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Therapeutic radiation plays an important role in the management of thymoma and thymic carcinoma. These two tumor types differ substantially in their aggressiveness and prognosis. The most pressing issue in radiotherapy is which thymoma and thymic carcinoma patients need radiation. Given that these are rare cancers, few randomized trials have been published. Controversy remains regarding which patients benefit from adjuvant radiation therapy. Existing literature spans patients treated over nearly 50 years, during which time radiation therapy has evolved from rudimentary 2-dimensional based planning to conformal 3-dimensional planning to yet more conformal dose painting techniques such as intensity-modulated radiation therapy and proton therapy. If the effect of radiation is small and the natural history of a disease long, as is the case for stage I favorable histology thymoma, then differences in techniques and toxicities may have as much of an impact as whether radiation was given or not. LESS      Full article

Pancreatic ductal adenocarcinoma is a highly aggressive malignancy with a poor prognosis. Effective treatment with acceptable outcomes is yet to be found, with chemo- and radioresistance comprising major impediments towards this goal. Although upfront surgery is the established therapeutic approach for resectable and borderline resectable disease, neoadjuvant treatment has recently monopolized the interest in clinical trials. This also applies to locally advanced pancreatic adenocarcinomas that could potentially be rendered operable. Chemotherapy and chemoradiotherapy are the most utilized therapeutic modalities in the neoadjuvant setting, while immunotherapy and targeting agents have been gaining significant attention. This critical review focuses on the clinical experience gained from retrospective and phase II/III randomized trials, reporting on the outcomes of neoadjuvant chemotherapy and chemoradiotherapy for pancreatic adenocarcinoma. Moreover, the ongoing trials, including those that involve immunotherapy and targeting agents, are summarized. LESS      Full article

Mesothelioma is a rare malignant tumor of the serosal membranes that can be challenging to diagnose, especially on small biopsy specimens. There are updated guidelines on the diagnosis and classification of mesothelioma, which incorporate advancements in understanding mesothelioma biology published in the literature over recent years. This review will discuss marked developments and/or improvements that have been made, including: (1) to the histologic classifications of mesothelioma; (2) the use of such classifications and nuclear grading in prognosis; (3) the indispensability of ancillary studies in the diagnosis of mesothelioma; (4) the application of these pleural based classifications and diagnostic schemes in peritoneal mesothelioma; and (5) the potential for diagnosis of mesothelioma in situ. LESS      Full article

Malignant mesothelioma (MM) is an aggressive cancer that affects the pleural and peritoneal mesothelial lining of the lungs and abdomen. Survival rates for patients with MM remain extremely low and effective treatments are limited. MM tumors harbor both genotypic and phenotypic features that indicate MM tumor cells are under increased oxidative stress, similar to other aggressive cancers. This increased oxidative stress in MM cells supports aggressive growth while providing a therapeutic vulnerability exploitable by redox-modulating compounds. MM tumor cells also exhibit altered mitochondrial structure and function that contribute to the disease through perturbations in metabolism and reactive oxygen species (ROS) production and metabolism. Targeting the altered redox status in cancer through increasing cellular ROS levels directly or inhibiting cellular antioxidant pathways and disrupting ROS scavenging mechanisms has become an exciting area for therapeutic intervention. This review discusses ROS sources and signaling, mitochondrial structure and function and targeting mitochondria ROS as a therapeutic approach for the treatment of MM. LESS      Full article

Cervical cancer is the fourth most common cancer in women worldwide, with a global incidence of 604,127 and an annual death rate of 341,831 in 2020. Patients with recurrent, persistent, or metastatic disease not amenable to curative therapy represent a patient population with a dismal prognosis. Until recently, the standard of care for these patients was based on platinum doublet chemotherapy with or without bevacizumab. However, significant advances in the treatment landscape of this disease have recently been achieved with the incorporation, among others, of immunotherapy in the therapeutic armamentarium. This review summarizes the main treatment approaches developed throughout the past decades, with particular emphasis on immunotherapy and novel targeted therapies. LESS      Full article

Aims: Palbociclib has been approved in combination with endocrine therapy (ET) for hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC), regardless of age. Even though ABC is one of the most prevalent cancers in older patients, very few patients ≥ 65 years old were included in pivotal trials. Therefore, the current study evaluated the safety and efficacy of palbociclib in “real-world” routine treatment of unselected older patients with HR+/HER2- ABC. Methods: Data were collected on patients > 70 years old who were treated with palbociclib plus ET for HR+/HER2- ABC in our institution. We analyzed safety data (CTCAE v4.0 criteria) and outcomes, such as progression-free survival (PFS) and overall survival (OS), as well as any associations between main geriatric characteristics and our results. Furthermore, we assessed safety at a national level by analyzing all palbociclib-related adverse events (AEs) reported in the French Pharmacovigilance Database (FPVD) during the same period. Results: From February 2016 to July 2019, 52 patients were identified with a median age of 80.9 years, of whom 88% presented an AE. The most common grade 3-4 AE was neutropenia (64%). Median PFS and OS were nine months and not reached, respectively. The FPVD reports 227 cases of palbociclib-related AEs, with older and younger patients sharing similar characteristics. Conclusion: Palbociclib is well tolerated in older patients with efficacy comparable to that in younger patients. However, the addition of palbociclib to ET should be evaluated individually in this older and frailer subgroup. LESS      Full article

Aberrant activation of signal transducer and activator of transcription (STAT) proteins is associated with the development and progression of solid tumors. However, as transcription factors, these proteins are difficult to target directly. In this review, we summarize the role of targeting Janus kinases (JAKs), upstream activators of STATs, as a strategy for decreasing STAT activation in solid tumors. Preclinical studies in solid tumor cell line models show that JAK inhibitors decrease STAT activation, cell proliferation, and cell survival; in in vivo models, they also inhibit tumor growth. JAK inhibitors, particularly the JAK1/2 inhibitor ruxolitinib, sensitize cell lines and murine models to chemotherapy, immunotherapy, and oncolytic viral therapy. Ten JAK inhibitors have been or are actively being tested in clinical trials as monotherapy or in combination with other agents in patients with solid tumors; two of these inhibitors are already Food and Drug Administration (FDA) approved for the treatment of myeloproliferative disorders and rheumatoid arthritis, making them attractive agents for use in patients with solid tumors as they are known to be well-tolerated. Four JAK inhibitors (two of which are FDA approved for other indications) have exhibited promising anti-cancer effects in preclinical studies; however, clinical studies specifically assessing their activity against the JAK/STAT pathway in solid tumors have not yet been conducted. In summary, JAK inhibition is a viable option for targeting the JAK/STAT pathway in solid tumors and merits further testing in clinical trials. LESS      Full article

Cancer is not just a lump of cells that divide, invade, and spread randomly, but rather a multi-layered precisely tuned process that requires the participation of the whole organism. There is an urgent need to zoom-out from the cellular and the local stromal view and broaden our perspective by including the whole organism level. Geographically separated cancer tissues communicate between themselves, forming a system that interacts with the rest of the organism through cancer induced systemic pathogenic networks. In the present paper, I introduce six systemic hallmarks of cancer that emerge as a result of these interactions. I also describe several potential therapeutic approaches that can be developed using the cancer system concept. Overall, I argue that the tumoricentric paradigm should be replaced with a broader approach that brings into focus the “cancerized” organism. LESS      Full article

The discovery that all cells secrete extracellular vesicles (EVs) to shuttle proteins and nucleic acids to recipient cells suggested they play an important role in intercellular communication. EVs are widely distributed in many body fluids, including blood, cerebrospinal fluid, urine and saliva. Exosomes are nano-sized EVs of endosomal origin that regulate many pathophysiological processes including immune responses, inflammation, tumour growth, and infection. Healthy individuals release exosomes with a cargo of different RNA, DNA, and protein contents into the circulation, which can be measured non-invasively as biomarkers of healthy and diseased states. Cancer-derived exosomes carry a unique set of DNA, RNA, protein and lipid reflecting the stage of tumour progression, and may serve as diagnostic and prognostic biomarkers for various cancers. However, many gaps in knowledge and technical challenges in EVs and extracellular RNA (exRNA) biology, such as mechanisms of EV biogenesis and uptake, exRNA cargo selection, and exRNA detection remain. The NIH Common Fund-supported exRNA Communication Consortium was launched in 2013 to address major scientific challenges in this field. This review focuses on scientific highlights in biomarker discovery of exosome-based exRNA in cancer and its possible clinical application as cancer biomarkers. LESS      Full article

Pancreatic ductal adenocarcinoma (PDAC) remains a disease with a dismal prognosis. Since 1996 there have only been two upfront regimens found to be superior to gemcitabine: FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan and oxaliplatin), and gemcitabine plus nab-paclitaxel. Despite the improvement noted in these trials, PDAC is highly chemo-resistant and patients who respond will inevitably develop resistance. The unique immunosuppressive tumor microenvironment with extensive desmoplasia has posed challenges to developing new and effective treatments. Therapeutic vaccines, combination treatments, adoptive T cell transfer, as well as immunomodulators are being explored. With the emerging use of immunotherapy and immunomodulators, the scope of this review is to present the current data on these agents as well as focus on the advancements in the treatment of PDAC. Overall, results in this realm have been disappointing to date reflecting the non-immunogenic and complex tumor microenvironment of PDAC. LESS      Full article