Osteoradionecrosis incidence in pre-radiation teeth extractions: A prospective study.

AIMS: To evaluate osteoradionecrosis (ORN) incidence in a cohort of patients undergoing tooth extraction (TE) before radiotherapy (RT) for head and neck cancers. METHODS: The study protocol was approved by the Ethics Committee of Università Cattolica del Sacro Cuore (ID-2132) and registered at clinicaltrials.gov (ID: NCT04009161). TE was performed in case of signs of pericoronitis, periapical lesions, restorative impossibility, severe periodontitis. ORN was defined as exposed bone at an unhealed post-extraction socket in the absence of oncological recurrence. The RT plans were reviewed, and each post-extractive socket was contoured to calculate the received radiation dose. RESULTS: In total, 156 patients with 610 TE were enrolled. The mean follow-up was 567 days. ORN was diagnosed in four patients (2.6% of patients and 0.7% of TE). Need for osteotomy and radiation dose at the extraction site were associated with ORN (OR for osteotomy: 21.9, 95% CI: 2.17-222.2, p = 0.009; OR for RT dose: 1.1, 95% CI: 1-1.15, p = 0.05). CONCLUSIONS: TE appears to be a significant risk factor for ORN, particularly when osteotomy is required, and post-extraction sockets receive a high RT dosage. This study proposes a decision-making algorithm for TE and outlines a straightforward surgical protocol.

A phase 2 study of temozolomide in pretreated metastatic colorectal cancer with MGMT promoter methylation.

BACKGROUND: Presently, few options are available for refractory colorectal cancer (CRC). O6-methyl-guanine-DNA-methyltransferase (MGMT) promoter methylation is a frequent and early event in CRC tumourigenesis. This epigenetic silencing is a predictor of response to the alkylating drug temozolomide in glioblastoma. Preclinical evidences and some case reports showed temozolomide activity in CRC with MGMT silencing, but the available data from clinical trials are inconsistent. METHODS: This was a multicentre, phase 2 trial, planned according to a two-stage Simon's optimal design to investigate activity and safety of temozolomide in refractory CRC harbouring MGMT promoter methylation. The primary end point was overall response rate (ORR). Patients who failed two or more prior treatments received temozolomide at a dose of 150-200 mg m-2 per day on days 1-5 every 28 days. RESULTS: From July 2012 to June 2016, 225 patients were screened, 80 showed MGMT promoter methylation and 41 were enrolled. Overall response rate was 10% and disease control rate was 32%. Median progression-free survival and overall survival were 1.9 and 5.1 months, respectively. CONCLUSIONS: Temozolomide showed a modest activity in this heavily pretreated population and the study did not meet its primary end point. The role of temozolomide in CRC remains still controversial and further research is warranted.

Trastuzumab-induced corneal ulceration: successful no-drug treatment of a "blind" side effect in a case report.

BACKGROUND: We report the first successful treatment of limbal lesions and corneal erosion experienced by a breast cancer patient undergoing trastuzumab treatment. CASE PRESENTATION: A 49-year-old Caucasian woman with early stage breast cancer was treated with adjuvant trastuzumab and subsequently showed persistent bilateral corneal marginal infiltrates resistant to topical steroid and antibiotic treatment. Autologous serum was applied in the conjunctival sac as an experimental treatment to antagonize the inhibitory effect of the HER2 receptor antibody on the corneal epithelial cells. Topical application of autologous serum led to rapid improvement of the ulcerative keratitis, with complete healing of the corneal defect after 7 days. Continued administration of the serum allowed the resumption of trastuzumab therapy without any further side effects. CONCLUSIONS: Persistent bilateral corneal marginal infiltrates may occasionally arise as a side effect of trastuzumab treatment. Topical medication with autologous serum may be an effective therapeutic option for the ocular side effects of trastuzumab therapy.

KRAS mutational status affects oxaliplatin-based chemotherapy independently from basal mRNA ERCC-1 expression in metastatic colorectal cancer patients.

BACKGROUND: In this study, we evaluated the possibility that KRAS mutational status might be predictive of oxaliplatin (OXA) efficacy. We also explored the role of excision repair cross complementing group-1 (ERCC-1). METHODS: Ninety anti-epidermal growth factor receptor-naive advanced colorectal cancer patients were retrospectively analysed. In all patients KRAS mutational status was assessed. In 60 patients mRNA ERCC-1 expression was also investigated. Response rate (RR) and progression-free survival (PFS) after FOLFOX-6±bevacizumab were evaluated according to KRAS status and mRNA ERCC-1 expression. RESULTS: Among 90 patients 47% wild-type (wt) and 53% mutated (mt) KRAS tumours were found. Response rate was 26% in the wt KRAS group, whereas it was 56% in the mt KRAS group; the difference is statistically significant in the total sample (P=0.008) and when only patients receiving FOLFOX-6±bevacizumab as first-line are considered (P=0.01). Progression-free survival was longer in mt than in wt KRAS patients over all patients (10 vs 8 months, respectively, P=0.001) and in those treated as first-line (10 vs 8 months, respectively, P=0.0069). Mt KRAS patients experienced a longer survival (24 vs 18 months; P=0.01). ERCC-1 mRNA expression was not found to correlate with FOLFOX activity in our analysis. CONCLUSION: Our results suggest that activating mutation of KRAS oncogene may predict response to OXA. Basal expression of ERCC-1 mRNA does not explain the high efficacy of FOLFOX-6 in mt KRAS patients.

Reactor modeling in heterogeneous photocatalysis: toxicity and biodegradability assessment.

Photocatalysis employing titanium dioxide is a useful method to degrade a wide variety of organic and inorganic pollutants from water and air. However, the application of this advanced oxidation process at industrial scale requires the development of mathematical models to design and scale-up photocatalytic reactors. In the present work, intrinsic kinetic expressions previously obtained in a laboratory reactor are employed to predict the performance of a bench scale reactor of different configuration and operating conditions. 4-Chlorophenol was chosen as the model pollutant. The toxicity and biodegradability of the irradiated mixture in the bench photoreactor was also assessed. Good agreement was found between simulation and experimental data. The root mean square error of the estimations was 9.9%. The photocatalytic process clearly enhances the biodegradability of the reacting mixture, and the initial toxicity of the pollutant was significantly reduced by the treatment.

Degradation of a mixture of pollutants in water using the UV/H2O2 process.

The degradation reaction of a simple mixture of pollutants (dichloroacetic acid + formic acid) employing H2O2 and UVC radiation (253.7 nm) has been studied in a well-mixed reactor which operates inside a recycling system. The aim of this work is to develop a systematic methodology for treating degradation of mixtures of pollutants, starting from a rather manageable system to more complex aggregates. In this contribution, the effects of different variables such as hydrogen peroxide/pollutant mixture initial concentration ratio, pH and incident radiation at the reactor wall were studied. The results show that the best degrading conditions are: pH = 3.5 and hydrogen peroxide concentrations from 3.9 to 11.8 mM (134-400 mg/L), for initial concentrations of 1.10 and 0.39 mM for formic acid and dichoroacetic acid respectively (50 mg/L for both pollutants). The influence of the incident radiation at the reactor wall on the degradation rates of the mixture is significant. In addition to this, it has been shown that in the employed aqueous solution no stable reaction intermediates are formed. On this basis, a complete reaction scheme for the mixture is proposed that is suitable for a reaction kinetics mathematical modeling of the mixture and further studies of increasing complexity.

Ivor Lewis vs Mckeown esophagectomy: analysis of operative outcomes from the ACS NSQIP database.

OBJECTIVES: Ivor Lewis and McKeown esophagectomy are common techniques to treat esophageal cancer. In this study, we aim to compare these two approaches. METHOD: We used the American College of Surgeons National Surgical Quality Improvement Project database (2005-2017) to compare both techniques using bivariate analysis after propensity matching. RESULTS: We identified 6136 patients with esophagectomy and divided them into 2 groups based on whether they received a McKeown (1676; 27.31%) or an Ivor Lewis (4460; 70.14%) esophagectomy. McKeown esophagectomy was associated with higher rates of superficial surgical site infections (8.02% vs 3.67%, p < 0.001), anastomotic leaks (9.12% vs 7.71%, p = 0.02), prolonged intubation (15.06% vs 10.10%, p < 0.001), re-intubation (15.30% vs 10.34%, p ≤ 0.001), and return to the OR (16.46% vs 11.32%, p < 0.001). The McKeown esophagectomy patients also had longer hospital length of stay (14.5 ± 11.99 vs 13.37 ± 11.8, p = 0.002), higher re-admission rate (21.56% vs 16.87%, p = 0.002), and higher discharges to nursing/rehabilitation institutions (14.06% vs 11.99%, p = 0.004).The mortality rate and positive resection margins were not significantly different. There was a trend toward more utilization of Ivor Lewis esophagectomy over years. CONCLUSION: When compared to Ivor Lewis esophagectomy, McKeown esophagectomy is associated with more unplanned intubation, increased difficulty weaning from the ventilator, incisional surgical site infections, anastomotic leak, and higher length of stay.

Enhancement of fibroblast proliferation, collagen biosynthesis and production of growth factors as a result of combining sodium hyaluronate and aminoacids.

Fibroblasts play a key role in tissue healing by producing the majority of extracellular matrix components, favouring granulation tissue formation, and stimulating re-epithelialization. Hyaluronan is a component of ECM and its anti-inflammatory effects and properties in enhancing wound closure are well known. In this study, we examined the effects of Aminogam gel, a new pharmacological preparation suggested to improve wound healing, composed of hyaluronic acid, proline, lysine, glycine and leucine, on human fibroblasts. Results show that fibroblasts treated with hyaluronic acid plus aminoacid solution increased their proliferative activity, collagen I and III, and fibronectin synthesis. Moreover, HA plus aminoacid solution increased the expression of transforming growth factor beta, connective tissue growth factor, interleukin-6 and -8, assayed by RT-PCR. These results suggested that Aminogam gel, involved in several stages of wound healing, as fibroblast proliferation, granulation tissue formation, ECM component deposition, and production of cytokines, may be a useful device to favour and accelerate wound closure.

Lying in the medicolegal field: Malingering and psychodiagnostic assessment.

The simulation of mental illness, so-called "Malingering", is a very difficult phenomenon for professionals to identify when making an assessment, especially in the medicolegal and forensic psychology and psychiatry fields. When malingering, the subject implements strategies that mimic the symptoms related to a possible psychiatric disease, with the aim of misleading the operator. It is necessary, therefore, to elicit a complete medical history and make a close clinical examination and, especially, to be able to rely on appropriate diagnostic tools. Another important aspect, in the legal medicine, and forensic psychology and psychiatry fields, is the opposite strategy, namely that of dissimulating, or masking, a disease. Several diagnostic tools that the professional clinician can employ to identify dissembling strategies are considered in this article, namely the MMPI- 2, PAI, M- Fast, the SIRS and, finally, the SIMS.

The wish 'not to be'. Survey of suicide cases arriving at the Prosecutor's Office of the Court in Bari in the years 2014-2016.

The issue of suicide has always been a very sensitive and important problem, that raises many questions in the society where it occurs, that is not always able to oppose an adequate response. Every scientist in the field agrees that this is an act provoked by multifaceted reasons, which include cultural, social and biographical motives. Therefore, this topic also poses ethical and civil problems, as well as epistemologic and research methodology issues, because of its complexity as a subject of study. The authors propose a case-by-case contribution, evaluating the judicial acts on 73 suicides made available by the Bari Public Prosecutor's Office for the years 2014-2016. The authors believe collected and systematized data, and the ensuing considerations, can offer a contribution to the debate in the field of legal and socio-healthcare actors, who are often the first to deal with and confront this complex and tragic phenomenon.

Percutaneous radiofrequency ablation using internally cooled wet electrodes for the treatment of patients with lung tumors.

OBJECTIVE: To assess the safety and feasibility of computed tomography-guided radiofrequency ablation (CT-guided RFA) in unresectable lung neoplasms, using a new 15G monopolar internally cooled wet electrode. PATIENTS AND METHODS: 15 consecutive patients with lung neoplasms (< 4 cm), both primary and secondary, unsuitable for or refusing surgery, underwent percutaneous CT-guided RFA using a 15G electrode with a 3-cm exposed tip. The prevalence and grade of adverse events and technical success were evaluated, as well as the extension of the ablation zone, the complete response rates, and the time to progression, determined at CT examination performed 1, 6, and 12 months after the procedure. RESULTS: A total of 22 lung neoplasms were treated (mean diameter: 28 mm; range: 20-39 mm). Technical success was obtained in all patients, without major complications or intraprocedural deaths. Mild or moderate pneumothorax was registered in 46.7% of patients, while a perilesional hemorrhage was observed in 5/15 cases. During the follow-up period, a complete response was obtained in 19 out of 22 lesions (86.4%) with three partial response, two of them successfully retreated with the same technique. CONCLUSIONS: Percutaneous RFA using a 15G internally cooled wet electrode is a safe and feasible treatment for unresectable lung neoplasms, with high complete response rates.

A histochemical approach to the evaluation of the in vivo cytotoxicity of the nitrobutadienes (1E,3E)-1,4-bis(1-naphthyl)-2,3-dinitro-1,3-butadiene and methyl (2Z,4E)-2-methylsulfanyl-5-(1-naphthyl)-4-nitro-2,4-pentadienoate in mice liver and kidney.

Two new molecules (1E,3E)-1,4-bis(1-naphthyl)-2,3-dinitro-1,3-butadiene (1-Naph-DNB) and (2Z,4E)-2-methylsulfanyl-5-(1-naphthyl)-4-nitro-2,4-pentadienoate (1-Naph-NMCB) in previous studies showed interesting antiproliferative activity in vitro. Furthermore, toxicological tests and histological analysis provided promising results, in particular for 1-Naph-NMCB that displayed lower toxic activity both in terms of lethal effect and tissue damage of the main organs. Finally, studies of the antitumour activity in vivo confirmed the efficacy of both molecules, though with some differences in tumour selectivity and levels of activity. In this investigation the activities of some specific enzymes, acid phosphatase (AcPase), alkaline phosphatase (AlkPase), catalase (Cat), succinic dehydrogenase (SDH), glucose-6-phosphatase (G6Pase) and K+ p-nitrophenyl phosphatase (K+ pNPPase) were studied in the liver and kidney as histopathological biomarkers, to assess the effects of the two compounds in organs generally involved in the metabolism and excretion of different drugs. As oxidative stress may also develop as a consequence of the toxic effect of chemicals, reactive oxygen species (ROS) production was evaluated by a histochemical method. The results indicated that some enzyme activities and ROS expression changed in a dose-related manner. Nevertheless, neither in the liver nor in the kidney were dramatic toxic effects evident. By contrast, the variations of some enzyme activities (AlkPase, AcPase, Cat, K+ pNPPase) were interpreted as possible defensive mechanisms for tolerating high dosage of the compounds.

Accelerated wound healing of oral soft tissues and angiogenic effect induced by a pool of aminoacids combined to sodium hyaluronate (AMINOGAM).

In this study we investigated the property of a new medical substance, in the form of a gel compound containing four aminoacids (glycine, leucine, proline, lysine) and sodium hyaluronate (AMINOGAM), to accelerate the wound healing process of the soft oral tissues and to promote angiogenesis in vivo in the vascular proliferation in chick embryo chorioallantoic membrane (CAM) assay. Furthermore, we investigated the capacity of AMINOGAM to induce the expression of an angiogenic cytokine, namely vascular endothelial growth factor (VEGF) in human fibroblasts in vitro. Results showed that AMINOGAM promoted wound healing in post-surgical wounds (after teeth extraction, oral laser surgery with secondary healing without direct suture of the surgical wound, and after dental implant insertion). Stimulated angiogenesis in vivo in the CAM assay and the response was similar to that obtained with vascular endothelial growth factor, a well-known angiogenic cytokine, tested in the same assay, and confirmed by clinical outcomes, which showed reduction of the healing time of oral soft tissues after three different kinds of surgery and also the absence of post-operative infections.

Quantum efficiencies in a multi-annular photocatalytic reactor.

Radiative energy efficiencies of a multi-annular photocatalytic reactor were evaluated and analysed. The total quantum efficiency, defined as the ratio of the number of molecules of the pollutant reacted to the number of photons emitted by the lamp, is expressed as the product of three factors: (i) the reactor radiation incidence efficiency, (ii) the catalyst radiation absorption efficiency, and (iii) the overall reaction quantum efficiency. By means of a detailed mathematical model, the numerical values of each one were 83, 92, and 0-2.5%, respectively. The dependence of the overall reaction quantum efficiency upon operating variables was also studied.

Modelling the kinetics of UV/H2O2 oxidation of dichloroacetic acid.

The intrinsic reaction kinetics of the decomposition of dichloroacetic acid (DCA) using UV/H2O2 was studied. A complete mathematical model, including the effect of the absorbed radiation intensities and H2O2 concentration was developed. The results of the kinetic measurements were analysed using a complete mathematical model of the experimental device that was used for the laboratory operation (a differential reactor inside a recycle). In this way it was expected to obtain intrinsic kinetic parameters. Experimental data agree well with theoretical predictions esmploying just two kinetic parameters derived from the proposed reaction mechanism.

A singular case of asphyxia by choking on a handkerchief: accidental event or suicide to "shut-up" spirits.

Choking in adults can prove fatal, despite resuscitation attempts. The manner of death can be natural, homicide or accident. When a death is due to choking, one must consider what conditions contributed to or predisposed the person to choking (eg. alcohol, drugs and physical and mental impairments). Homicidal deaths by choking are relatively uncommon, being more frequently accidental. The diagnosis of death by choking is made at autopsy when the airway is found occluded. If the individual had an occluded airway and the object or food was removed during resuscitation, the only way to make the diagnosis would be on the history. Here, we present a case of asphyxia (accidental or suicidal) by choking on a handkerchief in a patient with a long history of schizophrenia. The woman had attempted a previous suicide driven by evil spirits coming from inside her body, especially from the head and throat; in order to "shut-up" the spirit, she was trying to suffocate it with her hands or by a belt from her pants.

HUS1 regulates in vivo responses to genotoxic chemotherapies.

Cells are under constant attack from genotoxins and rely on a multifaceted DNA damage response (DDR) network to maintain genomic integrity. Central to the DDR are the ATM and ATR kinases, which respond primarily to double-strand DNA breaks (DSBs) and replication stress, respectively. Optimal ATR signaling requires the RAD9A-RAD1-HUS1 (9-1-1) complex, a toroidal clamp that is loaded at damage sites and scaffolds signaling and repair factors. Whereas complete ATR pathway inactivation causes embryonic lethality, partial Hus1 impairment has been accomplished in adult mice using hypomorphic (Hus1(neo)) and null (Hus1(Δ1)) Hus1 alleles, and here we use this system to define the tissue- and cell type-specific actions of the HUS1-mediated DDR in vivo. Hus1(neo/Δ1) mice showed hypersensitivity to agents that cause replication stress, including the crosslinking agent mitomycin C (MMC) and the replication inhibitor hydroxyurea, but not the DSB inducer ionizing radiation. Analysis of tissue morphology, genomic instability, cell proliferation and apoptosis revealed that MMC treatment caused severe damage in highly replicating tissues of mice with partial Hus1 inactivation. The role of the 9-1-1 complex in responding to MMC was partially ATR-independent, as a HUS1 mutant that was proficient for ATR-induced checkpoint kinase 1 phosphorylation nevertheless conferred MMC hypersensitivity. To assess the interplay between the ATM and ATR pathways in responding to replication stress in vivo, we used Hus1/Atm double mutant mice. Whereas Hus1(neo/neo) and Atm(-/-) single mutant mice survived low-dose MMC similar to wild-type controls, Hus1(neo/neo)Atm(-/-) double mutants showed striking MMC hypersensitivity, consistent with a model in which MMC exposure in the context of Hus1 dysfunction results in DSBs to which the ATM pathway normally responds. This improved understanding of the inter-dependency between two major DDR mechanisms during the response to a conventional chemotherapeutic illustrates how inhibition of checkpoint factors such as HUS1 may be effective for the treatment of ATM-deficient and other cancers.

Gemcitabine versus FOLFIRINOX in patients with advanced pancreatic adenocarcinoma hENT1-positive: everything was not too bad back when everything seemed worse.

PURPOSE: hENT1 is a transmembrane protein which acts as a nucleoside transporter and is the main mediator of Gemcitabine (GEM) uptake into human cells. In this retrospective study we compared GEM versus FOLFIRINOX in patients with metastatic pancreatic cancer in which hENT1 evaluation was available. METHODS: 149 patients affected by unresectable metastatic pancreatic cancer, treated in our institution from 2009 to 2013, have been screened for inclusion in this retrospective study. Seventy patients, treated with GEM or FOLFIRINOX in first-line therapy, fulfilled clinical inclusion criteria for survival analysis. Thirty-one patients were available and contained sufficient quality/quantity RNA for evaluation of hENT1 expression by RT-PCR. The primary endpoint was OS and the secondary endpoint was PFS. RESULTS: The survival analysis, carried out on 70 patients regardless of hENT1 expression, showed a statistically longer OS and PFS in the group treated with FOLFIRINOX compared to GEM. Within the exploratory analysis, which included 31 patients, no differences were found in hENT1 positive patients treated with FOLFIRINOX compared to GEM in terms of OS (8.5 vs 7 months, HR: 0.89; 95 % CI 0.3-2.5; p = 0.8) and PFS (5.5 vs 5 months, HR: 0.8, 95 % CI 0.2-2.2; p = 0.61). GEM-treated hENT1 positive patients showed a statistically significant improvement both of OS (8 vs 2 months; p = 0.0012) and PFS (5 vs 1 months; p = 0.0004) in comparison to GEM-treated hENT1 negative patients. CONCLUSIONS: In our exploratory analysis GEM seems as effective as FOLFIRINOX in terms of survival with a better safety profile in hENT1 positive metastatic pancreatic cancer.

Association of IL-8 and eNOS polymorphisms with clinical outcomes in bevacizumab-treated breast cancer patients: an exploratory analysis.

BACKGROUND: The role of bevacizumab in metastatic breast cancer is controversial. Identification of predictive biomarkers could help to select patients who really benefit from it. We evaluated the association of angiogenesis-related gene polymorphisms with the treatment outcome of bevacizumab in metastatic breast cancer patients. PATIENTS AND METHODS: eNOS-786T/C and -894G/T, IL-8-251T/A genomic polymorphisms were assessed in 31 metastatic breast cancer patients treated with bevacizumab plus chemotherapy in the first-line setting. Testing for association between each polymorphism and treatment outcome was performed. RESULTS: Patients with IL-8 251 AA genotype showed a significantly lower progression-free survival in each combination comparison: "TT" vs "AA" (13 vs 8 months; p = 0.008); TT vs TA vs AA (13 vs 11 vs 8 months; p = 0.02); TT vs TA +AA (13 vs 11 months; p = 0.01); TT + TA vs AA (12 vs 8 months; p = 0.01) and a lower overall survival when compared with TT +TA genotype (26 vs 51 months, p = 0.04). Patients carrying eNOS 894 TT genotype showed a statistically significant lower progression-free survival than patients with GG genotype (11.5 vs 26.5 months; p = 0.04) with no differences in the overall survival. No association with response rate was found with any of the polymorphisms analyzed. CONCLUSION: These findings suggest that IL-8 251T/A and eNOS-894 G/T polymorphisms might have a role in predicting treatment outcome of bevacizumab in metastatic breast cancer. Our results are hypothesis generating and need to be confirmed in larger clinical trials.

Assessment of in silico models for acute aquatic toxicity towards fish under REACH regulation.

We evaluated the performance of eight QSAR in silico modelling packages (ACD/ToxSuite™, ADMET Predictor™, DEMETRA, ECOSAR, TerraQSAR™, Toxicity Estimation Software Tool, TOPKAT™ and VEGA) for acute aquatic toxicity towards two species of fish: Fathead Minnow and Rainbow Trout. For the Fathead Minnow, we compared model predictions for 567 substances with the corresponding experimental values for 96-h median lethal concentrations (LC50). Some models gave good results, with r2 up to 0.85. We also classified the predictions of all the models into four toxicity classes defined by CLP. This permitted us to assess other parameters, such as the percentage of correct predictions for each class. Then we used a set of 351 substances with toxicity data towards Rainbow Trout (96-h LC50). In this case the predictability was unacceptable for all the in silico models. The calculated r2 gave poor correlations (≤0.53). Another analysis was performed according to chemical classes and for mode of action. In the first case, all the classes show a high percentage of correct predictions, in the second case only narcotics and polar narcotics were predicted with good confidence. The results indicate the possibility of using in silico methods to estimate aquatic toxicity within REACH regulation, after careful evaluation.