From central to sentral (Serum angiogenesis central): Circulating predictive biomarkers to anti-VEGFR therapy

Background: In the last decade, a series of analyses failed to identify predictive biomarkers of resistance/susceptibility for anti-angiogenic drugs in metastatic colorectal cancer (mCRC). We conducted an exploratory preplanned analysis of serum pro-angiogenic factors (SErum aNgiogenesis-cenTRAL) in 72 mCRC patients enrolled in the phase II CENTRAL (ColorEctalavastiNTRiAlLdh) trial, with the aim to identify potential predictive factors for sensitivity/resistance to first line folinic acid-fluorouracil-irinotecan regimen (FOLFIRI) plus bevacizumab. Methods: First-line FOLFIRI/bevacizumab patients were prospectively assessed for the following circulating pro-angiogenic factors, evaluated with ELISA (enzyme-linked immunosorbent assay)-based technique at baseline and at every cycle: Vascular endothelial growth factor A (VEGF-A), hepatocyte growth factor (HGF), stromal derived factor-1 (SDF-1), placental derived growth factor (PlGF), fibroblast growth factor-2 (FGF-2), monocyte chemotactic protein-3 (MCP-3), interleukin-8 (IL-8). Results: Changes in circulating FGF-2 levels among different blood samples seemed to correlate with clinical outcome. Patients who experienced an increase in FGF-2 levels at the second cycle of chemotherapy compared to baseline, had a median Progression Free Survival (mPFS) of 12.85 vs. 7.57 months (Hazard Ratio—HR: 0.73, 95% Confidence Interval—CI: 0.43-1.27, p = 0.23). Similar results were seen when comparing FGF-2 concentrations between baseline and eight-week time point (mPFS 12.98 vs. 8.00 months, HR: 0.78, 95% CI: 0.46–1.33, p = 0.35). Conclusions: Our pre-planned, prospective analysis suggests that circulating FGF-2 levels’ early increase could be used as a marker to identify patients who are more likely to gain benefit from FOLFIRI/bevacizumab first-line therapy

Autoimmune/inflammatory syndrome induced by adjuvants (ASIA): clues and pitfalls in the pediatric background

The development and increasing diffusion of new vaccinations and global immunization protocols have aroused burning debates about safety of adjuvants and their immunogenicity-enhancing effect in vaccines. Shoenfeld and Agmon-Levin have grouped under the term "autoimmune/inflammatory syndrome induced by adjuvants" (ASIA) a complex of variable signs and symptoms that may occur after a previous exposure to different adjuvants and also external environmental triggers, even eliciting specific overt immune-mediated disorders. This entity subsumes five medical conditions: post-vaccination phenomena, gulf war syndrome, macrophagic myofasciitis syndrome, siliconosis, and sick building syndrome, but the relevance and magnitude of the syndrome in the pediatric age is fundamentally limited to post-vaccination autoimmune or inflammatory disorders. The occurrence of vaccine-triggered phenomena represents a diagnostic challenge for clinicians and a research conundrum for many investigators. In this paper, we will analyze the general features of ASIA and focus on specific post-vaccination events in relation with the pediatric background. In the presence of a favorable genetic background, many autoimmune/inflammatory responses can be triggered by adjuvants and external factors, showing how the man himself might breach immune tolerance and drive many pathogenetic aspects of human diseases. Nonetheless, the elective application of ASIA diagnostic criteria to the pediatric population requires further assessment and evaluations. Additional studies are needed to help clarify connections between innate or adaptive immunity and pathological and/or protective autoantibodies mostly in the pediatric age, as children and adolescents are mainly involved in the immunization agendas related to vaccine-preventable diseases

Connectivity Between Posterior Parietal Cortex and Ipsilateral Motor Cortex Is Altered in Schizophrenia

Background: Recent advances have highlighted the hypothesis of schizophrenia as a disorder causing defective connectivity among distinct cortical regions. Neurophysiological evidence supporting this hypothesis, however, is still lacking. Methods: In the present study, we used a novel twin-coil transcranial magnetic stimulation (tcTMS) approach to investigate ipsilateral parieto-motor connectivity in 20 schizophrenic patients (14 medicated, 6 unmedicated) and in 15 healthy age-matched volunteers. Results: In healthy subjects, a conditioning TMS pulse applied over the ipsilateral posterior parietal cortex (PPC) at 90% of resting motor threshold (RMT) intensity was able to increase the excitability of the hand area of the right primary motor cortex, with peaks at interstimulus intervals (ISIs) of 4 and 15 msec. This paradigm of stimulation failed to reveal any facilitatory parieto-motor interaction in medicated and unmedicated schizophrenic patients. The between-group difference in paired-pulse facilitation was not ISI-specific. In following analyses, we found that the effects across ISIs induced by PPC conditioning at 90% RMT correlated with the Global Assessment Functioning score and with the negative subscale of the Positive and Negative Syndrome Scale, showing that patients with a better global functioning and lower negative symptoms had less impaired connectivity. Moreover the same parameter correlated with illness duration. Conclusions: Parieto-motor connectivity is impaired in schizophrenia. Cortico-cortical disconnection might be a core feature of schizophrenia

Surgical and non surgical treatment

OBJECTIVES This contribution aims to update the dentist on some important knowledge about cancer of the mouth, particularly on the surgical, medical and radiotherapy treatment in a multidisciplinary approach. MATERIALS AND METHODS The material reported here represents the most up-to-date data on the subject, in a sort of a summary of the indications found in the medical literature and the experience of operators engaged on a daily basis in the treatment of head and neck cancer patients. RESULTS As already reported in the previous Modules of this ECM Course, the neoplasms of the head and neck area, and of the oral cavity in particular, represent aggressive diseases, burdened by 50% of loco- regional recurrences or distant metastases. For this reason, their treatment requires an initial collaboration between surgeon, oncologist and radiotherapist. Moreover, there are many other figures who play a crucial role in the overall management of these patients. The choice of the optimal treatment option, in the single patient, has recently become more difficult in consideration of the different possibilities that derive from the advances in surgery, radiotherapy and medical treatment: only a multidisciplinary approach is able to offer the right treatment in the right patient. It is now widely known that carcinoma of the posterior third of the tongue that is HPV-positive (Human Papilloma Virus, HPV) has a better response to treatment if radiotherapy is provided, and better overall survival when compared with HPV-negatives case. Radiotherapy (RT) has become an integral part of the multidisciplinary approach and frequently accompanies the fundamental therapeutic strategy still represented by surgery. The adoption of Intensity Modulated Radiation Therapy (IMRT) has reformed the approach to oral cancer. IMRT has been shown to improve accuracy towards tumor tissue, reducing the involvement of surrounding healthy tissues, leading to lower general toxicities. Surgical intervention in the most advanced cases always requires large excisions followed by reconstructions with loco-regional flaps or free microvascular flaps. It is always necessary, when anatomicalpossibilit\ue0 ly possible, to provide a margin of at least 1 cm of clinically healthy tissue and, in any case, intraoperative sections of frozen tissue allow to obtain confirmation of free margins. The optimal reconstructive option is represented by free microvascular flaps, which offer the best results obtainable in relation to speech and swallowing functions. With regard to medical therapy, cetuximab is one of the few drugs authorized for use in head-neck neoplasms. It is a monoclonal antibody, targeting Epidermal Growth Factor Receptor (EGFR), whose efficacy when used alone is rather modest. Other agents, such as cisplatin or 5-fluorouracil, which interfere with cell division, often used in combination with cetuximab increase responses. CONCLUSIONS The function of the multidisciplinary team in head-neck tumours is to bring together different healthcare professionals whose goal is to improve the prognosis and quality of life of patients. There are numerous clinical researches that testify to the advantages of this approach. Surgeons, radiotherapists and oncologists must be involved but also other figures (speech therapists, dieticians, psychologists, dentists\u2026 whose role will be described in the next Module). CLINICAL SIGNIFICANCE Only a multidisciplinary approach, with a careful initial assessment of the stage of the disease and of the psycho-physical conditions of the patient, is able to obtain the best possible results in the case of malignant neoplasms of the oral cavity and of the head-neck district

Clinical outcomes and prognostic factors in recurrent and/or metastatic head and neck cancer patients treated with chemotherapy plus cetuximab as first-line therapy in a real-world setting

Aim: The aims of the study are to evaluate the clinical outcomes of first-line treatment with platinum-based chemotherapy and cetuximab in patients with relapsing/metastatic head and neck cancer (RM HNC) and to identify predictors of treatment response. Methods: This is a retrospective, observational, longitudinal, real-world study involving 6 oncology centres in Italy. All consecutive patients with RM HNC treated between January 2007 and December 2016 with a first-line therapy consisting of a platinum-based chemotherapy regimen plus cetuximab were included. The primary objective of the study was to assess overall survival (OS) and progression-free survival (PFS). Secondary objectives included the identification of predictors of treatment response. Results: Overall, 297 patients were identified. Median OS was 10.8 months (95% confidence interval [CI] 9.3–12.2), whereas median PFS was 4.8 months (95% CI 4.3–5.5). On multivariable analysis, independent unfavourable prognostic factors for OS were performance status (PS) Eastern Cooperative Oncology Group (ECOG) >0, presence of residual tumour at primary site, platinum resistance and lack of objective response. Unfavourable predictors for PFS included cancer primary site (paranasal sinuses, hypopharynx), PS ECOG >0, presence of residual tumour at primary site, platinum resistance and lack of objective response. Independent unfavourable predictors of objective response were tumour site (oral cavity, larynx-hypopharynx), residual tumour at primary site and prior chemotherapy. Conclusions: The availability of new treatment modalities and epidemiological changes make the periodic reassessment of prognostic factors of great relevance to guide clinical practice and the design of future randomised clinical trials