The role of cytokines in head and neck squamous cell carcinoma: A review.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy worldwide, accounting for approximately 6% of all cancer cases and responsible for an estimated 1-2% of all cancer deaths. Much research evidence has accumulated in the recent years on the changes in the expression of pro-inflammatory and, to a lesser extent, anti-inflammatory cytokines, that (i) may have a role in the malignant transformation of HNSCC, (ii) may be used as diagnostic markers in the sera of patients because of their excessive production by the tumor cells and (iii) may act as possible immunotherapeutic targets. Among pro-inflammatory cytokines, interleukin-8 (IL--8) has been reported to have an important role in cancer invasion, angiogenesis and metastasis. Recent studies have shown an increased concentration of IL--8 in patients with HNSCC and a positive association with lymph node metastasis and tumor classification, although IL--8 was not significantly associated with shorter overall survival and cancer progression-free survival. Additional evidence on the pathological mechanism of origin, invasion, and metastasis of HNSCC, as well as a better understanding of the implications of cytokines, chemokines and growth factors, are of paramount importance for the advancement of research in head and neck oncology.

FAS-ligand regulates differential activation-induced cell death of human T-helper 1 and 17 cells in healthy donors and multiple sclerosis patients.

Functionally distinct T-helper (Th) subsets orchestrate immune responses. Maintenance of homeostasis through the tight control of inflammatory Th cells is crucial to avoid autoimmune inflammation. Activation-Induced Cell Death (AICD) regulates homeostasis of T cells, and it has never been investigated in human Th cells. We generated stable clones of inflammatory Th subsets involved in autoimmune diseases, such as Th1, Th17 and Th1/17 cells, from healthy donors (HD) and multiple sclerosis (MS) patients and we measured AICD. We find that human Th1 cells are sensitive, whereas Th17 and Th1/17 are resistant, to AICD. In particular, Th1 cells express high level of FAS-ligand (FASL), which interacts with FAS and leads to caspases' cleavage and ultimately to cell death. In contrast, low FASL expression in Th17 and Th1/17 cells blunts caspase 8 activation and thus reduces cell death. Interestingly, Th cells obtained from healthy individuals and MS patients behave similarly, suggesting that this mechanism could explain the persistence of inflammatory IL-17-producing cells in autoimmune diseases, such as MS, where their generation is particularly substantial.

Ureteroscopy and laser lithotripsy: technologic advancements.

Ureteroscopic lithotripsy has evolved since the first reported cases employing rigid rod-lens endoscopes and stiff ultrasonic lithotrites. Fiber optics facilitated rigid endoscope miniaturization and the development of a steerable, deflectable flexible ureteroscopes. Over 30 years of technical innovations culminating in digital imagers and powerful, precise laser lithotrites, complimented by progressive endoscopic techniques have produced efficient endoscopic therapies with minimal morbidity and commonly performed in an outpatient setting.

Long-term results of the GIMEMA VEL-03-096 trial in MM patients receiving VTD consolidation after ASCT: MRD kinetics' impact on survival.

Polymerase chain reaction (PCR)-based minimal residual disease (MRD) analysis is a useful prognostic tool in multiple myeloma (MM), although its long-term impact still needs to be addressed. This report presents the updated results of the GIMEMA-VEL-03-096 trial. Thirty-nine MM patients receiving bortezomib-thalidomide-dexamethasone after autologous transplantation were monitored for MRD by both nested and real-time quantitative-PCR until relapse. Our data confirm the strong impact of MRD on survival: overall survival was 72% at 8 years median follow-up for patients in major MRD response versus 48% for those experiencing MRD persistence (P=0.041). In addition, MRD kinetics resulted predictive for relapse: indeed median remission duration was not reached for patients in major MRD response, 38 months for those experiencing MRD reappearance and 9 months for patients with MRD persistence (P<0.001). Moreover: (1) 26 patients achieving major MRD response (67%) benefit of excellent disease control (median TNT: 42 months); (2) MRD reappearance heralds relapse, with a TNT comparable to that of MRD persistence (9 versus 10 months, P=0.706); (3) the median lag between MRD reappearance and need for salvage treatment is 9 months. These results suggest the usefulness of a long-term MRD monitoring in MM patients and the need for maintenance or pre-emptive treatments ensuring durable responses.

Use of cidofovir in HPV patients with recurrent respiratory papillomatosis.

Recurrent respiratory papillomatosis is a viral-induced disease, associated with exophytic epithelial lesions affecting the upper airways. Problem of treatment is the high recurrence of papilloma growth after surgical removal; therefore, adjuvant therapy schemes have been established. We used cidofovir, 7.5 mg/ml, in adjuvant therapy in the past years. Out of 31 adult patients treated with the drug, 26 (83.9 %) are at the moment in complete response. 19 (73 % of pts with CR) of those 26 patients were cured with a number of injections between 1 and 4 (mean 2.5). We did not see any clinical manifestation of renal toxicity or neutropenia (superinfection) necessitating a blood test. Six patients presented dysplasia during the treatment with the drug, while six patients had dysplasia prior to cidofovir injection. Due to recurrent nature of the disease and the high number of mechanical and laser surgeries required we treated one tracheal stenosis, two scarred larynx, and two glottic synechiaes. There is still an ongoing discussion within the European Laryngological Society about the effectiveness and possible side effects of this drug. Results show promising long-term effects of adjuvant use of cidofovir, without any relevant side effects.

Recurrent respiratory papillomatosis by HPV: review of the literature and update on the use of cidofovir.

Recurrent respiratory papillomatosis is a viral induced disease characterised by exophytic epithelial lesions affecting the larynx. The problem with its treatment is the high recurrence of papilloma growth after surgical removal. The aim of our review is to analyse the actual use of cidofovir, an agent used in adjuvant therapy. We have reviewed 6 manuscripts that included a total of 118 patients. The parameters taken into account were: concentration of infiltrated cidofovir (mg/ml), therapeutic response, relapse-free time (months), side effects, genotypes (HPV-6/11/18) and evolution of dysplasia. Cidofovir was injected at concentrations from 2.5 to 15 mg/ml, therapeutic response was from 56.25% to 82.3% and relapse-free time was from 10.05 to 49 months. There were 2 cases of dysplasia during therapy. Ten patients had been infected by HPV-6, 4 patients by HPV-11 and 10 patients by HPV-6 and HPV-11. The purposes of our review include the following: to stress that the juvenile form is more aggressive than other forms, to demonstrate than the drug has good adjuvant action although it does not significantly change the final response to the disease, to show that side effects are modest and, finally, to disprove the hypothesis that cidofovir may promote evolution towards dysplasia. In conclusion, combination of surgical removal and injection of cidofovir is associated with good response in recurrent respiratory papillomatosis.

The Italian National External quality assessment program in molecular genetic testing: results of the VII round (2010-2011).

Since 2001 the Istituto Superiore di Sanità established a quality assurance programme for molecular genetic testing that covers four pathologies: Cystic Fibrosis (CF), Beta Thalassemia (BT), Fragile X Syndrome (FX), and Familial Adenomatous Polyposis Coli (APC). Since 2009 this activity is an institutional activity and participation is open to both public and private laboratories. Seven rounds have been performed until now and the eighth is in progress. Laboratories receive 4 DNA samples with mock clinical indications. They analyze the samples using their routine procedures. A panel of assessors review the raw data and the reports; all data are managed through a web utility. In 2010 the number of participants was 43, 17, 15, 5 for CF, BT, FX, APC schemes respectively. Genotyping results were correct in 96%, 98.5%, 100%, and 100% of CF, BT, FX, and APC samples, respectively. Interpretation was correct in 74%, 91%, 88%, and 60% of CF, BT, FX, and APC reports, respectively; however in most of them it was not complete but a referral to genetic counseling was given. Reports were satisfactory in more than 60% of samples in all schemes. This work presents the 2010 results in detail comparing our data with those from other European schemes.

Lenalidomide-prednisone induction followed by lenalidomide-melphalan-prednisone consolidation and lenalidomide-prednisone maintenance in newly diagnosed elderly unfit myeloma patients.

This multicenter phase II trial evaluated the safety and efficacy of lenalidomide-prednisone (RP) induction, followed by lenalidomide-melphalan-prednisone (MPR) consolidation and RP maintenance in elderly unfit newly diagnosed myeloma patients. Patients received four 28-day RP induction courses (lenalidomide 25 mg/day on days 1-21 and prednisone 50 mg three times/week), followed by six 28-day MPR consolidation cycles (melphalan 2 mg, prednisone 50 mg three times/week and lenalidomide 10-15 mg/day on days 1-21), and maintenance with lenalidomide (10 mg/day on days 1-21 every 28 days) plus prednisone (25 mg three times/week). Forty-six patients were enrolled. Median age was 75 years, 59% of patients had at least one comorbidity and 35% at least two. Partial response rate was 80%, including 29% very good partial response. Median time to progression was 19.6 months, median progression-free survival was 18.4 months and 2-year overall survival was 80%. At the tolerated consolidation dose (melphalan 25 mg/month and lenalidomide 10 mg/day), the most frequent grade 3 adverse events were neutropenia (36.4%), anemia (12.1%), cutaneous reactions (18.2%) and infections (12.1%). Grade 4 neutropenia occurred in 12.1% of patients. In conclusion, RP induction followed by MPR consolidation and RP maintenance showed a manageable safety profile, and reduced the risk of severe hematological toxicity in unfit elderly myeloma patients.

Glioblastoma in elderly patients: safety and efficacy of adjuvant radiotherapy with concomitant temozolomide.

The aim of this study was to evaluate the impact of radiotherapy plus concomitant and adjuvant temozolomide (TMZ), in terms of feasibility and activity, in elderly patients with glioblastoma. From January 2002 to December 2007, 42 consecutive patients with glioblastoma (27 men and 15 women) aged 65 years or more (median age 71.3 years), received radiotherapy plus concomitant and adjuvant TMZ. Nineteen patients (45.2%) had a Karnofsky index >or=80. Thirty-six patients (85.8%) underwent complete or subtotal resection, while 6 patients (14.2%) were only biopsied. All patients received adjuvant radiotherapy within 4 weeks from surgery. Twenty-two patients (54.8%) underwent adjuvant TMZ. Early discontinuation of concomitant TMZ program due to toxicity was observed in 8 patients. Considered variables were: age, Karnofsky index, surgery versus no surgery, radiation dose, and chemotherapy. At a median follow-up of 10.2 months, the 6- and 12-month overall survival rates were 81.9% and 27.8%, respectively. There was a significantly better survival for patients with a performance status according to Karnofsky >80 (p<0.0001). Actuarial progression-free survival at 6- and 12-month was 46.4% and 9.8%, respectively. Globally, the treatment was well tolerated with no treatment-related toxicity in 69% of patients. In conclusion, in elderly patients, the adjuvant chemo-radiotherapy was well tolerated with an acceptable rate of toxicity, and patients with a good performance status had a significantly better survival. However, further prospective trials are needed to confirm these results.

Pathogenic FBN1 mutations in 146 adults not meeting clinical diagnostic criteria for Marfan syndrome: further delineation of type 1 fibrillinopathies and focus on patients with an isolated major criterion.

Mutations in the FBN1 gene cause Marfan syndrome (MFS) and have been associated with a wide range of milder overlapping phenotypes. A proportion of patients carrying a FBN1 mutation does not meet diagnostic criteria for MFS, and are diagnosed with "other type I fibrillinopathy." In order to better describe this entity, we analyzed a subgroup of 146 out of 689 adult propositi with incomplete "clinical" international criteria (Ghent nosology) from a large collaborative international study including 1,009 propositi with a pathogenic FBN1 mutation. We focused on patients with only one major clinical criterion, [including isolated ectopia lentis (EL; 12 patients), isolated ascending aortic dilatation (17 patients), and isolated major skeletal manifestations (1 patient)] or with no major criterion but only minor criteria in 1 or more organ systems (16 patients). At least one component of the Ghent nosology, insufficient alone to make a minor criterion, was found in the majority of patients with isolated ascending aortic dilatation and isolated EL. In patients with isolated EL, missense mutations involving a cysteine were predominant, mutations in exons 24-32 were underrepresented, and no mutations leading to a premature truncation were found. Studies of recurrent mutations and affected family members of propositi with only one major clinical criterion argue for a clinical continuum between such phenotypes and classical MFS. Using strict definitions, we conclude that patients with FBN1 mutation and only one major clinical criterion or with only minor clinical criteria of one or more organ system do exist but represent only 5% of the adult cohort.

Retroperitoneal laparoscopic partial nephrectomy: surgical experience and outcomes.

PURPOSE: We present outcomes in 110 consecutive patients who underwent retroperitoneal laparoscopic partial nephrectomy performed in a 72-month period by a single surgeon (MG). MATERIALS AND METHODS: Patients were placed in the flank position and the retroperitoneal space was developed using a balloon dissector. Hilar control was achieved with bulldog clamps. Tumor depth and extent were evaluated using intraoperative sonography. Perioperative data were assessed and outcomes were retrospectively analyzed at a mean followup of 23 months. RESULTS: Mean patient age was 62 years. Mean operative time was 199.7 minutes and mean postoperative stay was 2.6 days. Mean blood loss was 260.0 ml and mean tumor size was 2.4 cm. Final pathological evaluation revealed negative positive margins in these cases. Of all tumors 63.7% were pathologically confirmed renal cell carcinoma. In 57 patients mean preoperative and postoperative creatinine was 1.1 and 1.3 mg/dl, respectively, at a mean of 20.6 months. In 47 patients with renal cell carcinoma who underwent computerized tomography or magnetic resonance imaging during the mean 23-month followup there was 1 incidence of local recurrence at 1 year. Conversion to open surgery occurred in 2 cases and laparoscopic radical nephrectomy was performed in 4. The rate of major complications was 4.5%. CONCLUSIONS: Although it is technically challenging, the retroperitoneal approach to laparoscopic partial nephrectomy can be performed in a safe and timely manner with perioperative outcomes comparable to those reported for open and transperitoneal approaches. Furthermore, this approach allows the containment of blood and urine outside the peritoneal cavity. Our intermediate term results revealed excellent cancer control and preserved renal function.

Inclusion body myopathy, Paget's disease of the bone and frontotemporal dementia: recurrence of the VCP R155H mutation in an Italian family and implications for genetic counselling.

The acronym IBMPFD denotes a syndrome including inclusion body myopathy, Paget's disease of the bone (PDB) and frontotemporal dementia (FTD) as cardinal features, which is caused by missense mutations in the VCP gene. We studied the clinical characteristics and the histopathological features in two siblings and their mother who presented with adult-onset myopathy and presenile, rapidly progressive FTD. One sibling also showed PDB. Light and electron microscopy performed on muscle biopsies demonstrated degenerative changes with inclusion bodies and abnormal aggregates. Mutation analysis of the VCP gene on affected siblings revealed a heterozygous missense mutation (R155H) in a hot spot. This is the first Italian family with multiple individuals diagnosed as having IBMPFD and carrying the recurrent R155H mutation. The implications for genetic counselling were also discussed, with regard to the procedures that may be offered to families suffering from a multisystem disorder with high risk of cognitive decline.

Parotid metastasis from renal cell carcinoma: a case report and review of the literature.

Renal cell carcinoma metastasis to the parotid gland after tumour nephrectomy is extremely rare. Herewith a review of the literature on this topic is discussed and a case report is presented of a 69-year-old man affected by parotid localization of renal clear cell carcinoma with neck lymph node metastases and involvement of the masseter muscle 2 years after nephrectomy. When an otolaryngologist encounters a parotid mass, diverse differential diagnoses have to be considered. A high level of suspicion of metastatic disease from the specific primary site will help in achieving correct diagnosis and evaluation of the extension of the disease. Surgical resection, even enlarged parotidectomy with neck dissection, should be considered as a therapeutic option for exclusive location of the disease in the head and neck.

[Preliminary study on efficacy and tolerance of a "coupage" of olive oil in patients with chronic kidney disease. Nutritonal evaluation]. / Estudio preliminar sobre eficacia y tolerancia de un "coupage" de aceite de oliva en pacientes con enfermedad renal crónica. Evaluación del estado de nutrición.

The discrepancies among data reported by using olive oil (OO) in humans appear to be due to the great differences between the different OO used. Based on structure/function relationships we have chemically optimized an OO through the rational mixture ("coupage") of several Spanish extra virgin olive oils (methodology "oHo"). Patients with chronic kidney disease (CKD) develop a progressive picture of malnutrition and inflammation that lead them to an elevated risk of cardiovascular disease. In a pilot, randomised trial the nutritional efficacy and safety of "oHo" were evaluated in 32 patients (mean age 60,8 +/- 13,2 years old; 16 women) with CKD (KDIGO stages 4-5) at predialysis. After a 7 days wash out for statins and ACE inhibitors 19 patients had "oHo" at doses of 60 mL/day (20 mL t.i.d) for 30 consecutive days, whilst 13 patients remain as a control group without "oHo". At the end of the study only patients having "oHo" showed significant increases of serum albumin (p<0.05) and not significant increases of total proteins, weight, and BMI. Total cholesterol (p<0.05) and HDL-cholesterol (p<0.01) increased with "oHo". The number of cases with pathologic HOMA-IR in the control group increased from 1 to 2 patients whilst in the "oHo" group decreased from 2 to none. No significant changes of minerals, arterial pressure, hemoglobin, and other parameters related to CKD were seen. After a 30 days follow-up in the "oHo" group all parameters came back to basal ones, excepting for blood pressure that significantly decreased (p<0,05). Tolerance was excellent and constipation significantly diminished (p<0,001) in the "oHo" group. Of importance, none of these biological changes were seen in regular consumers of other conventional olive oils (control group). These intriguing results, seen by the first time, appear to partially satisfy the recent claims ("reverse epidemiology") about the need of a more correct nutrition in CKD patients. However, these data need to be proved in more larger trials as well as in CKD patients under dialysis with harder inflammatory/malnutrition conditions.

Perioperative management of four anaemic female Jehovah's Witnesses undergoing urgent complex cardiac surgery.

Previous studies have demonstrated that preoperative haemoglobin concentration and female gender are related to an increased need for perioperative allogeneic transfusions in cardiac surgery. Hence, urgent cardiac surgery presents a dilemma for female patients who are Jehovah's Witnesses, because of their refusal of allogeneic transfusion. This report describes the management of four high-risk anaemic female patients undergoing urgent complex cardiac surgery. In these Jehovah's Witness patients, strict application of a comprehensive blood-sparing protocol permitted safe avoidance of allogeneic transfusions. The protocol involved intraoperative acute normovolaemic haemodilution, intraoperative administration of tranexamic acid, intra- and postoperative use of a cell-saver system, postoperative administration of erythropoietin, iron and folic acid, and a careful surgical technique to avoid perioperative bleeding.

Positive margins in laparoscopic partial nephrectomy in 855 cases: a multi-institutional survey from the United States and Europe.

PURPOSE: Open partial nephrectomy has emerged as the standard of care in the management of renal tumors smaller than 4 cm. While laparoscopic radical nephrectomy has been shown to be comparable to open radical nephrectomy with respect to long-term outcomes, important questions remain unanswered regarding the oncological efficacy of laparoscopic partial nephrectomy. We examined the practice patterns and pathological outcomes following laparoscopic partial nephrectomy. MATERIALS AND METHODS: A survey was sent to academic medical centers in the United States and in Europe performing laparoscopic partial nephrectomy. The total number of laparoscopic partial nephrectomies, positive margins, indications for intraoperative frozen biopsy as well as tumor size and position were queried. RESULTS: Surveys suitable for analysis were received from 17 centers with a total of 855 laparoscopic partial nephrectomy cases. Mean tumor size was 2.7 cm (+/-0.6). There were 21 cases with positive margins on final pathology, giving an overall positive margin rate of 2.4%. Intraoperative frozen sections were performed selectively at 10 centers based on clinical suspicion of positive margins on excised tumor. Random biopsies were routinely performed on the resection bed at 5 centers. Frozen sections were never performed at 2 centers. Of the 21 cases with positive margins 14 underwent immediate radical nephrectomy based on the frozen section and 7 were followed expectantly. CONCLUSIONS: Early experience with laparoscopic partial nephrectomy in this multicenter study demonstrates oncological efficacy comparable to that of open partial nephrectomy with respect to the incidence of positive margins. The practice of intraoperative frozen sections varied among centers and is not definitive in guiding the optimal surgical treatment.