Anna Castiglione

Seizure control following radiotherapy in patients with diffuse gliomas: a retrospective study

BACKGROUND Little information is available regarding the effect of conventional radiotherapy on glioma-related seizures. METHODS In this retrospective study, we analyzed the seizure response and outcome following conventional radiotherapy in a cohort of 43 patients with glioma (33 grade II, 10 grade III) and medically intractable epilepsy. RESULTS At 3 months after radiotherapy, seizure reduction was significant (≥ 50% reduction of frequency compared with baseline) in 31/43 patients (72%) of the whole series and in 25/33 patients (76%) with grade II gliomas, whereas at 12 months seizure reduction was significant in 26/34 (76%) and in 19/25 (76%) patients, respectively. Seizure reduction was observed more often among patients displaying an objective tumor response on MRI, but patients with no change on MRI also had a significant seizure reduction. Seizure freedom (Engel class I) was achieved at 12 months in 32% of all patients and in 38% of patients with grade II tumors. Timing of radiotherapy and duration of seizures prior to radiotherapy were significantly associated with seizure reduction. CONCLUSIONS This study showed that a high proportion of patients with medically intractable epilepsy from diffuse gliomas derive a significant and durable benefit from radiotherapy in terms of epilepsy control and that this positive effect is not strictly associated with tumor shrinkage as shown on MRI. Radiotherapy at tumor progression seems as effective as early radiotherapy after surgery. Prospective studies must confirm and better characterize the response to radiotherapy.

C-peptide and the risk for incident complications and mortality in type 2 diabetic patients: a retrospective cohort study after a 14-year follow-up

OBJECTIVE C-peptide, a cleavage product of insulin, exerts biological effects in patients with type 1 diabetes mellitus, but its role in type 2 diabetes mellitus is controversial. Our aim was to examine the associations between fasting C-peptide levels and all-cause mortality, specific-cause mortality and the incidence of chronic complications in patients with type 2 diabetes. DESIGN Retrospective cohort study with a median follow-up of 14 years. METHODS A representative cohort of 2113 patients with type 2 diabetes mellitus and a subgroup of 931 individuals from this cohort without chronic complications at baseline from a diabetic clinic were studied. RESULTS Patients with higher C-peptide levels had higher baseline BMI and triglyceride and lower HDL-cholesterol values. During the follow-up, 46.1% of the patients died. In a Cox proportional hazard model, after multiple adjustments, no significant association was found between the C-peptide tertiles and all-cause mortality or mortality due to cancer, diabetes or cardiovascular diseases. In the subgroup of 931 patients without chronic complications at baseline, the incidence of microvascular complications decreased from the first to the third C-peptide level tertile, while the incidence of cardiovascular disease did not differ. The risks for incident retinopathy (hazard ratio (HR)=0.33; 95% confidence interval (CI) 0.23-0.47), nephropathy (HR=0.27; 95% CI 0.18-0.38) and neuropathy (HR=0.39; 95% CI 0.25-0.61) were negatively associated with the highest C-peptide tertile, after adjusting for multiple confounders. CONCLUSIONS Higher baseline C-peptide levels were associated with a reduced risk of incident microvascular complications but imparted no survival benefit to patients with type 2 diabetes mellitus.

Interim positron emission tomography and clinical outcome in patients with early stage Hodgkin lymphoma treated with combined modality therapy

Abstract The aim of the study was to investigate whether interim positron emission tomography (iPET) is prognostic in a cohort of patients with early stage Hodgkin lymphoma (HL) homogeneously treated with 3–4 cycles of ABVD (adriamycin, bleomycin, vinblastine and dacarbazine) followed by 30 Gy involved field radiotherapy. Eighty patients were selected (stage I–IIA HL, availability of iPET, minimum follow-up of 12 months), and after central review, 70 were judged negative (iPET−: 87.5%) and 10 positive (iPET+: 12.5%). The two groups were then analyzed for response, progression-free survival (PFS) and overall survival (OS). Only one out of 70 iPET− patients relapsed, with 69 in continuous complete remission (CCR). All 10 iPET + patients achieved a complete response and maintained persistent CCR at follow-up. The 3-year PFS and OS were, respectively, 97% and 98.4% for iPET− and 100% and 100% for iPET+ (p = 0.63). iPET positivity does not seem to be a significant prognostic factor, and change in therapeutic strategy on the basis of iPET does not appear currently advisable outside clinical trials.

Mortality outcomes of different sulphonylurea drugs: the results of a 14-year cohort study of type 2 diabetic patients.

OBJECTIVE Available data about mortality of type 2 diabetic patients treated with different sulphonylureas are scarce and contradictory. DESIGN We evaluated the associations between all-cause and cause-specific mortality and treatments with different sulphonylureas in a retrospective cohort of type 2 diabetic patients from a diabetes clinic. METHODS All 1277 patients treated with sulphonylureas during 19961997 were enrolled: 159 patients were treated with tolbutamide, 977 glibenclamide and 141 gliclazide. The baseline data (centralised laboratory parameters, anthropometric data and presence of chronic complications) were abstracted from the clinical records. Information on vital status was collected from demographic files after 14-year follow-up. Adjusted hazard ratios (HR) were estimated with Cox (all-cause mortality) or Fine and Gray models (cause-specific mortality), including several potential confounders. RESULTS Five hundred and fifty-six patients died during the follow-up: 262 from cardiovascular causes, 158 from cancer and 136 from other causes. When compared with the glibenclamide users, the gliclazide and tolbutamide users showed a significantly lower cancer mortality (HR=0.30; 95% CI 0.16-0.55, and HR=0.48; 95% CI 0.29-0.79 respectively). These results were strongly confirmed in the 555 patients on sulphonylurea monotherapy. None of the patients who were treated with gliclazide monotherapy died from cancer during the follow-up, and the patients on tolbutamide treatment exhibited a lower cancer mortality than the glibenclamide users (HR=0.40; 95% CI 0.22-0.71). Data did not change after stratification for the duration of sulphonylurea treatment from diabetes diagnosis to the study enrollment. CONCLUSIONS Cancer mortality was markedly reduced in the patients on gliclazide and tolbutamide treatment. These results suggest additional benefits for these drugs beyond their blood glucose-lowering effect and strongly advocate for further investigation.

Clinical epidemiology in Italian Registry of Infective Endocarditis (RIEI): Focus on age, intravascular devices and enterococci.

INTRODUCTION The epidemiology of infective endocarditis (IE) is changing due to a number of factors, including aging and health related comorbidities and medical procedures. The aim of this study is to describe the main clinical, epidemiologic and etiologic changes of IE from a large database in Italy. METHODS We prospectively collected episodes of IE in 17 Italian centers from July 2007 to December 2010. RESULTS We enrolled 677 patients with definite IE, of which 24% health-care associated. Patients were male (73%) with a median age of 62 years (IQR: 49-74) and 61% had several comorbidities. One hundred and twenty-eight (19%) patients had prosthetic left side IE, 391 (58%) native left side IE, 94 (14%) device-related IE and 54 (8%) right side IE. A predisposing cardiopathy was present in 50%, while odontoiatric and non odontoiatric procedures were reported in 5% and 21% of patients respectively. Symptoms were usually atypical and precocious. The prevalent etiology was represented by Staphylococcus aureus (27%) followed by coagulase-negative staphylococci (CNS, 21%), Streptococcus viridans (15%) and enterococci (14%). CNS and enterococci were relatively more frequent in patients with intravascular devices and prosthesis and S. viridans in left native valve. Diagnosis was made by transthoracic and transesophageal echocardiography in 62% and 94% of cases, respectively. The in-hospital mortality was 14% and 1-year mortality was 21%. CONCLUSION The epidemiology is changing in Italy, where IE more often affects older patients with comorbidities and intravascular devices, with an acute onset and including a high frequency of enterococci. There were few preceding odontoiatric procedures.

Radiofrequency ablation: technical and clinical long-term outcomes for single hepatocellular carcinoma up to 30 mm.

Background and aims Western guidelines consider radiofrequency ablation (RF) as the standard treatment for ‘very early’ and ‘early’ hepatocellular carcinoma (HCC) in nonsurgical cirrhotic patients. RF has also been proposed as the first-line therapy for ‘surgical’ candidates with a single nodule of 20 mm or less. The aim of this monocentric cohort study was to evaluate the technical and clinical outcomes of RF in the treatment of cirrhotic patients with a single HCC of 30 mm or less. Patients and methods We included all 209 consecutive patients treated between January 2001 and June 2011. The primary endpoints were the overall survival (OS) rate and safety; the secondary endpoints were primary technique effectiveness, local tumor progression, and the disease-free survival rate. Results The 5-year OS rate of the entire sample was 44.3% (95% confidence interval: 36.7–55.8); Child–Pugh class B was the worst negative prognostic factor (hazard ratio: 2.06; P=0.008). A subgroup of 70 Child–Pugh class A patients suitable for surgical resection according to current Western operability criteria showed a 5-year OS rate of 60.6%. Treatment-related mortality and morbidity rates were 0 and 3.4%, respectively. Primary technique effectiveness rate was 95.2% after one to three RF sessions. The 5-year cumulative incidence of local tumor progression was 21.5 and 32.5% for nodules ⩽20 and 21–30 mm, respectively. The 5-year disease-free survival rate (comprehensive of any kind of tumor progression or death) was 17.8% (95% confidence interval: 11.1–25.8). Conclusion RF is an effective and very safe therapy for HCC up to 30 mm; in ‘surgical’ cirrhotic patients, the OS rate was similar to those reported in surgical series, although the local recurrence rate was higher.

Ultrasound surveillance for radiation-induced thyroid carcinoma in adult survivors of childhood cancer

INTRODUCTION The optimal surveillance strategy to screen for thyroid carcinoma childhood cancer survivors (CCS) at increased risk is still debated. In our clinical practice, beside neck palpation we routinely perform thyroid ultrasound (US). Here we describe the results obtained using this approach. METHODS We considered all CCS referred to our long term clinic from November 2001 to September 2014. One hundred and ninety-seven patients who had received radiation therapy involving the thyroid gland underwent US surveillance. Thyroid US started 5 years after radiotherapy and repeated every 3 years, if negative. RESULTS Among 197 CCS previously irradiated to the thyroid gland, 74 patients (37.5%) developed thyroid nodules, and fine-needle aspiration was performed in 35. In 11 patients the cytological examination was suspicious or diagnostic for malignancy (TIR 4/5), whereas a follicular lesion was diagnosed in nine. Patients with TIR 4/5 cytology were operated and in all cases thyroid cancer diagnosis was confirmed. The nine patients with TIR 3 cytology also underwent surgery and a carcinoma was diagnosed in three of them. Prevalence of thyroid cancer was 7.1%. Tumour size ranged between 4 and 25 mm, but six (43%) were classified T3 because of extra-thyroidal extension. Six patients had nodal metastases; in eight patients the tumour was multifocal. At the time of the study all patients are disease free, without evidence of surgery complications. CONCLUSION Applying our US surveillance protocol, the prevalence of radiation-induced thyroid cancer is high. Histological features of the thyroid cancers diagnosed in our cohort suggest that most of them were clinically relevant tumours.

Protein disulfide isomerase A3-specific Th1 effector cells infiltrate colon cancer tissue of patients with circulating anti-protein disulfide isomerase A3 autoantibodies

To investigate novel colorectal cancer (CRC)-associated antigens that could be targets of humoral or cellular responses, we analyzed the reactivity of serum from a long-surviving CRC patient (for more than 100 months of follow-up) in clinical remission, by serologic proteome analysis. Two-dimensional Western blotting (2D-WB) and mass spectrometry analysis revealed a strong reactivity of this serum against protein disulfide isomerase A3 (PDIA3). Anti-PDIA3 antibodies are not a diagnostic marker of CRC, 2D-WB and Luminex analysis revealed that they were equally present in about 10% of sera from healthy subjects and CRC patients. Kaplan-Meier analysis of survival in CRC patient cohort, after 48 months of follow-up, showed a trend of higher survival in patients with increased levels of autoantibodies to PDIA3. Therefore, the interplay between the presence of these antibodies and T-cell response was investigated. Peripheral blood T cells from CRC patients with high immunoglobulin G (IgG) reactivity to PDIA3 also secreted interferon gamma (IFN-γ) when stimulated in vitro with recombinant PDIA3, whereas those from CRC with low IgG reactivity to PDIA3 did not. PDIA3-pulsed dendritic cells efficiently induced proliferation and IFN-γ production of autologous CD4(+) and CD8(+) T cells. Finally, ex vivo analysis of tumor-infiltrating T lymphocytes from CRC patients with autoantibodies to PDIA3 revealed that PDIA3-specific Th1 effector cells accumulated in tumor tissue. These data indicate that the presence of autoantibodies to PDIA3 favors the development of an efficient and specific T-cell response against PDIA3 in CRC patients. These results may be relevant for the design of novel immunotherapeutic strategies in CRC patients.

Mortality and timing of surgery in the left-sided infective endocarditis: an Italian multicentre study

OBJECTIVES Observational studies on early surgery in infective endocarditis have conflicting results. This study aims to compare the treatment strategies for early surgery (within 2 weeks of diagnosis) and late surgery/medical therapy in terms of survival among patients with the left-sided infective endocarditis. METHODS This study included patients with the left-sided infective endocarditis registered between 2006 and 2010 in the Italian Registry of Infective Endocarditis (RIEI). A Cox proportional hazards model was used to estimate the effect of these treatment strategies on overall survival and included sociodemographic and clinical characteristics associated with treatment, risk factors for mortality and early surgery as a time-dependent covariate to avoid indication and immortal time biases. RESULTS Among the 502 patients included, 184 (36.7%) underwent early surgery. Of the remaining 318 patients, 138 underwent late surgery. The early surgery group had fewer patients with comorbidities and with enterococcus as the causative microorganism, but this group had more complicated cardiac conditions. No difference in mortality risk was estimated between the treatment groups including early surgery as time-dependent variables (adjusted hazard ratio  = 0.95, 95% confidence interval 0.55-1.63), while a distorted and overestimated beneficial effect of surgery was estimated considering surgery as a non-time-dependent variable (adjusted hazard ratio 0.41, 95% confidence interval 0.25-0.70). CONCLUSIONS Our study did not confirm a better overall survival in patients undergoing early surgery. However, even with the use of statistical techniques to control biases, we could not draw definitive conclusions that early surgery is not beneficial. Our results need to be assessed by randomized trials before any changes in clinical practice can be recommended.

Erythroid response during iron chelation therapy in a cohort of patients affected by hematologic malignancies and aplastic anemia with transfusion requirement and iron overload: a FISM Italian multicenter retrospective study

Emanuela Messa, Lucia Biale, Anna Castiglione, Monia Lunghi, Margherita Bonferroni, Flavia Salvi, Bernardino Allione, Dario Ferrero, Chiara Calabrese, Marco De Gobbi, Paolo Nicoli, Daniela Gioia, Alessandro Levis, Giuseppe Saglio and Daniela Cilloni Department of Internal Medicine, ASL To5-Turin, Italy; AOU Citt a della Salute e della Scienza di Torino – Presidio Ospedaliero Molinette – SC Banca del Sangue e del plasma, Turin, Italy; Unit of Cancer Epidemiology and CPO Piedmont, S. Giovanni Battista Hospital, Torino, Italy; Division of Haematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Italy, Novara, Italy; Department of Hematology, Ospedale S. Croce e Carle, Cuneo, Italy; Department of Hematology, AO SS Antonio e Biagio e C. Arrigo, Alessandria, Italy; Division of Hematology, AOU Citt a della Salute e della Scienza di Torino, Torino, Italy; Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy; Department of Clinical and Biological Sciences, University of Turin, Orbassano, Italy; FISM Registry, SS Antonio e Biagio e C. Arrigo Hospital, Alessandria, Tuscany, Italy; Department of Clinical and Biological Sciences, Division of Hematology, University of Turin, Turin, Italy