Papillary thyroid microcarcinoma: optimal management versus overtreatment Purpose of review The treatment of small, low-risk papillary thyroid carcinoma has undergone a paradigm shift, with many tumors now initially treated with active surveillance rather than upfront surgery. Further studies on patients enrolled in active surveillance have refined our knowledge of the clinical behavior of papillary thyroid microcarcinomas. Recent findings This article summarizes the major conclusions of landmark trials that launched active surveillance as a viable treatment option for selected patients. We discuss patient factors such as age and tumor size, the assessment of candidates for active surveillance, barriers to acceptance of active surveillance, quality of life issues, and economic considerations. Summary Active Surveillance is a viable first-line treatment option for select papillary microcarcinomas.

Circulating biomarkers for the detection of tumor recurrence in the postsurgical follow-up of differentiated thyroid carcinoma Purpose of review To discuss advances and challenges in thyroglobulin and Tg-antibody (TgAb) measurement and their impact on clinical management of differentiated thyroid carcinoma (DTC). Recent findings Basal high-sensitive Tg (hsTg) measurement avoids the need for stimulation and greatly simplifies DTC patients’ management. In addition, patients with undetectable hsTg after thyroid ablation are at a very low risk of recurrence and can be safely managed by periodic hsTg measurement alone. When TgAb is present, its trend over time serves as primary (surrogate) tumor marker. However, an undetectable hsTg measurement appears to indicate a complete remission of DTC even in the presence of TgAb. Finally, reliable reference values are not yet available for low-risk DTC who are treated with less than total thyroid ablation, and caution is needed before well-designed studies addressing these issues have been published. Summary The use of hsTg assays has changed paradigms for DTC monitoring even in the presence of TgAb, and greatly reduced patients’ discomfort and overall case-management costs. Reliable Tg interpretation criteria are urgently needed for patients treated with less than total thyroid ablation.

Novel therapeutic options for radioiodine-refractory thyroid cancer: redifferentiation and beyond Purpose of review Radioiodine-refractory thyroid cancers represent the main cause of thyroid cancer-related death. At present, targeted therapies with multikinase inhibitors represent a unique therapeutic tool, though they have limited benefit on patient survival and severe drug-associated adverse events. This review summarizes current treatment strategies for radioiodine-refractory thyroid cancer and focuses on novel approaches to redifferentiate thyroid cancer cells to restore responsiveness to radioiodine administration. Recent findings We summarize and discuss recent clinical trial findings and early data from real-life experiences with multikinase-inhibiting drugs. Possible alternative strategies to traditional redifferentiation are also discussed. Summary The current review focuses primarily on the major advancements in the knowledge of the pathophysiology of iodine transport and metabolism and the genetic and epigenetic alterations occurring in thyroid neoplasia as described using preclinical models. Results of clinical studies employing new compounds to induce thyroid cancer cell redifferentiation by acting against specific molecular targets are also discussed. Finally, we describe the current scenario emerging from such findings as well as future perspectives.

Malignant pheochromocytoma and paraganglioma: management options Purpose of review Although the majority of pheochromocytoma and paraganglioma are benign, 15–17% develop metastatic disease, being present at the initial diagnosis in about 11–31% of cases. The natural course of metastasized disease is highly heterogeneous, with an overall 5-year survival rate varying between 40% and 85%. For individual patients, overall survival, progression-free survival, and clinical outcome are difficult to predict. Management of metastasized pheochromocytoma and paraganglioma is challenging. Currently available therapeutic options are surgical debulking, treatment with radiopharmaceuticals (131I-MIBG, 90Y and 177Lu-DOTATATE), chemotherapy and targeted therapy. Recent findings The pathogenesis of pheochromocytoma and paraganglioma (PPGL) is largely driven by genomic alterations in PPGL susceptibility genes related to three different clusters: altered pseudo-hypoxic signaling (cluster-1), altered MAP-kinase signaling (cluster-2) and altered Wnt signaling (cluster-3). Novel targeted therapies (tyrosine kinase inhibitors) and potential future therapeutic options, guided by improved knowledge about the oncogenic cluster 1–3 signaling pathways, will be discussed. Summary Treatment of metastasized pheochromocytoma and paraganglioma remains challenging. Profiling of gene expression and methylation can serve as a powerful tool for characterizing disease clusters and for guiding targeted therapy to improve selectivity and efficacy. Current knowledge of signatures involved in molecular signaling, metabolism, and resistance mechanisms of PPGLs suggests that therapeutic regimens can be optimized to each molecular subtype.

Adrenal tumours: open surgery versus minimally invasive surgery Purpose of review The aim of this article is to focus on state-of-the-art minimally invasive adrenalectomy (MIA) and the most recent role of open adrenalectomy for adrenal tumours, respect to MIA and open adrenalectomy for adrenocortical cancer (ACC). Recent findings The laparoscopic (both transperitoneal and retroperitoneal) approach is the first-choice treatment in cases of small-to-medium benign adrenal tumours. This approach is feasible and well tolerated even for larger lesions without radiological signs of malignancy. Robotic adrenalectomy has recently increased in popularity, although the results appear to be fully comparable with those of laparoscopy. Open approach is the keystone of ACC surgery, especially when neighbour tissues, organs, or vessels are involved. Recent evidence suggests caution in treating localized ACC with laparoscopy, because of the higher rate of local or peritoneal recurrence, and shorter recurrence-free survival rates with respect to open adrenalectomy. Summary MIA has progressively replaced the traditional open approach and plays a complementary role in the treatment of adrenal tumour. It is the first option for benign lesions, whereas open adrenalectomy is a cornerstone treatment for ACC. The overlap of indications for laparoscopic adrenalectomy and open adrenalectomy is today confined to the treatment of organ-confined adrenal cancer, in which the role of laparoscopic surgery is far from being clearly defined.

Editorial: Individualizing treatment of nonsmall cell lung cancer No abstract available

Novel molecular targets for the treatment of lung cancer Purpose of review The mutational landscape in lung adenocarcinoma (LADC) is broadly recognized, particularly regarding the presence of the epidermal growth factor receptor (EGFR) mutation in non-smokers. However, even in the EGFR canonical-mutant LADC, other accompanying alterations surface which may have a major impact in prognosis and open possibilities to explore new therapeutic approaches. Recent findings Complex genomic rearrangements, including chromothripsis and chromoplexy, are the origin of most-known fusion oncogenes, including echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase, Cluster of Differentiation 74-c-ros oncogene 1, and kinesin-1 heavy chain- rearranged during transfection. Quite often LADCs driven by fusion oncogenes are accompanied by SET domain containing 2 (SETD2) mutations. SETD2 mutations have been described in renal cancer and have been related to cisplatin resistance in LADCs. Suppression of the SETD2 function inhibits the signal transducer and transcription activator function and the interferon-signaling pathway, which could partially explain the lack of effectiveness of immunotherapy in LADCs driven by fusion oncogenes. Summary Targeted next-generation sequencing of DNA in the tumor tissue or in the circulating plasma of LADC is becoming indispensable for the accurate classification of LADCs that can receive appropriate targeted therapy. It is unquestionable that additional techniques, like RNA sequencing or the nCounter technology, can accomplish accurate assessment of an ample array of fusion oncogenes involved in LADCs.

Angiogenesis inhibition in non-small cell lung cancer: a critical appraisal, basic concepts and updates from American Society for Clinical Oncology 2019 Purpose of review Recently, the combination of antiangiogenic agents, chemotherapy and immunotherapy has shown synergistic anticancer effects in non-small cell lung cancer (NSCLC). The future for this approach appears bright in lung cancer treatment; however, many challenges remain to be overcome regarding its true potential, optimal sequence and timing of therapy, and safety profile. In this review, we will discuss the current status and future direction of antiangiogenic therapy for the treatment of NSCLC, and highlight emerging strategies, such as tumor vessel normalization (TVN). Recent findings Bevacizumab was the first antiangiogenic agent approved for the treatment of advanced NSCLC. Recently, the combination of chemotherapy/antiangiogenic therapy with immunotherapy showed high efficacy in first-line settings. A subgroup of patients with liver metastasis and driver mutation-addicted tumors benefited most, suggesting that the metastatic location, as well as the genetic background of the tumor, are key determinants for therapy responses. Summary The efficacy of antiangiogenic therapies in unselected patients is rather limited. The tumor microenvironment has appeared to be more complex and heterogeneous than previously assumed. Only a contextual rather than a cell-specific approach might provide valuable insights towards the clinical validation of combinational therapies.

Local treatment of stage IIIA-N2 nonsmall cell lung cancer: surgery and/or radiotherapy Purpose of review Controversy exists regarding the optimal treatment of patients with stage IIIA-N2 nonsmall cell lung cancer because of its heterogeneity. Patients are at risk for both local and distant disease relapse after primary local treatment. However, there may be a window of opportunity for surgery, if mediastinal downstaging has been obtained after induction therapy. This manuscript reviews the outcome of patients treated by neo-adjuvant chemotherapy (NA-C) followed by surgery, compared with patients treated with either definitive sequential or concurrent chemoradiotherapy (cCRT), illustrated by a single-centre retrospective case series. Recent findings Of 53 eligible patients, 19 received NA-C and underwent surgical resection, whilst 20 and 14 received concurrent or sequential definitive CRT, respectively. A significant difference in progression-free survival favouring NA-C followed by surgery over both CRT modalities was found. However, this translated only in an overall survival benefit in comparison with sequential definitive CRT. A trend for better outcome was observed in selected surgical patients with single-level mediastinal involvement and complete resection. Summary Our case series results are consistent with the present standard of care of CRT, which restricts surgical resection to carefully selected patients. Immunotherapy will likely change the treatment paradigm.