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Studies testing the addition of lapatinib to neoadjuvant trastuzumab + chemotherapy reported an increase in pathologic complete response (pCR), with, nevertheless, discordant results in terms of survival, mainly due to suboptimal power. We here leverage the meta-analytic approach to resolve these inconsistencies.We conducted a meta-analysis of randomized phase II/III studies testing lapatinib + trastuzumab in combination with neoadjuvant chemotherapy for human epidermal growth factor receptor (HER2)-positive early breast cancer (BC). Recurrence-free survival (RFS) and overall survival (OS) were adopted as survival endpoints. Pooled hazard ratios (HR) were obtained for the effect of lapatinib + trastuzumab versus trastuzumab, pCR versus no-pCR in the whole study populations and pCR versus no-pCR according to hormone receptor status.Four phase II/III randomized trials were included in the meta-analysis (CALGB 40601, Cher-LOB, NSABP-B41, NeoALTTO) for an overall population of 1410 patients receiving neoadjuvant chemotherapy in association with either trastuzumab, lapatinib or their combination. RFS was significantly improved with dual HER2 blockade as compared to trastuzumab [HR 0.62, 95% confidence interval (CI) 0.46-0.85]. Dual blockade also led to significantly improved OS (HR 0.65, 95% CI 0.43-0.98). For all treatments combined, patients achieving pCR had better RFS and OS than those with residual disease (HR 0.45, 95% CI 0.34-0.60, and HR 0.32, 95% CI 0.22-0.48, for RFS and OS, respectively). In patients with hormone receptor-negative tumors, pCR was associated with 65% and 73% relative reduction of risk of relapse and death, respectively. Patients with hormone receptor-positive tumors also experienced improved RFS if they achieved pCR; however, the benefit was smaller than that in hormone receptor-negative disease.Findings from this meta-analysis further validate the role of pCR as a strong predictor of outcome in patients with HER2-positive BC, especially in hormone receptor-negative disease. Moreover, we provide robust evidence that dual blockade with lapatinib + trastuzumab in combination with neoadjuvant chemotherapy prolongs OS, suggesting that the role of lapatinib could be reconsidered in the early setting.

This thesis provides a comprehensive examination of world-wide variation in population-based survival from brain tumours in children and adults, by histology. It comprises five chapters in the form of research papers. Population-based cancer survival estimates are key to assessing the overall effectiveness of a health care system in managing cancer. The third cycle of the CONCORD programme for the global surveillance of cancer survival (CONCORD-3), which included data for more than 37.5 million cancer patients diagnosed during 2000-2014, highlighted substantial world-wide disparities in survival for all brain tumours combined, in both children and adults. Survival comparisons for all brain tumours combined, however, are potentially confounded by international variation in histology distribution and the clinical heterogeneity of the various tumour subtypes. Robust comparisons of brain tumour survival require clinically relevant data by histology because histology is the main outcome predictor. Granular survival estimates by histology are therefore warranted. The first and second chapters, two systematic reviews, appraise the geographical coverage and methodology of studies of brain tumour survival by histology. The first chapter focusses on children, while the second centres on adolescents and young adults. Adolescents and young adults are a transitional age group for which the strategy for presenting epidemiological data by histology is still debated. These reviews show that very little is known about brain tumour survival by histology beyond Europe and North America, and that differences in study design may indeed hamper robust comparisons. The two systematic reviews inform the scope of the third chapter, in which distinct histology groupings for children and adults are defined. The groupings for children represent an enhanced version of the International Classification of Childhood Cancer (third edition), while those for adults are designed to produce clinically meaningful categories. These groupings schemes form the basis for an examination of the global variation in the histology distribution of brain tumours and for an account of some of the key quality indicators for cancer registration. 7 The histology distribution of brain tumours varied widely world-wide (2000- 2014). In children, the proportion of low-grade astrocytic tumours ranged from less than 10% to more than 30%. In adults, the proportion of glioblastoma varied between 9% and 69%. International comparisons were made difficult by wide differences in the proportion of tumours of unspecified histology, which accounted for up to 52% of diagnoses in children and up to 65% in adults. These histology groupings are then used to produce up-to-date analyses of global trends in brain tumour survival by histology, for children (chapter 4) and adults (chapter 5), using individual records from CONCORD-3 for 610,710 patients diagnosed with a brain tumour during 2000-2014 in 60 countries. Many of these countries have never previously been included in studies of brain tumour survival by histology. The studies deploy the same protocol for data collection, quality control and statistical methods for all the data sets. Brain tumour survival in children and adults were examined in two separate analyses. Five-year net survival for low-grade astrocytoma in children was in the range 84-100%, while it varied between 47% and 86% for medulloblastoma. In adults, survival from glioblastoma improved substantially after 2005 in most countries, mainly in the short term (up to two years from diagnosis). The increase in two-year survival between 2000-2004 and 2010-2014 was more remarkable for adults aged 40-70 years than for younger patients (15-39 years). Trends for 2000-2014 were upward for the 40-70 age group, while they were somewhat flat for the 15-39 age group. To our knowledge, this is the largest study of population-based survival from brain tumours by histology. The geographical breadth, the methodology for data collection and analysis, and the proposed histology groupings are expected to set a benchmark for future global comparisons.

Objectives: The aim of this study was to compare the durabilities of efavirenz (EFV) and rilpivirine (RPV) in combination with tenofovir/emtricitabine (TDF/FTC) in first-line regimens. Methods: A multicentre prospective and observational study was carried out. We included all patients participating in the Italian Cohort Naive Antiretrovirals (ICONA) Foundation Study who started first-line combination antiretroviral therapy (cART) with TDF/FTC in combination with RPV or EFV, with a baseline viral load < 100 000 HIV-1 RNA copies/mL. Survival analyses using Kaplan–Meier (KM) curves and Cox regression with time-fixed covariates at baseline were employed. Results: Overall, 1490 ART-naïve patients were included in the study, of whom 704 were initiating their first cART with EFV and 786 with RPV. Patients treated with EFV, compared with those on RPV, were older [median 36 (interquartile range (IQR) 30–43) years vs. 33 (IQR 27–39) years, respectively; P < 0.001], were more frequently at Centers for Disease Control and Prevention (CDC) stage C (3.1% vs. 1.4%, respectively; P = 0.024), and had a lower median baseline CD4 count [340 (IQR 257–421) cells/μL vs. 447 (IQR 347–580) cells/μL, respectively; P < 0.001] and a higher median viral load [4.38 (IQR 3.92–4.74) log10 copies/mL vs. 4.23 (IQR 3.81–4.59) log10 copies/mL, respectively], (P = 0.004). A total of 343 patients discontinued at least one drug of those included in the first cART regimen, more often EFV (26%) than RPV (13%), by 2 years (P < 0.0001). After adjustment, patients treated with EFV were more likely to discontinue at least one drug for any cause [relative hazard (RH) 4.09; 95% confidence interval (CI) 2.89–5.80], for toxicity (RH 2.23; 95% CI 1.05–4.73) for intolerance (RH 5.17; 95% CI 2.66–10.07) and for proactive switch (RH 10.96; 95% CI 3.17–37.87) than those starting RPV. Conclusions: In our nonrandomized comparison, RPV was better tolerated, less toxic and showed longer durability than EFV, without a significant difference in rates of discontinuation because of failures.