioning Analysis of Patients Affected by Oligometastatic Renal Cancer Treated with Stereotactic Radiotherapy.

AIMS: Due to the absence of consensus on metastases-directed treatment in kidney cancer, we conducted an analysis of patients treated with stereotactic radiotherapy (SRT) on cranial or extracranial metastases to classify them in survival class risk according to pre-treatment characteristics. MATERIALS AND METHODS: We included oligometastatic kidney cancer patients treated with SRT on up to five metastases. Concomitant systemic treatment was allowed. End points included overall survival and the binary classification tree approach with recursive partitioning analysis was applied to stratify patients into overall survival risk groups. RESULTS: In total, 129 patients were treated on 242 metastases. The brain was the most common site (34.71%), followed by lung (25.62%). With a median follow-up of 19.4 months, 1- and 3-year overall survival were 82.62 and 55.11%. The recursive partitioning analysis identified four prognostic classes. Class 1 included patients aged ≤ 65 years treated on extracranial metastases, with 3-year overall survival of 82.66%. Class 2 included patients aged > 65 years, without history of metastatic bone disease, treated on extracranial metastases, with a 3-year overall survival of 67.91%. Patients aged > 65 years and a history of bone disease, treated on extracranial metastases, were classified as class 3, with a 3-year overall survival of 37.50%. Class 4 included patients treated on brain metastases, with a 3-year overall survival of 9.70%. CONCLUSION: We produced a stratification model that can predict survival of oligometastatic kidney cancer patients treated with metastases-directed SRT. Site of disease, patient's age and presence of bone disease can help clinicians in the decision-making process.

Transoral robotic surgery for hilo-parenchymal submandibular stones: step-by-step description and reasoned approach.

The conservative transoral approach to hilo-parenchymal submandibular stones has been proposed as an alternative to traditional sialadenectomy. The main purpose is to preserve the gland and eliminate the risk of a cervical scar and damage to the marginal mandibular branch of the facial nerve. The spread of transoral robotic surgery has favoured its application not only in the oropharynx, but also in the anterior oral cavity. This article describes a transoral robotic approach for hilo-parenchymal submandibular stones. In January 2019, two patients with a right and a left hilo-parenchymal submandibular stone of 15mm and 8mm, respectively, underwent removal of the stone with transoral robotic surgery using the Si Da Vinci surgical robot. The procedure was performed successfully and tolerated well, with a one-night hospitalization. There were no complications such as lingual nerve damage, painful gland swelling, infection, or ranula. The patients were followed up clinically and ultrasonographically for the first 3 months to verify symptom relief and persistence of stones; no symptoms or stones were found. The transoral robotic surgical approach seems to be safe and adequate for the conservative management of large hilo-parenchymal submandibular stones. An adequate diagnosis together with proper docking and an appropriate approach to the oral floor is mandatory.

AM404, an anandamide transport inhibitor, reduces plasma extravasation in a model of neuropathic pain in rat: role for cannabinoid receptors.

Neuropathic pain consequent to peripheral nerve injury has been associated with local inflammation. Following noxious stimulation afferent fibres release substance P (SP) and calcitonin-gene related peptide (CGRP), which are closely related to oedema formation and plasma leakage. The effect of the anandamide transport blocker AM404 has been studied on plasma extravasation after chronic constriction injury (CCI) which consists in a unilateral loose ligation of the rat sciatic nerve (Bennett and Xie, 1988). AM404 (1-3-10 mg kg(-1)) reduced plasma extravasation in the legated paw, measured as mug of Evans Blue per gram of fresh tissue. A strong effect on vascular permeability was also produced by the synthetic cannabinoid agonist WIN 55,212-2 (0.1-0.3-1 mg kg(-1)). Using specific antagonists or enzyme inhibitors, we demonstrate that cannabinoids act at several levels: data on the 3rd day suggest a strong involvement of substance P (SP) and calcitonin gene-related peptide (CGRP) in the control of vascular tone, whereas at the 7th and 14th days the major role seems to be played by prostaglandins (PGs) and nitric oxide (NO). Capsaicin injection in ligated paws of AM404- or WIN 55,212-2-treated rats resulted in an increase of Evans Blue extravasation, suggesting the involvement of the cannabinergic system in the protective effect of C fibres of ligated paws. Taken together, these data demonstrate the efficacy of cannabinoids in controlling pain behaviour through the modulation of several pain mediators and markers of vascular reactivity, such as SP, CGRP, PGs and NO.

Isolated porcine bronchi provide a reliable model for development of bronchodilator anti-muscarinic agents for human use.

BACKGROUND AND PURPOSE: In human airways, muscarinic acetylcholine receptors (mAChRs) exert a predominant role in the control of airways resistance and anti-muscarinic agents are currently included in the pharmacological treatment of chronic obstructive pulmonary disease (COPD). However, the development of more effective mAChR antagonists is hampered by considerable species variability in the ultrastrucural and functional control of airway smooth muscle, making extrapolation of any particular animal model questionable. This study was designed to characterize the mAChRs in a bronchial preparation from pigs, animals considered to provide close models of human biology. EXPERIMENTAL APPROACH: Smooth muscle bronchial strips were examined by electron microscopy in order to compare their neuromuscular structure with that of human bronchi and used to study the affinity of a series of selective mAChR antagonists, estimated as pKis in competition binding assays with NMS and pA2, by Schild analysis, in contractile experiments. KEY RESULTS: Pharmacodynamic binding parameters and affinity profiles of a series of antagonists were consistent with the presence of a majority of M2 mAChRs along with a minor population of M3 mAChRs. Functionally, the highly significant correlation between postjunctional pA2 affinities and corresponding affinity constants at human recombinant M1-M5 subtypes indicated that smooth muscle contraction in porcine bronchi, as in human bronchi, was dependent on the M3 subtype. CONCLUSION AND IMPLICATIONS: Based on the characterization of mAChRs, isolated porcine bronchi provide an additional experimental model for development of mAChR antagonists for the treatment of human airway dysfunctions.