Prevalence and indicators of cure of Italian women with vulvar squamous cell carcinoma: A population-based study.

OBJECTIVE: Five-year net survival and conditional survival from vulvar squamous cell carcinoma (VSCC) patients in Italy have shown no progress during the past three decades. This study aims to estimate the complete prevalence and multiple indicators of cure. METHODS: Observed prevalence was estimated using 31 Italian cancer registries covering 47 % of Italian women. A subset of 22 cancer registries was used to estimate model-based long-term survival and indicators of cure, i.e., complete prevalence, cure fraction (CF), time to cure (TTC), proportion of 'already cured' patients, and cure prevalence. RESULTS: In 2018, VSCC patients alive in Italy (complete prevalence) were 6620 or 22 per 100,000 women. The cure fraction (the proportion of newly diagnosed patients who will not die of VSCC) did not change between 2000 and 2010 both for all patients (32 %) and in each age group. The time to cure (5-year conditional net survival >95 %) was 11 years for patients aged ≥44 years, but excess mortality remained for >15 years in the other age groups. This led to a negligible (5 %) proportion of 'already cured' patients (living longer than time to cure). The proportion of patients alive <2 years (21 %) was the same as that of patients surviving ≥15 years. The cure prevalence (patients who will not die of VSCC) was 64 %. A considerable proportion of patients will not be cured even among those who survived ≥5 years. CONCLUSION: There is an urgent need to reshape the current vulvar care model in Italy.

Indicators of cure for women living after uterine and ovarian cancers: a population-based study.

This study aims to estimate long-term survival, cancer prevalence, and several cure indicators for Italian women with gynecological cancers. Thirty-one cancer registries, representing 47% of the Italian female population, were included. Mixture cure models were used to estimate net survival, cure fraction, time to cure (when 5-year conditional net survival becomes > 95%), cure prevalence (women who will not die of cancer), and already cured (living longer than time to cure). In 2018, 0.4% (121 704) of Italian women were alive after diagnosis of corpus uteri cancer, 0.2% (52 551) after cervical cancer, and 0.2% (52 153) after ovarian cancer. More than 90% of patients with uterine cancers and 83% with ovarian cancer will not die from their neoplasm (cure prevalence). Women with gynecological cancers have a residual excess risk of death <5% at 5 years after diagnosis. The cure fraction was 69% for corpus uteri, 32% for ovarian, and 58% for cervical cancer patients. Time to cure was ≤10 years for women with gynecological cancers aged <55 years; 74% of patients with cervical cancer, 63% with corpus uteri cancer, and 55% with ovarian cancer were already cured. These results can contribute to improving follow-up programs for women with gynecological cancers and supporting efforts against discrimination of already cured ones. This article is part of a Special Collection on Gynecological Cancers.

Cure indicators and prevalence by stage at diagnosis for breast and colorectal cancer patients: A population-based study in Italy.

People alive many years after breast (BC) or colorectal cancer (CRC) diagnoses are increasing. This paper aimed to estimate the indicators of cancer cure and complete prevalence for Italian patients with BC and CRC by stage and age. A total of 31 Italian Cancer Registries (47% of the population) data until 2017 were included. Mixture cure models allowed estimation of net survival (NS); cure fraction (CF); time to cure (TTC, 5-year conditional NS >95%); cure prevalence (who will not die of cancer); and already cured (prevalent patients living longer than TTC). 2.6% of all Italian women (806,410) were alive in 2018 after BC and 88% will not die of BC. For those diagnosed in 2010, CF was 73%, 99% when diagnosed at stage I, 81% at stage II, and 36% at stages III-IV. For all stages combined, TTC was >10 years under 45 and over 65 years and for women with advanced stages, but ≤1 year for all BC patients at stage I. The proportion of already cured prevalent BC women was 75% (94% at stage I). Prevalent CRC cases were 422,407 (0.7% of the Italian population), 90% will not die of CRC. For CRC patients, CF was 56%, 92% at stage I, 71% at stage II, and 35% at stages III-IV. TTC was ≤10 years for all age groups and stages. Already cured were 59% of all prevalent CRC patients (93% at stage I). Cancer cure indicators by stage may contribute to appropriate follow-up in the years after diagnosis, thus avoiding patients' discrimination.

The incidence and risk factors of selected drug prescriptions and outpatient care after SARS-CoV-2 infection in low-risk subjects: a multicenter population-based cohort study.

Background: Knowledge about the dynamics of transmission of SARS-CoV-2 and the clinical aspects of COVID-19 has steadily increased over time, although evidence of the determinants of disease severity and duration is still limited and mainly focused on older adult and fragile populations. Methods: The present study was conceived and carried out in the Emilia-Romagna (E-R) and Veneto Regions, Italy, within the context of the EU's Horizon 2020 research project called ORCHESTRA (Connecting European Cohorts to increase common and effective response to SARS-CoV-2 pandemic) (www.orchestra-cohort.eu). The study has a multicenter retrospective population-based cohort design and aimed to investigate the incidence and risk factors of access to specific healthcare services (outpatient visits and diagnostics, drug prescriptions) during the post-acute phase from day-31 to day-365 after SARS-CoV-2 infection, in a healthy population at low risk of severe acute COVID-19. The study made use of previously recorded large-scale healthcare data available in the administrative databases of the two Italian Regions. The statistical analysis made use of methods for competing risks. Risk factors were assessed separately in the two Regions and results were pooled using random effects meta-analysis. Results: There were 35,128 subjects in E-R and 88,881 in Veneto who were included in the data analysis. The outcome (access to selected health services) occurred in a high percentage of subjects in the post-acute phase (25% in E-R and 21% in Veneto). Outpatient care was observed more frequently than drug prescriptions (18% vs. 12% in E-R and 15% vs. 10% in Veneto). Risk factors associated with the outcome were female sex, age greater than 40 years, baseline risk of hospitalization and death, moderate to severe acute COVID-19, and acute extrapulmonary complications. Conclusion: The outcome of interest may be considered as a proxy for long-term effects of COVID-19 needing clinical attention. Our data suggest that this outcome occurs in a substantial percentage of cases, even among a previously healthy population with low or mild severity of acute COVID-19. The study results provide useful insights into planning COVID-19-related services.

Complete prevalence and indicators of cancer cure: enhanced methods and validation in Italian population-based cancer registries.

Objectives: To describe the procedures to derive complete prevalence and several indicators of cancer cure from population-based cancer registries. Materials and methods: Cancer registry data (47% of the Italian population) were used to calculate limited duration prevalence for 62 cancer types by sex and registry. The incidence and survival models, needed to calculate the completeness index (R) and complete prevalence, were evaluated by likelihood ratio tests and by visual comparison. A sensitivity analysis was conducted to explore the effect on the complete prevalence of using different R indexes. Mixture cure models were used to estimate net survival (NS); life expectancy of fatal (LEF) cases; cure fraction (CF); time to cure (TTC); cure prevalence, prevalent patients who were not at risk of dying as a result of cancer; and already cured patients, those living longer than TTC at a specific point in time. CF was also compared with long-term NS since, for patients diagnosed after a certain age, CF (representing asymptotical values of NS) is reached far beyond the patient's life expectancy. Results: For the most frequent cancer types, the Weibull survival model stratified by sex and age showed a very good fit with observed survival. For men diagnosed with any cancer type at age 65-74 years, CF was 41%, while the NS was 49% until age 100 and 50% until age 90. In women, similar differences emerged for patients with any cancer type or with breast cancer. Among patients alive in 2018 with colorectal cancer at age 55-64 years, 48% were already cured (had reached their specific TTC), while the cure prevalence (lifelong probability to be cured from cancer) was 89%. Cure prevalence became 97.5% (2.5% will die because of their neoplasm) for patients alive >5 years after diagnosis. Conclusions: This study represents an addition to the current knowledge on the topic providing a detailed description of available indicators of prevalence and cancer cure, highlighting the links among them, and illustrating their interpretation. Indicators may be relevant for patients and clinical practice; they are unambiguously defined, measurable, and reproducible in different countries where population-based cancer registries are active.

Trends in radioactive iodine treatment after total thyroidectomy in Italy, 2001-2018.

Objective: A decrease in the use of radioactive iodine (RAI) treatment for thyroid cancer has been described in the last decade in the US following subsequent updates of the American Thyroid Association guidelines. By contrast, population-based data from European countries are lacking. The study aims to assess the frequency and long-term trends in the use of RAI in Italy. Methods: From the Italian national hospital discharge database, the proportion of RAI treatment after total thyroidectomy with thyroid cancer diagnosis has been assessed by sex and age class during 2001-2018. Results: Throughout the whole study period, RAI was performed after 58% of 149,419 total thyroidectomies. The use of RAI was higher for men and younger patients; it peaked in 2007 (64% in women and 68% in men) and declined thereafter (2018: 46% in women and 53% in men), with a similar pattern observed across all ages and areas. Conclusion: National data show that in Italy trends in RAI treatment paraleled those observed in the US. Further monitoring of the use of RAI is warranted in Italy, as elsewhere, to assess the impact of international guidelines on real-life clinical management of thyroid cancer.

Perioperative Mortality and Long-Term Survival after Radical Cystectomy: A Population-Based Study in a Southern European Country on 4,389 Patients.

PURPOSE: Population-based data on survival after radical cystectomy (RC) are lacking from Southern Europe. The aim of this study was to assess trends and determinants of perioperative mortality and long-term survival in the Veneto region (Northeastern Italy). METHODS: All patients submitted to RC for bladder cancer from January 2004 to December 2016 were identified from the regional archive of hospital discharge records. Age at surgery, gender, comorbidities, hospital volume, calendar period of surgery, and type of urinary diversion were retrieved; vital status and cause of death were obtained by linkage with mortality records. Determinants of 90-day mortality were assessed by multilevel logistic regression; long-term survival was investigated by the Kaplan-Meier method and Cox regression. RESULTS: Among 4,389 included patients, an increase in the share of patients aged ≥80 years (from 13% in 2004-2008 to 24% in 2013-2016, p < 0.001) and a decline in performing continent diversion (from 34.9 to 23.4%, p < 0.001) were observed across the study period. Ninety-day mortality did not change over time and was 4% for patients aged <70 years and 13.7% for those aged ≥80 years. Age- and comorbidities-adjusted mortality was significantly lower in hospitals performing >30 RCs/year (odds ratio 0.67, 95% confidence interval 0.48-0.93). At a median follow-up of 67 months, overall survival at 1 year and 5 years was 72 and 40%, respectively, with a higher rate among younger patients treated in high-volume hospitals. CONCLUSION: The population of patients treated with RC is rapidly ageing, with a high risk of perioperative and long-term mortality; this changing epidemiological scenario and better outcomes observed in high-volume hospitals support regionalization of the procedure.

Prevalence of chronic liver disease among young/middle-aged adults in Northern Italy: role of hepatitis B and hepatitis C virus infection by age, sex, ethnicity.

BACKGROUND: Sparse population-based data are available on the prevalence and etiology of chronic liver disease (CLD) in Italy. The study aims to assess the role of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection in CLD according to age, gender and ethnicity. METHODS: Clinically diagnosed CLD in the general population aged 20-59 years in the Veneto Region (North-Eastern Italy) were identified through the Adjusted Clinical Groups System, by record linkage of the archive of subjects enrolled in the Regional Health System with Hospital Discharge Records, Emergency Room visits, Chronic disease registry for copayment exemptions, and the Home care database. Age-standardized prevalence rates (PR) were computed in Italians and immigrants, based on country of citizenship. RESULTS: Overall 22,934 subjects affected by CLD in 2016 were retrieved, 21% related to HBV and 43% to HCV infection. The prevalence of HCV-related CLD was higher in males, peaking at 50-54 years (males = 11/1000; females = 4/1000). The PR of HBV-related CLD was almost negligible in the Italian population (1/1000), and higher among immigrants, especially from East Asia (males = 17/1000; females = 11/1000) and Sub-Saharan Africa (males = 13/1000; females = 10/1000). CONCLUSION: Specific population sub-groups identified by age, gender, and ethnicity, were demonstrated to be at increased risk, and these trends are in line with global epidemiological patterns of viral hepatitis.

Addition of dose-intensified doxorubicin to standard chemotherapy for rhabdomyosarcoma (EpSSG RMS 2005): a multicentre, open-label, randomised controlled, phase 3 trial.

BACKGROUND: Rhabdomyosarcoma is an aggressive tumour that can develop in almost any part of the body. Doxorubicin is an effective drug against rhabdomyosarcoma, but its role in combination with an established multidrug regimen remains controversial. Therefore, we aimed to evaluate the possible benefit of early dose intensification with doxorubicin in patients with non-metastatic rhabdomyosarcoma. METHODS: We did a multicentre, open-label, randomised controlled, phase 3 trial involving 108 hospitals from 14 countries. We included patients older than 6 months but younger than 21 years with a pathologically proven diagnosis of rhabdomyosarcoma. We assigned each patient to a specific subgroup according to the EpSSG stratification system. Those with embryonal rhabdomyosarcoma incompletely resected and localised at unfavourable sites with or without nodal involvement, or those with alveolar rhabdomyosarcoma without nodal involvement were considered at high risk of relapse. These high-risk patients were randomly assigned (1:1) to receive either nine cycles of IVA (ifosfamide 3 g/m2 given as a 3-h intravenous infusion on days 1 and 2, vincristine 1·5 mg/m2 weekly during the first 7 weeks then only on day 1 of each cycle [given as a single intravenous injection], and dactinomycin 1·5 mg/m2 on day 1 given as a single intravenous injection) or four cycles of IVA with doxorubicin 30 mg/m2 given as a 4-h intravenous infusion on days 1 and 2 followed by five cycles of IVA. The interval between cycles was 3 weeks. Randomisation was done using a web-based system and was stratified (block sizes of four) by enrolling country and risk subgroup. Neither investigators nor patients were masked to treatment allocation. The primary endpoint was 3-year event-free survival assessed by the investigator at each centre in the intention-to-treat population. Patients who received at least one dose of study treatment were considered in the safety analysis. In agreement with the independent data monitoring committee, the study was closed to patient entry on Dec 16, 2013, after futility analysis. This trial is registered with EudraCT, number 2005-000217-35, and is currently in follow-up. FINDINGS: Between Oct 1, 2005, and Dec 16, 2013, 484 patients were randomly assigned to receive each chemotherapy regimen (242 in the IVA group and 242 in the IVA plus doxorubicin group). Median follow-up was 63·9 months (IQR 44·6-78·9). The 3-year event-free survival was 67·5% (95% CI 61·2-73·1) in the IVA plus doxorubicin group and 63·3% (56·8-69·0) in the IVA group (hazard ratio 0·87, 95% CI 0·65-1·16; p=0·33). Grade 3-4 leucopenia (232 [93%] of 249 patients in the IVA plus doxorubicin group vs 194 [85%] of 227 in the IVA group; p=0·0061), anaemia (195 [78%] vs 111 [49%]; p<0·0001), thrombocytopenia (168 [67%] vs 59 [26%]; p<0.0001), and gastrointestinal adverse events (78 [31%] vs 19 [8%]; p<0·0001) were significantly more common in the IVA plus doxorubicin group than in the IVA group. Grade 3-5 infections (198 [79%] vs 128 [56%]; p<0·0001) were also significantly more common in the IVA plus doxorubicin group than in the IVA group, in which one patient had grade 5 infection. Two treatment-related deaths were reported (one patient developed septic shock and one affected by Goldenhar syndrome developed intractable seizures) in the IVA plus doxorubicin group, both occurring after the first cycle of treatment, and none were reported in the IVA group. INTERPRETATIONS: The addition of dose-intensified doxorubicin to standard IVA chemotherapy did not show a significant improvement in the outcome of patients with high-risk non-metastatic rhabdomyosarcoma. Therefore, the IVA chemotherapy regimen should remain the standard of care for patients with localised rhabdomyosarcoma in Europe. FUNDING: Fondazione Città della Speranza, Italy, and the Association Léon Berard Enfant Cancéreux, France.

Pediatric patients with cutaneous melanoma: A European study.

INTRODUCTION: Cutaneous melanoma is rare in childhood and published studies have mainly been retrospective single-institution series or small case series. Given the absence of clinical protocols dedicated to pediatric melanoma, the treatment approach is generally extrapolated from the ones applied to adults. METHODS: Coordinated by the European Cooperative Study Group for Pediatric Rare Tumors (EXPeRT), this study collected patients prospectively registered between 2002 and 2012 under national cooperative projects dedicated to rare pediatric tumors in Italy, Poland, Germany, and France. Additional cases were collected from dermatology registries in Germany and Israel. RESULTS: A total of 219 patients aged 0-18 years (median 14.4) were included in the analysis. Sentinel lymph node biopsy was performed in 112 patients (76% of those with Breslow thickness > 0.75 mm) and was positive in 37.5%. Systemic therapy was used in 33 cases. In stage III cases, survival rates were similar for patients who received (23 cases) or not (21 cases) adjuvant therapy. For the whole series, 3-year overall and disease-free survival rates were 91.4% and 84.0%, respectively (median follow-up 41.8 months). Tumor site, tumor stage, and ulceration influenced survival rates. Patients treated by pediatric oncologists (n = 140) were more likely to have advanced disease than those treated by dermatologists (n = 79). DISCUSSION: This study would suggest that the clinical history of melanoma in children and adolescents might resemble that of adult counterpart. Cooperative efforts are needed to make new drugs more readily available to pediatric patients to increase the outcome of patient with advanced disease.

A European randomised controlled trial of the addition of etoposide to standard vincristine and carboplatin induction as part of an 18-month treatment programme for childhood (≤16 years) low grade glioma - A final report.

BACKGROUND: The use of chemotherapy to manage newly diagnosed low grade glioma (LGG) was first introduced in the 1980s. One randomised trial has studied two- versus four-drug regimens with a duration of 12 months of treatment after resection. METHODS: Within the European comprehensive treatment strategy for childhood LGG, the International Society of Paediatric Oncology-Low Grade Glioma (SIOP LGG) Committee launched a randomised trial involving 118 institutions and 11 countries to investigate the addition of etoposide (100 mg/m2, days 1, 2 & 3) to a four-course induction of vincristine (1.5 mg/m2 × 10 wkly) and carboplatin (550 mg/m2 q 3 weekly) as part of 18-month continuing treatment programme. Patients were recruited after imaging diagnosis, resection or biopsy with progressive disease/symptoms. Some 497 newly diagnosed patients (M/F 231/266; median age 4.26 years (interquartile range (IQR) 2.02-7.06)) were randomised to receive vincristine carboplatin (VC) (n = 249) or VC plus etoposide (VCE) during induction (n = 248), stratified by age and tumour site. FINDINGS: No differences between the two arms were found in term of survival and radiological response. Response and non-progression rates at 24 weeks for VC and VCE, were 46% versus 41%, and 93% versus 91% respectively; 5-year Progression-Free Survival (PFS) and Overall Survival (OS) were 46% (StDev 3.5) versus 45% (StDev 3.5) and 89% (StDev 2.1) versus 89% (StDev 2.1) respectively. Age and diencephalic syndrome are adverse clinical risk factors for PFS and OS. 5-year OS for patients in early progression at week 24 were 46% (StDev 13.8) and 49% (StDev 16.5) in the two arms, respectively. INTERPRETATION: The addition of etoposide to VC did not improve PFS or OS. High non-progression rates at 24 weeks justify retaining VC as standard first-line therapy. Infants with diencephalic syndrome and early progression need new treatments to be tested. Future trials should use neurological/visual and toxicity outcomes and be designed to discriminate between the impact on disease outcomes of 'duration of therapy' and 'age at stopping therapy'.

LKB1 Expression Correlates with Increased Survival in Patients with Advanced Non-Small Cell Lung Cancer Treated with Chemotherapy and Bevacizumab.

Purpose: LKB1 is a key sensor of metabolic stress, including hypoxia and glucose deprivation, two features of the tumor microenvironment exacerbated by antiangiogenic therapy. We investigated the role of LKB1 as a potential predictive marker of sensitivity to bevacizumab in advanced non-small cell lung cancer (aNSCLC).Experimental design: We retrospectively analyzed LKB1 expression by IHC in 98 samples from 125 patients with aNSCLC, including 59 patients treated with chemotherapy and 39 treated with chemotherapy plus bevacizumab. IHC intensity was recoded in two classes (negative/weak vs. moderate/intense) and correlated with outcome according to treatment arm. Patient-derived tumor xenografts (PDXs) were used to investigate mechanisms involved in preclinical models.Results: In the whole study population (125), median OS and PFS were 11.7 [95% confidence interval (CI), 9.1-15.3] and 6.7 (95% CI, 5.7-7.2) months, respectively. Differential impact of the marker on outcome of the 98 patients was highlighted according to the treatment. Patients with negative/weak LKB1 status did not have a statistically significant benefit from bevacizumab added to chemotherapy (HR for patients treated with bevacizumab: 0.89; 95% CI, 0.51-1.56; P = 0.6803), whereas patients expressing moderate/intense LKB1 and receiving bevacizumab had significant lower risk of death compared with those not receiving bevacizumab (HR, 0.26; 95% CI, 0.10-0.64; P = 0.0035). Loss of LKB1 was associated with reduced AMPK activation in PDXs and increased tumor necrosis following bevacizumab administration, highlighting impaired control of the metabolic stress caused by this antiangiogenic drug.Conclusions: Our data hint at a possible predictive impact of LKB1 expression in patients with aNSCLC treated with chemotherapy plus bevacizumab. Clin Cancer Res; 23(13); 3316-24. ©2017 AACR.

Outcome and prognostic factors in high-risk childhood adrenocortical carcinomas: A report from the European Cooperative Study Group on Pediatric Rare Tumors (EXPeRT).

OBJECTIVES: The aim of this retrospective international analysis was to evaluate the role of risk factors in pediatric patients with adrenocortical carcinoma (ACC) observed in European countries (2000-2013) in an attempt to identify factors associated with poor prognosis. PROCEDURES: Data were retrieved from databases of Germany, France, Poland, and Italy, which form the European Cooperative Study Group on Pediatric Rare Tumors (EXPeRT). Patients were less than 18 years old, with at least one of the following tumor-related risk factors: metastases, volume more than 200 cm3 , Cushing syndrome, vascular or regional lymph node invasion, initial biopsy, or incomplete excision. Role of patients' age was also evaluated. RESULTS: Eighty-two patients were evaluated: 62 with localized disease and 20 with metastases. The 3-year progression-free survival (PFS) and overall survival (OS) were 39% and 55% for the whole population, respectively, and 51% and 73% for localized diseases, respectively. Concerning the whole population, PFS and OS were influenced by distant metastases, tumor volume, lymph node involvement, age, and presence of two or more risk factors. Factors significant only at OS were vascular involvement and incomplete surgery. At multivariable analysis, the main factors at PFS were volume more than 200 cm3 (hazard ratio [HR]: 2.6, 95% confidence interval [CI]: 1.18-5.70) and presence of distant metastases (HR: 8.26, 95% CI: 3.49-19.51). The OS was significantly influenced by the presence of metastases (P < 0.0001). Concerning patients with localized tumors, the only significant prognostic factor was volume more than 200 cm3 with a HR of 4.38 (95% CI: 1.60-12.00) for PFS and of 3.68 (95% CI: 1.02-13.30) for OS. CONCLUSIONS: Distant metastases and large tumor volume were the main unfavorable prognostic factors. Presence of two or more factors related to ACC was associated with an aggressive behavior of disease.

Access to clinical trials for adolescents with soft tissue sarcomas: Enrollment in European pediatric Soft tissue sarcoma Study Group (EpSSG) protocols.

BACKGROUND: Adolescents with cancer are enrolled in clinical trials at far lower rates than children. This report compares the number of adolescents (15-19-year-olds) and children (0-14-year-olds) enrolled in the protocols of the European pediatric Soft tissue sarcoma Study Group (EpSSG) with the number of cases expected to occur. METHODS: The observed-to-expected (O/E) ratio was detected in the EpSSG countries contributing most of the cases, that is, Italy, France, Spain, the Netherlands, United Kingdom, and Ireland. The observed cases included patients enrolled in any of the EpSSG protocols from October 2008 to October 2015, when all EpSSG protocols were open in these countries. The number of expected cases was calculated from the incidence rates estimated throughout the RARECAREnet database in the countries' population-based cancer registries. RESULTS: In the countries considered, 2,118 cases aged 0-19 years were enrolled in the EpSSG trials from 2008 to 2015: 82.8% were children and 17.2% were adolescents. The O/E ratio was 0.30 among patients 15-19 years old, as opposed to 0.64 for those 0-14 years old. The O/E ratio differed for the different subtypes: in adolescents, it was 0.64 and 0.18 for rhabdomyosarcoma (RMS) and non-rhabdomyosarcoma soft tissue sarcomas (NRSTS), respectively; in children, it was 0.77 and 0.50, respectively. The O/E ratios differed across the countries considered. CONCLUSIONS: Adolescents were less well represented than children on the EpSSG protocols, with better enrolment for RMS than for NRSTS for all age groups.

Resistance to glucose starvation as metabolic trait of platinum-resistant human epithelial ovarian cancer cells.

Deregulated glucose metabolism is observed in cancer but whether this metabolic trait influences response to or is modulated by cytotoxic drugs is unknown. We show here that tumor cells from epithelial ovarian cancer (EOC) patients can be categorized, according to their in vitro viability under glucose starvation, into glucose deprivation-sensitive (glucose-addicted, GA) and glucose deprivation-resistant (glucose non-addicted, GNA). When EOC cells were cultured in the absence of glucose, all samples from platinum (PLT)-sensitive patients felt into the GA group; they disclosed higher expression of glucose metabolism enzymes, higher proliferation rates and in vitro sensitivity to PLT. Moreover, GA patients showed reduced multi-drug resistance pump expression and autophagy, compared to GNA samples. The close association between PLT sensitivity and glucose metabolic profile was confirmed in a xenograft model, where a stringent parallelism between PLT sensitivity/resistance and glucose metabolism was identified. Finally, in a cohort of naïve EOC patients categorized as GA or GNA at diagnosis, Kaplan Meier curves showed that the GA phenotype was associated with significantly better progression-free survival, compared to GNA patients.

Outcome of extracranial malignant rhabdoid tumours in children registered in the European Paediatric Soft Tissue Sarcoma Study Group Non-Rhabdomyosarcoma Soft Tissue Sarcoma 2005 Study-EpSSG NRSTS 2005.

BACKGROUND: Extracranial malignant rhabdoid tumours (MRT) are rare lethal childhood cancers that often occur in infants and have a characteristic genetic mutation in the SMARCB1 gene. The European Paediatric Soft Tissue Sarcoma Study Group (EpSSG) conducted a multinational prospective study of registered cases of extracranial MRT to test an intensive multimodal approach of treatment for children with newly diagnosed extracranial MRT. METHODS: Between December 2005 and June 2014, we prospectively registered 100 patients from 12 countries with a diagnosis of MRT tumour at an extracranial site on the EpSSG Non-Rhabdomyosarcoma Soft Tissue Sarcoma 2005 Study (NRSTS 2005). They were all treated on a standard multimodal protocol of surgery, radiotherapy, and chemotherapy over 30 weeks as follows: vincristine, cyclophosphamide, and doxorubicin (VDCy) at weeks 1, 10, 13, 22, and 28; vincristine was also given alone on weeks 2, 3, 11, 12, 14, 15, 23, 24, 29, and 30. Cyclophosphamide, carboplatin, and etoposide (Cy*CE) was given at weeks 4, 7, 16, 19, and 25. Radiotherapy was recommended for all primary tumour sites and all sites of metastatic disease. RESULTS: Forty-three patients completed the protocol treatment. Median follow-up for alive patients of the complete cohort was 44.6 months (range 11.5-84.6). For the whole cohort, the 3-year event-free survival (EFS) was 32.3% (95% confidence interval [CI] 23.2-41.6%) with a 3-year overall survival (OS) of 38.4% (95% CI 28.8-47.9%). For localised disease, the 4-year EFS was 39.3% (95% CI 28.2-50.1%) with a 4-year OS of 40.1% (95% CI 28.4-51.5%). For metastatic disease, the 2-year EFS was 8.7% (95% CI 1.5-24.2%) with a 2-year OS of 13.0% (95% CI 3.3-29.7%). Multivariable analysis disclosed that all patients ≤1 year of age were associated with at higher risk of death (hazard ratio [HR]: 2.6; 95% CI 1.0-6.8; p-value = 0.0094). Risk of death was also related with gender in metastatic patients (HR for males: 2.9, 95% CI 1.0-8.0; p-value = 0.0077). CONCLUSIONS: The EpSSG NRSTS 2005 protocol of intensive therapy can be delivered to extracranial MRT patients, with a possible improvement in outcome. The outcome, however, remains poor for patients who progress or with metastatic disease.

Conservative strategy in infantile fibrosarcoma is possible: The European paediatric Soft tissue sarcoma Study Group experience.

BACKGROUND: Infantile fibrosarcoma (IFS) is a very rare disease occurring in young infants characterised by a high local aggressiveness but overall with a favourable survival. To try to reduce the total burden of therapy, the European pediatric Soft tissue sarcoma Study Group has developed conservative therapeutic recommendations according to initial resectability. MATERIAL AND METHODS: Between 2005 and 2012, children with localised IFS were prospectively registered. Initial surgery was suggested only if possible without mutilation. Patients with initial complete (IRS-group I/R0) or microscopic incomplete (group II/R1) resection had no further therapy. Patients with initial inoperable tumour (group III/R2) received first-line vincristine-actinomycin-D chemotherapy (VA). Delayed conservative surgery was planned after tumour reduction. Aggressive local therapy (mutilating surgery or external radiotherapy) was discouraged. RESULTS: A total of 50 infants (median age 1.4 months), were included in the study. ETV6-NTRK3 transcript was present in 87.2% of patients where investigation was performed. According to initial surgery, 11 patients were classified as group I, 8 as group II and 31 as group III. VA chemotherapy was first delivered to 25 children with IRS-III/R2 and one with IRS-II/R1 disease. Response rate to VA was 68.0%. Mutilating surgery was only performed in three cases. After a median follow-up of 4.7 years (range 1.9-9.0), 3-year event-free survival and overall survival were respectively 84.0% (95% confidence interval [CI] 70.5-91.7) and 94.0% (95% CI 82.5-98.0). CONCLUSIONS: Conservative therapy is possible in IFS as only three children required mutilating surgery, and alkylating or anthracycline based chemotherapy was avoided in 71.0% of patients needing chemotherapy. VA regimen should be first line therapy in order to reduce long term effects.

Adrenocortical tumors in Italian children: analysis of clinical characteristics and P53 status. Data from the national registries.

AIM: Adrenocortical tumors are very rare in children. The distinction between adenoma and carcinoma is complex because of their clinical/histological characteristics. The analysis of the cases registered in two consecutive Italian Studies is described, in order to provide additional insight into their nature and possibly identify benign and malignant lesions. MATERIALS AND METHODS: The analysis includes patients registered from?? 1.1982 to 6.2011 into two consecutive Italian protocols. RESULTS: Fifty-eight children (age 2-210months) were evaluated. Endocrine manifestations were the most frequent symptoms. Stage distribution at diagnosis was: ST I 35, ST II 17, ST III 1, ST IV 5. Treatment consisted in mitotane for ST II, mitotane+chemotherapy for ST III/IV. Forty-four patients are alive without evidence of disease, 1 is alive with disease, 12 died of disease and 1 because of cardiomyopathy. The Wienecke score system was applied in 24 patients with good significance. A p53 mutation was found in 7 cases, and it was diagnostic for Li-Fraumeni syndrome in 2 benign tumors. CONCLUSIONS: The results highlight the importance of a complete excision to obtain the cure of patients. The efficacy of chemotherapy is controversial, however it was able to control the disease in 4 patients in ST II. The value of the Wienecke score system in predicting patients' outcome was confirmed. p53 mutation was more frequent in malignant tumors and represented the sentinel of the Li-Fraumeni syndrome.

Synovial sarcoma in children and adolescents: a critical reappraisal of staging investigations in relation to the rate of metastatic involvement at diagnosis.

BACKGROUND: European protocols for paediatric synovial sarcoma (SS) require that all children routinely undergo chest computed tomography (CT) scanning and bone scanning as initial staging procedures. This study aims to determine the rate of initial metastases in paediatric SS based on specific clinical characteristics, thereby investigating whether these diagnostic procedures are really necessary in all patients. METHODS: Data on 258 previously-untreated SS patients <21 years old were pooled from the databases of different European paediatric groups (study period 1988-2005) for this analysis, and the associations between patients' characteristics and any presence of metastasis were estimated. RESULTS: Fifteen cases (5.8%) had distant metastases at diagnosis (86% pulmonary). The presence of metastases was unassociated with patients' gender or age, tumour grade or site, but it was influenced by T-status, and especially primary tumour size: the risk of metastases was 32 times higher in cases of tumour >5 cm than for tumours ≤ 5 cm. CONCLUSIONS: Our findings suggest that tumour diameter can be used as a variable for identifying patients at greater risk of metastases and warranting more accurate radiological investigations. Chest CT scanning may improve the accuracy of pulmonary staging over X-ray, but requires different ionising radiation exposures that might have carcinogenic potential: it can be omitted for patients with tumours ≤ 5 cm. Given the very low risk of bone metastases, bone scans may be recommended only in cases with evidence of lung metastases.