The British variant of the new coronavirus-19 (Sars-Cov-2) should not create a vaccine problem.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a highly contagious virus that infects humans and a number of animal species causing coronavirus disease-19 (COVID-19), a respiratory distress syndrome which has provoked a global pandemic and a serious health crisis in most countries across our planet. COVID-19 inflammation is mediated by IL-1, a disease that can cause symptoms such as fever, cough, lung inflammation, thrombosis, stroke, renal failure and headache, to name a few. Strategies that inhibit IL-1 are certainly helpful in COVID-19 and can represent one of the therapeutic options. However, until now, COVID-19 therapy has been scarce and, in many cases, ineffective, since there are no specific drugs other than the vaccine that can solve this serious health problem. Messenger RNA (mRNA) vaccines which are the newest approach, are already available and will certainly meet the many expectations that the population is waiting for. mRNA vaccines, coated with protected soft fatty lipids, use genetic mRNA (plus various inactive excipients) to make a piece of the coronavirus spike protein, which will instruct the immune system to produce specific antibodies. The soft fatty lipids allow the entry of mRNA into cells where it is absorbed into the cytoplasm and initiates the synthesis of the spike protein. In addition, vaccination also activates T cells that help the immune system respond to further exposure to the coronavirus. mRNA induces the synthesis of antigens of SARS-CoV-2 virus which stimulate the antibody response of the vaccinated person with the production of neutralizing antibodies. The new variant of the coronavirus-19 has been detected in the UK where, at the moment, the London government has imposed a lockdown with restrictions on international movements. The virus variant had already infected 1/4 of the total cases and in December 2020, it reached 2/3 of those infected in the UK. It has been noted that the spreading rate of the British variant could be greater than 70% of cases compared to the normal SARS-CoV-2 virus, with an R index growth of 0.4. Recent studies suggest that coronavirus-19 variation occurs at the level N501Y of the spike protein and involves 23 separate mutations on the spike, 17 of which are linked to the virus proteins, thus giving specific characteristics to the virus. In general, coronaviruses undergo many mutations that are often not decisive for their biological behavior and does not significantly alter the structure and the components of the virus. This phenomenon also occurs in SARS-CoV-2. It is highly probable that the variants recently described in the UK will not hinder vaccine-induced immunity. In fact, the variant will not break the vaccine although it may have some chance of making it a little less effective. Therefore, it is pertinent to think that the vaccine will work against the SARS-CoV-2 variant as well. In today's pandemic, the D614G mutation of the amino acid of corronavirus-19, which emerged in Europe in February 2020 is the most frequent form and causes high viral growth. The previously infrequent D614G mutation is now globally dominant. This variant, which is being tested by many international laboratories, is rapidly spreading across the countries and a series of vaccinated subjects are testing to see if their antibodies can neutralize the new variant of SARS-CoV-2. This variant has a very high viral growth and is less detectable with the RT-PCR technique in the laboratory. It has been reported that the British variant that increases viral load does not cause more severe effects in the respiratory tract and lung disease, therefore, it is certain that the variant is growing rapidly and must be kept under control; for this reason, laboratory data is expected impatiently. The study on the many variants that coronavirus-19 presents is very interesting and complete and clearer data on this topic will be ready in the near future. In addition, it is still unclear whether the different variants discovered in many countries, including Africa, share the same spike protein mutation and therefore, this is another study to elaborate on. In order to be certain and to not have unexpected surprises, we need to reduce the spread and the transmission speed of viral variants that could appear around the world, creating new pandemics. For this reason, the scientific community is on the alert since laboratory tests on serum antibodies from COVID-19 survivors have been reported to be less effective in attacking the variant. In light of the above, the scientific community must be on the alert as larger variants of the spike protein could escape vaccine-induced antibodies, which for now are of great help to the community and can save millions of lives. Deepening the study of spike protein mutations will help to better understand how to combat coronavirus-19 and its variants.

Cervical myelopathy caused by ventrally located atlanto-axial synovial cysts: An open quest for the safest and most effective surgical management. Case series and systematic review of the literature.

OF BACKGROUND DATA: Despite a good understanding of the natural history of spinal synovial cysts (SCs), a widespread agreement regarding their optimal management is still lacking. This is particularly true for SCs occurring at the C1-C2 level, which are rare, but oftentimes lead to a rapidly evolving cervical myelopathy. METHODS: We report a series of 4 patients (M:F ratio=1:1; mean age 63.5 years) presenting with progressive cervical myelopathy secondary to ventrally located C1-C2 SCs. All patients underwent a postero-lateral facet-sparing intradural approach with total excision of the SCs. Functional status was assessed pre- and postoperatively with Nurick scale and the modified Japanese Orthopaedic association grading. Furthermore we conducted a systematic review, following PRISMA guidelines of pertinent literature to contextualize the options for surgical management of such lesions. RESULTS: Complete excision of the SCs was confirmed radiologically and on histological analysis. All measures of functional status improved post-operatively, and no cyst recurrence or need for instrumented fusion were noted during follow up (range from 22 to 88 months). CONCLUSION: Our experience suggests that the facet-sparing intradural approach provides excellent clinical outcomes without causing any C1-C2 instability. This is in keeping with the take home message emerging from our literature review, which confirms that treatment should aim at radical resection of SCs while minimizing the risk of postoperative instability.

Mast cells activated by SARS-CoV-2 release histamine which increases IL-1 levels causing cytokine storm and inflammatory reaction in COVID-19.

SARS-CoV-2 virus is an infectious agent commonly found in certain mammalian animal species and today also in humans. SARS-CoV-2, can cause a pandemic infection with severe acute lung injury respiratory distress syndrome in patients with COVID-19, that can lead to patient death across all ages. The pathology associated with pandemic infection is linked to an over-response of immune cells, including virus-activated macrophages and mast cells (MCs). The local inflammatory response in the lung that occurs after exposure to SARS-CoV-2 is due to a complex network of activated inflammatory innate immune cells and structural lung cells such as bronchial epithelial cells, endothelial cells and fibroblasts. Bronchial epithelial cells and fibroblasts activated by SARS-CoV-2 can result in the up-regulation of pro-inflammatory cytokines and induction of MC differentiation. In addition, endothelial cells which control leukocyte traffic through the expression of adhesion molecules are also able to amplify leukocyte activation by generating interleukin (IL)-1, IL-6 and CXC chemokines. In this pathologic environment, the activation of mast cells (MCs) causes the release of histamine, proteases, cytokines, chemokines and arachidonic acid compounds, such as prostaglandin D2 and leukotrienes, all of which are involved in the inflammatory network. Histamine is stored endogenously within the secretory granules of MCs and is released into the vessels after cell stimulation. Histamine is involved in the expression of chemokine IL-8 and cytokine IL-6, an effect that can be inhibited by histamine receptor antagonists. IL-1 is a pleiotropic cytokine that is mainly active in inflammation and immunity. Alveolar macrophages activated by SARS-CoV-2 through the TLR produce IL-1 which stimulates MCs to produce IL-6. IL-1 in combination with IL-6 leads to excessive inflammation which can be lethal. In an interesting study published several years ago (by E. Vannier et al., 1993), it was found that histamine as well as IL-1 are implicated in the pathogenesis of pulmonary inflammatory reaction, after micorganism immune cell activation. IL-1 in combination with histamine can cause a strong increase of IL-1 levels and, consequently, a higher degree of inflammation. However, it has been reported that histamine alone has no effect on IL-1 production. Furthermore, histamine enhances IL-1-induced IL-6 gene expression and protein synthesis via H2 receptors in peripheral monocytes. Therefore, since MCs are large producers of histamine in inflammatory reactions, this vasoactive amine, by increasing the production of IL-1, can amplify the inflammatory process in the lung infected with SARS-CoV-2. Here, we have proposed for the first time an emerging role for histamine released by MCs which in combination with IL-1 can cause an increase in lung inflammation induced by the viral infection SARS-CoV-2.

IL-1 induces throboxane-A2 (TxA2) in COVID-19 causing inflammation and micro-thrombi: inhibitory effect of the IL-1 receptor antagonist (IL-1Ra).

IL-1 induces a significant number of metabolic and hematological changes. In experimental animals, IL-1 treatments cause hypotension due to rapid reduction of systemic blood pressure, reduced vascular resistance, increased heart rate and leukocyte aggregations. IL-1 causes endothelial dysfunction, the triggering factor of which may be of a different nature including pathogen infection. This dysfunction, which includes macrophage intervention and increased protein permeability, can be mediated by several factors including cytokines and arachidonic acid products. These effects are caused by the induction of IL-1 in various pathologies, including those caused by pathogenic viral infections, including SARS-CoV-2 which provokes COVID-19. Activation of macrophages by coronavirus-19 leads to the release of pro-inflammatory cytokines, metalloproteinases and other proteolytic enzymes that can cause thrombi formation and severe respiratory dysfunction. Patients with COVID-19, seriously ill and hospitalized in intensive care, present systemic inflammation, intravascular coagulopathy with high risk of thrombotic complications, and venous thromboembolism, effects mostly mediated by IL-1. In these patients the lungs are the most critical target organ as it can present an increase in the degradation products of fibrin, fibrinogen and D-dimer, with organ lesions and respiratory failure. It is well known that IL-1 induces itself and another very important pro-inflammatory cytokine, TNF, which also participates in hemodynamic states, including shock syndrome in COVID-19. Both IL-1 and TNF cause pulmonary edema, thrombosis and bleeding. In addition to hypotension and resistance of systemic blood pressure, IL-1 causes leukopenia and thrombocytopenia. The formation of thrombi is the main complication of the circulatory system and functionality of the organ, and represents an important cause of morbidity and mortality. IL-1 causes platelet vascular thrombogenicity also on non-endothelial cells by stimulating the formation of thromboxane A2 which is released into the inflamed environment. IL-1 is the most important immune molecule in inducing fever, since it is involved in the metabolism of arachidonic acid which increases from vascular endothelial organs of the hypothalamus. The pathogenesis of thrombosis, vascular inflammation and angigenesis involves the mediation of the activation of the prostanoid thromboxane A2 receptor. In 1986, in an interesting article (Conti P, Reale M, Fiore S, Cancelli A, Angeletti PU, Dinarello CA. In vitro enhanced thromboxane B2 release by polymorphonuclear leukocytes and macrophages after treatment with human recombinant interleukin 1. Prostaglandins. 1986 Jul;32(1):111-5), we reported for the first time that IL-1 induces thromboxane B2 (TxB2) releases in activated neutrophils and macrophages. An increase in thromboxane can induce leukocyte aggregation and systemic inflammation, which would account for the dramatic thrombi formation and organ dysfunction. Hence, IL-1 stimulates endothelial cell-leukocyte adhesion, and TxB2 production. All these events are supported by the large increase in neutrophils that adhere to the lung and the decrease in lymphocytes. Therefore, ecosanoids such as TxA2 (detected as TxB2) have a powerful action on vascular inflammation and platelet aggregation, mediating the formation of thrombi. The thrombogenesis that occurs in COVID-19 includes platelet and cell aggregation with clotting abnormalities, and anti-clotting inhibitor agents are used in the prevention and therapy of thrombotic diseases. Prevention of or induction of TxA2 avoids thrombi formation induced by IL-1. However, in some serious vascular events where TxA2 increases significantly, it is difficult to inhibit, therefore, it would be much better to prevent its induction and generation by blocking its inductors including IL-1. The inhibition or lack of formation of IL-1 avoids all the above pathological events which can lead to death of the patient. The treatment of innate immune cells producing IL-1 with IL-1 receptor antagonist (IL-1Ra) can avoid hemodynamic changes, septic shock and organ inflammation by carrying out a new therapeutic efficacy on COVID-19 induced by SARS-CoV-2.

Mesenchymal stem cells and IL-37: a powerful combination.

Mesenchymal stem cells (MSCs) are able to exert immunomodulatory and anti-inflammatory actions. Thanks to these properties, MSCs may be a promising alternative approach for the treatment of inflammatory disease. Important cytokines involved in inflammation are those included in the IL-1 family. Interleukin-37 (IL-37) is one of the member able to suppress both innate and adaptive immunity. Recently, it was found that MSCs and their derivatives can modulate IL-37, and MSCs expressing IL-37 seem to have an enhanced therapeutic efficacy.

CAR-T cell therapy causes inflammation by IL-1 which activates inflammatory cytokine mast cells: anti-inflammatory role of IL-37.

Chimeric antigen receptor (CAR) T cells are genetically modified T cells that act against cancer. When CAR-T cells are administered they can trigger inflammatory cytokines and increase toxicity. Interleukin (IL)-1 is the classic cytokine that mediates inflammatory reactions including those that occur in CAR-T-cell therapy. IL-1 also induces IL-33 in mast cells (MCs), amplifying the allergic reaction. IL- 37 (ILF7) is an IL-1 family member which binds IL-18 receptor alpha (IL-18Rα) chain and suppresses innate and acquired immunity. IL-37 is an anti-inflammatory cytokine which inhibits pro-inflammatory cytokines including IL-1 and IL-33. Here, we hypothesize that inflammation and toxicity generated in tumor CAR-T therapy could be inhibited by IL-37, contributing to an improvement in the treatment of tumors with CAR-T therapy.

Pure endoscopic management of epileptogenic hypothalamic hamartomas.

Hypothalamic hamartomas (HH) are rare congenital malformations located in the region of the tuber cinereum and third ventricle. Their usual clinical presentation is characterized by gelastic/dacrystic seizures which often become pharmaco-resistant and progress to secondary focal/generalized intractable epilepsy causing mostly in children cognitive and behavioral problems (particularly in cases of progressive epileptic encephalopathy) and precocious puberty. Whereas gelastic seizures can be surgically controlled either by resection of the lesion or disconnection (tissue-destructive) procedures, aimed at functionally prevent the spreading of the epileptic burst; generalized seizures tend to respond better to HH excision rather than isolated neocortical resections, which generally fail to control them. Prospective analysis of 14 consecutive patients harboring HH treated in an 8-year period; 12 patients had unilateral and two bilateral HH. All patients were managed by pure endoscopic excision of the HH. The mean operative time was 48 min and mean hospital stay was 2 days; perioperative blood loss was negligible in all cases. Two patients showed a transient diabetes insipidus (DI); no transient or permanent postoperative neurological deficit or memory impairment was recorded. Complete HH excision was achieved in 10/14 patients. At a mean follow-up of 48 months, no wound infection, meningitis, postoperative hydrocephalus, and/or mortality were recorded in this series of patients. Eight patients became seizure free (Engel class I), 2 other experienced worthwhile improvement of disabling seizures (Engel class II); 2 patients were cured from gelastic attacks while still experiencing focal dyscognitive seizures; and 2, having bilateral HH (both undergoing unilateral HH excision), did not experience significant improvement and required later on a temporal lobectomy coupled to amygdalohyppocampectomy. Overall, the followings resulted to be predictive factors for better outcomes in terms of seizure control: (1) cases of unilateral, Delalande class B, HH, (2) shorter history of epilepsy. Endoscopic resection of HH proved, in our series, to be effective in achieving complete control or in reducing the frequency of seizures. Furthermore, this approach has confirmed its minimally invasive nature with a very low morbidity rate: of note, it allowed to better preserve short-term memory and hypothalamic function.

Subarachnoid and intra-cerebral hemorrhage in young adults: rare and underdiagnosed.

OBJECTIVES: Convexity subarachnoid and intra-cerebral hemorrhages, in patients aged<50 years, are always a diagnostic challenge. This condition is characterized by acute headaches with or without neurological symptoms and/or seizures, and by the radiological demonstration of subarachnoid and/or intra-cerebral hemorrhages and, more rarely, by the association of ischemic events. PATIENTS AND METHODS: In a prospective series of 30 consecutive patients (median age 31 years; 22 women) with a subarachnoid and intra-cerebral hemorrhages, 19 were diagnosed with reversible cerebral vasoconstriction syndrome (RCVS), 7 with cerebral venous sinus thrombosis (CVST), and 4 with a bleeding mycotic aneurysm (MA). RESULTS: RCVS appeared spontaneously in 16 patients and was related to the postpartum period in three cases. Subarachnoid hemorrhage (SAH) was demonstrated in 24 patients as follows: 18 cases were in cortical areas, 4 were in the polygon of Willis, one was inter-hemispheric, and one was inter-hemispheric/intra-cerebral. A convexity pure intra-cerebral hemorrhage (ICH) was recorded in 6 cases. Among the 7 patients suffering from CVST, the superior sagittal sinus was involved in 4 cases, the transverse sinuses (TS) in 2, and the TS plus sigmoid sinus (SS) in one. CONCLUSION: The three most common causes in this series were RCVS, followed by CVST and bleeding from MA. Because of atypical clinical or radiological presentations, this large spectrum of etiologies can cause diagnostic difficulties. Therefore, careful analysis is needed to ensure correct and prompt diagnosis and to avoid any dangerous delays in management.

Dorsal epidural spinal lipomatosis.

The authors report a case of a thoracic epidural spinal lipomatosis causing severe neurological deficits along the review of pertinent literature. The patient is a 56-year-old woman who presented with acute onset of severe paraparesis; she was investigated with cervical and thoracic MRI and then surgically managed because of an intraspinal mass compressing the cord. The operation consisted in the excision of the mass confirmed to be a fibrolipoma by pathological analysis. The patient attained complete neurological recovery and at 18 months follow-up she reported a generalised well-being. Thoracic lipomas are rare lesions that presenting mostly with back pain; however, in rare instances they may cause progressive and/or abrupt neurological dysfunction. Appropriate imaging can help in the diagnosis and management of such cases.

Skull bone flap fixation - reliability and efficacy of a new grip-like titanium device (Skull Grip) versus traditional sutures: a clinical randomized trial.

BACKGROUND: After completing a craniotomy, it is important to replace the removed bone flap in its natural position in order to guarantee brain protection as well as improve cosmesis. A skull defect can expose the brain to accidental damage, and in cases of larger defects it may also cause the patients psychosocial problems. The ideal fixation device should provide reliable attachment of the flap to the skull and promote fast bony healing to avoid possible pseudo-arthrosis and/or osteolytic changes. MATERIALS AND METHODS: This is a pilot randomized clinical trial on a series of 16 patients undergoing different craniotomies for benign brain lesions in which the bone flaps were replaced using traditional sutures (Prolene 0.0) in 8 cases and with a new skull fixation device (Skull Grip) in the other 8 (randomly allocated). All patients underwent CT scans of the head with 3D reconstruction at day 1 and day 90 postoperatively to evaluate bone flap position and fusion. These scans were independently reviewed by a neuroradiologist. Cosmesis was also evaluated clinically by the surgeon and radiologically by the neuroradiologist in the 2 patient groups. RESULTS: The new "Skull Grip" device has shown stronger fixation qualities with optimal bone flap fusion and increased cosmetic healing features vs. traditional sutures. CONCLUSION: The "Skull Grip" has shown to be a reliable, effective and stronger bone flap fixation device when compared to traditional sutures.

Neurosurgery and elderly: analysis through the years.

The aging of the population in westernized countries constitutes an important issue for the health systems struggling with limited resources and increasing costs. Morbidity and mortality rates reported for neurosurgical procedures in the elderly vary widely. The lack of data on risk benefit ratios may result in challenging clinical decisions in this expanding group of patients. The aim of this paper is to analyze the elderly patients cohort undergoing neurosurgical procedures and any trend variations over time. The medical records of elderly patients (defined as an individual of 70 years of age and over) admitted to the Neurosurgical and Neuro-ICU Departments of a major University Hospital in Paris over a 25-year period were retrospectively reviewed. The analysis included: (1) number of admissions, (2) percentage of surgically treated patients, (3) type of procedures performed, (4) length of hospital stay, and (5) mortality. The analysis showed a progressive and significant increase in the proportion of elderly presenting for neurosurgical elective and/or emergency procedures over the last 25 years. The number of procedures on patients over 70 years of age increased significantly whereas the mortality dropped. Though the length of hospital stay was reduced, it remained significantly higher than the average stay. The types of procedures also changed over time with more craniotomies and endovascular procedures being performed. Age should not be considered as a contraindication for complex procedures in neurosurgery. However, downstream structures for postoperative elderly patients must be further developed to reduce the mean hospital stay in neurosurgical departments because this trend is likely to continue to grow.

Double skull lymphangioma. Case report and review of the literature.

OBJECTIVE: It is still controversial whether lymphangiomas are a true entity or a combination of congenital venous and lymphatic malformations. Lymphangioma diagnosis is made on a multifactorial basis and surgery should provide cosmetic and functional preserving results. Only few multiple localization have been described in the literature and to our knowledge this is the first case reported on a double localization (orbital and temporal) in the skull. CASE DESCRIPTION: A 10-year-old girl was referred to our department with a rapidly enlarging subcutaneous mass in the right eyebrow and upper eyelid, displacing the eyeball and causing proptosis and diplopia that occurred synchronous with her menarche. A head MRI scan showed two distinct lesions, one into the orbit causing bony destruction and the other one in the sub-temporal area. The little girl underwent an open biopsy, suggesting the diagnosis of lymphangioma. Surgery through an anterior approach with total removal of both lesions was performed. Pathological examination disclosed a lesion consisting of multiple cysts with erythrocytes and lymphs, confirming the diagnosis. At a 6- and 12-months follow-up, the girl was clinically intact with normal ocular movements and a follow-up MRI showed no evidence of residual disease and/or recurrence.

Skull bone flap fixation--comparative experimental study to assess the reliability of a new grip-like titanium device (Skull Grip) versus traditional sutures: technical note.

INTRODUCTION: After completing a craniotomy, whenever possible, it is crucial to replace and fix the removed bone flap to the cranium; this in order to keep the brain's protection as well as for cosmetic purposes. Visible skull defects might cause patients psychosocial problems and, most importantly, expose the brain to accidental damage. A fixation device should not only provide optimal attachment of the flap to the skull but also allow fast bony healing to avoid possible pseudoarthrosis and/or osteolytic changes. METHODS: After performing 12 different craniotomies on 4 human cadaver heads the skull flaps were replaced using traditional sutures and a new skull fixation device; for each fixation technique a load-bearing test was performed and the results compared. RESULTS: Bone flaps fixed with the "Skull Grip" showed a strong fixation with optimal plastic deformation when compared to flaps held by sutures that showed less resistance to pressure and could be easily dislocated. CONCLUSION: The "Skull Grip" has shown to be a reliable, effective, and stronger bone flap fixation superior to suturing technique.

p53 tumor suppressor protein and H-RAS oncogene in maxillofacial tumors: immunohistochemical and genetic investigation, induction chemotherapy response and prognosis evaluation.

The authors carried out immunohistochemical and genetic research on the tumor suppressor protein p53 and H-RAS oncogene in oromaxillofacial neoplasms. The purpose was to verify, genetically, the presence of correlations between the degree of histopathological overexpression (per cent) of oncogenes and chemoresistance. The study was carried out on 15 patients with squamous cell carcinoma of the oromaxillofacial region, of equal histopathological grade (G2), who underwent neoadjuvant chemotherapy: cis-diaminodichloroplatinum (CDDP, 20 mg/m2 i.v. days 1-5) and 5-fluorouracil (5-FU 1000 mg/m2 continuous infusion, volumetric pump 2 ml/h, for 5 days). Restaging was carried out after three cycles of chemotherapy to evaluate clinical response. The p53 immunohistochemical study (clone DO-7) showed a pathological overexpression in 9/15 cases; whereas the genetic exam (PCR method, wild DNA) showed mutations in 5/15 cases, with individual corresponding percentages of 95%, 80%, 70%, 45% and 95%. The H-RAS immunohistochemical study (AB-1) (clone 235-1.7.1) showed a pathological overexpression in 12/15 cases; the genetic exam showed mutations in 9/15 cases, corresponding to, respectively, 90%, 35%, 10%, 20%, 77%, 90%, 85%, 25%, 75%. The response to the neoadjuvant chemotherapy was as follows: 2 partial responses (PR) (90%) in 1 tumor of the cheek and in 1 tumor of the soft palate, with global survival (GS) of, respectively, 18 and 15 months. 1 PR (75%) and 4 PR (55%) in 5 tumors of the gum, with GS of, respectively, 10, 6, 8 , 9 and 8 months. Two objective improvements (OI) in, respectively, 1 tumor of the floor of the mouth and 1 tumor of the gum, with GS of, respectively, 5 and 6 months. Three patients had stable disease (S) in 2 tumors of the tongue and 1 tumor of the gum, with GS of, respectively, 10, 7 and 7 months. Three patients had progression (P) in 2 tumors of the floor of the mouth and in 1 tumor of the cheek, with GS of, respectively, 8, 8 and 6 months. This study showed some correlation between genetic analysis and immunohistochemical investigation of 73.3% of cases for p53 and of 80% of cases for H-RAS (Chi-Square Test: p=0.3089). These data do not permit definition of the range of oncogene overexpression which corresponds to mutation, thus serving as a marker of chemoresistance. However, the cases studied confirm that, in regard to p53, there is a certain degree of correlation between absence of mutations and sensitivity to neoadjuvant chemotherapy.

[p53 mutations and chemoresistance in oromaxillofacial squamous-cell carcinomas. The results of a molecular genetics study of p53 in metastatic oromaxillofacial tumors and an evaluation of the response to neoadjuvant chemotherapeutic treatment]. / Mutazioni della p53 e chemioresistenza nei carcinomi squamosi oro-maxillo-facciali. Risultati dello studio genetico molecolare della p53 in tumori oro-maxillo-facciali metastatizzati e valutazione della risposta al trattamento chemioterapico neoadiuvante.

MATERIAL AND METHODS: The authors carried out a p53 genetic research on native DNA in 15 oral-maxillofacial squamous cell carcinomas, lymph nodes metastasis, treated with neoadjuvant chemotherapy, checking the p53 "status" and the clinical response to the chemotherapeutic treatment (three 5-FU/CDDP cycles). RESULTS: The authors found p53 mutations in 3/15 cases. In these cases, at post-chemo restaging, it resulted 2 progressions and 1 stability of disease. In the 12 cases with wildtype p53: 4 objective improvements and partial responses (PR), respectively, of 55% (1), 60% (1), 65% (1), 70% (1), 75% (2) and 90% (2). The 15 patients were treated then by surgery and adjuvant chemotherapy (three C-F cycles). These results seem to confirm the outcome of the researches "in vitro" and they provide first correlations between p53 mutations and chemoresistance in oral squamous cell carcinomas. The survival evaluation also, in the examined cases, shows, but with medium-term follow-up, the tendency to a poor prognosis when p53 is altered. CONCLUSIONS: This research outlines the possibility, also for oral and maxillofacial tumors, to utilize, p53 as a prognostic and chemoresponse marker, useful, with the otherwise well-known prognostic factors, for the evaluation of advanced cancers, in the interests of a more suitable therapeutic protocol.

[p53 mutation and chemoresistance in oral-maxillofacial squamous cell carcinoma. Role of p53 in the cell cycle control and in the modulating action of chemotherapeutic agents]. / Mutazioni della p53 e chemioresistenza nei carcinomi squamosi oro-maxillo-facciali. Ruolo della p53 nel controllo del ciclo cellulare e nel modulare l'azione di composti chemioterapici.

p53 is a "tumor suppressor gene" with a basic function in the cellular cycle control and subsequently in the induction of the neoplastic process. p53 found changed in the majority of malignant human tumors. In the oral and maxillofacial cancers p53 mutations varies from 4% to 60% of the cases. Researches in vitro in tumors of the colon-rectum, breast, lung, ovary, testicle, bladder and in leukaemia, show a correlation between p53 overexpression (mutation) and resistance to the anti-tumor agents. The functional connection between the p53 and the chemotherapic drugs action which cause a direct DNA damage, is the apoptosis, a physiologic mechanism activated by p53 for regulating cell growth but also indispensable for the cytotoxic effects (apoptosis is an irreversible process culminating in cell death). Loss of the p53 activity (mutation) in the tumoral cells determines non-activation of the apoptosis and the drug resistance. These results have led to early clinical applications. In the breast cancers the p53 is already utilized as chemoresistance marker, directing the therapy, if changed to alternative drugs (Taxolo) which have a p53-independent action. Even into cell lung cancers a retroviral vector containing the wild-type p53 gene was produced to mediate transfer of wild-type p53, noting tumor regression. In oral and maxillofacial tumors surgery is elective. It is emphasized that, in advanced cancers, it is included in multimode protocols where the neoadjuvant chemotherapy has an important clinical function, with precise indications. The possibility to determine previously the p53 "status" in the cancer cells by genetic study, may give a specific factor of screening, indicative of the tumor chemoresponse, together with other well-known prognostic factors, with advantage for the therapeutic programming and especially for the known surgical treatment.