Metabolomics is the last frontier of modern molecular biology, and the state-of-the-art technique for studying metabolism. Mass spectrometry and nuclear magnetic resonance spectroscopy are the main analytical approaches in metabolomics. Cellular metabolism plays a pivotal role during cell resting and activation. Immune cells exhibit remarkable metabolic plasticity, fundamental to support their adaptation to inflammatory environments and functional requirements. Cancer is a metabolic and inflammatory disease. A metabolic shift is crucial for oncogenesis, tumor cell survival, invasion, metastasis, and the associated inflammatory process. The tumor microenvironment is mainly orchestrated by immune-inflammatory cells and essential for the neoplastic process. Inflammatory cells from tumor stroma adapt to different metabolic pathways during tumor progression, and this metabolic reprogramming affects macrophages, neutrophils, T cells, and others. Targeting the metabolism of tumor and immune cells may lead to important therapeutic implications in cancer. Thus, understanding the metabolic changes that drive the interactions between tumor and stromal cells is a promising avenue advances in cancer diagnostics and therapies, leading to more accurate guidance. In this review, we discuss the most recent metabolomics approaches in cancer studies on the tumor-associated inflammatory microenvironment.

Aim: The present in silico study aimed to evaluate the ATP-binding cassette (ABC) transporter inhibition potential of Bulbine frutescens (B. frutescens) phytochemicals.

Methods: Several previous studies and databases were used to retrieve the ligands and target protein structure. The molecular docking study was performed using the Auto Dock Tools, and the GROMACS package was applied to accomplish molecular dynamics simulation.

Results: Utilizing the molecular docking and simulation approach, ~25 phytochemicals were screened against the ABC transporter protein. Docking score analysis revealed that B. frutescens phytochemical 4’-Demethylknipholone 2’-β-D-glucopyranoside exhibited strong binding on the ABC transporter protein with a minimum binding score -9.8 kcal/mol in comparison to the standard ABC transporter inhibitor diltiazem (-6.86 kcal/mol). Furthermore, molecular dynamics simulation for 4’-Demethylknipholone 2’-β-D-glucopyranoside showed an acceptable root mean square deviation, radius of gyration, root mean square fluctuation, and hydrogen bond, in addition to other lead compounds.

Conclusion: The in-silico study demonstrated that B. frutescens phytochemical 4’-Demethylknipholone 2’-β-D-glucopyranoside possesses anti-drug resistance properties and requires further testing in preclinical settings.

Liquid biopsy, including both circulating tumor cells and circulating tumor DNA, is gaining momentum as a diagnostic modality adopted in the clinical management of breast cancer. Prospective studies testing several technologies demonstrated clinical validity and, in some cases, achieved the United States Food and Drug Administration approval. The initial testing and clinical application of liquid biopsy focused primarily on the diagnosis, while molecular characterization and monitoring of metastatic disease, with larger data from prospective studies, came in the last two decades. Although its role in metastatic setting is thus widely recognized, the current evidence does not provide support for the routine clinical use of liquid biopsy methods for the earlier stage of this disease. Considering the relevance of early detection, characterization, and management of breast cancer in the early-stage, this clinical setting is the most suitable to increase the chances for effective treatment selection and improved prognosis, and a better understanding of the main application of liquid biopsy tools in the earlier stage of breast cancer is therefore crucial. The aim of this review is to provide an overview of the clinical evidence and subsequent potential applications of liquid biopsy in early breast cancer, identifying the main existing caveats and the possible future scenarios.

Cancer remains the second leading cause of death worldwide and a major public health and economic issue. To reduce the burden, new approaches are necessary to diagnose the disease at early stages and improve clinical outcomes of cancer patients, for which understanding the molecular mechanisms of carcinogenesis is crucial. Autophagy is a pro-survival pathway that ensures the removal and renewal of cellular macromolecular structures, thus playing a crucial role in the maintenance of cellular homeostasis. Dysregulation of autophagy can favor chemoresistance and survival of dormant cancer cells, thus favoring cancer progression and relapse. Several studies report dysregulated expression of long non-coding RNAs and micro-RNAs acting as tumor suppressors or tumor promoters by targeting genes involved in the autophagy pathway. Here, we focus on the role played by non-coding RNAs-mediated regulation of autophagy in development and progression of cancers in women. Understanding how epigenetics can impact autophagy might open novel therapeutic strategies in the fight against cancers in women.

Aim: Therapeutic agents suppressing bone remodeling have been clinically approved to delay metastatic progression and skeletal-related events in patients with bone metastasis. However, therapeutic agents including zoledronic acid (ZA) are insufficient to regress established bone metastasis. Therefore, new treatment strategies are desired, and unraveling the status of cancer cells during bone metastatic progression will help develop therapeutic strategies.

Methods: We developed a unique multiplexed reporter system for bioluminescent imaging (MRS-BLI) using three luciferase reporter genes. This system allows for the noninvasive and quantitative monitoring of tumor growth and activities of nuclear factor-kappa B (NF-κB) and hypoxia-inducible factor (HIF), which are the key transcriptional factors in response to inflammation and hypoxia, respectively. PC-3/MRS-BLI, a human prostate cancer cell line that stably retains the MRS-BLI reporter genes, was applied to the caudal-artery injection model of bone metastasis to observe the status of cancer cells during bone metastasis development and ZA treatment (< 1 month).

Results: MRS-BLI reveals key events during the bone metastasis development: NF-κB and HIF are activated in cancer cells after migration to the bone marrow and are transiently reduced, followed by rapid activation before proliferation begins. ZA treatment suppresses the growth of metastasized cancer cells by suppressing NF-κB and HIF activities that may be indirectly induced by osteoclast activation.

Conclusion: By visualizing the NF-κB and HIF activities of PC-3/MRS-BLI in bone, MRS-BLI has enabled new discoveries regarding the regulation of bone metastases. Further analysis of the progression of bone metastases using MRS-BLI may provide important information for developing new therapeutic strategies.

This review provides the up-to-date physiological, pathophysiological, and carcinogenic roles of autophagy in the thyroid. The data on its physiological roles are mainly obtained with genetically engineered mice, demonstrating the importance of autophagy for the maintenance of cell homeostasis and survival as well as provision of building blocks for sufficient synthesis of proteins such as thyroglobulin. Positive and negative controls of autophagic activity by thyrotropin and thyroid hormone, respectively, are now apparent. In thyroid cancer, there is no published study on the role for autophagy in the initiation/development of thyroid cancer, and there exist many inconsistent data regarding its role in established thyroid cancer behavior. For example, definitive conclusions remain to be elucidated regarding the level of autophagic activity in thyroid cancer cells and the effect of autophagy inducers/inhibitors on cancer cell survival/proliferation. Especially, when autophagy is targeted in novel cancer therapeutics, some studies show its pro-survival, but others its anti-survival or context-dependent, effects on thyroid cancer cells. Further studies are in the future necessary to further elucidate the potential of autophagy as a therapeutic target for thyroid cancer.

Proximal humeral reconstructive options following radical resection of proximal humeral primary and metastatic bone malignancies have evolved over time. With the relatively recent advent of the reverse total shoulder (RTSA), this technique has been increasingly employed in this setting over hemiarthroplasty techniques. An array of options, including proximal humeral allograft-prosthetic composites (including both RTSA and hemiarthroplasty), megaprostheses, and osteoarticular allografts, is reviewed from the perspective of their indications, techniques, complications, and published results. An extensive case-based pictorial presentation illustrates these options.

The diagnosis of primary tumors of bone relies heavily on clinicopathological and radiological correlation and is often best performed in a multidisciplinary setting. Bone tumors comprise a heterogenous category of human lesions ranging from benign to malignant neoplasms. These tumors affect a wide age range and can become problematic for diagnosis when less common entities are encountered. Traditionally the pathological diagnosis of many bone tumors has been based primarily on the evaluation of hematoxylin and eosin-stained glass slides, sometimes combined with ancillary diagnostic techniques such as immunohistochemistry, conventional cytogenetics, fluorescence in situ hybridization, and polymerase chain reaction-based assays. More recently, the advent of massively parallel sequencing-based techniques has opened new avenues for diagnostic testing in bone tumors; however, these new testing modalities are sensitive to traditional decalcification procedures that are commonly used in the routine processing of bony specimens. Herein we provide a focused review concentrating on the molecular genetic features of bone tumors with specific, recurrent genetic alterations that make them appealing targets for directed ancillary testing by conventional or molecular techniques. In addition, specimen handling with regards to decalcification procedures are discussed and the different types of testing modalities available are reviewed.

The immune system plays an important role in breast cancer. Triple-negative breast cancer (TNBC) has a higher mutational load compared to other subtypes. In addition, higher levels of tumor-associated antigens suggests that immunotherapies are a promising treatment option especially for TNBC. Our review discusses both the complexity of the immune system and the cancer immune-cell cycle. In fact, a higher level of tumor-infiltrating lymphocytes is associated with an improved prognosis as well as a better response to chemotherapy in TNBC. Important target structures within the cancer immune-cell cycle are the so-called “immune checkpoints”. Immune checkpoint inhibitors (ICPi) block the interaction of certain cell surface proteins that serve as “brakes” of immune reactions. Recent studies have shown ICPi improved survival in early as well as advanced TNBC. However, this has the price of increasing, mainly, immune-mediated toxicity. ICPi strengthen tumor-specific T cell-mediated immunity by “releasing the brake” of the immune system. In combination with chemotherapy, ICPi are already approved for TNBC. As a further step, individualized vaccination strategies against tumor-associated neoantigens represent another promising approach. A liposome-formulated intravenous RNA vaccine encoding different tumor-associated antigens is currently being studied in TNBC and leads to neoantigen-specific immune responses. These novel strategies will improve the prognosis of patients with triple-negative breast cancer.

Since its inception, the COVID-19 pandemic has affected health care as a whole. Cancer patients in general and those suffering from lung cancer in particular are a vulnerable group because of their many intrinsic characteristics and care needs. How SARS-CoV-2 (COVID-19) infection affects these patients regarding their risk of infection and outcome in this patient cohort is still to be determined. In this review, we tried to summarize our main concerns regarding COVID-19 in the context of cancer patients from a clinical and multidisciplinary approach. Different types of lung cancer treatments (chemotherapy, radiation therapy and immunotherapy) may also influence the risk of infection and condition the patient´s risk of having a worse outcome. Lung cancer patients require frequent radiologic study follow-ups, which may be affected by COVID-19 pandemic. COVID-19 related incidental radiologic findings can appear in routinely scheduled radiology tests, which may be difficult to interpret. Also cancer treatment induced pneumonitis may have similar radiologic features similar to those in acute SARS-CoV-2 pneumonia and lead to a wrong diagnosis. The different health care needs, the requirement for continuous health care access and follow-ups, and the clinical traials in which this patient population might be enrrolled are all being affected by the current COVID-19 health crisis. The COVID-19 pandemic has put health care providers and institutions in difficult situations and obliged them to face challenging ethical scenarios. These issues, in turn, have also affected the psychological well-being of health care workers.

Bone is the most prevalent metastatic site for breast cancer affecting ~70% of patients with late-stage disease. Treatments for this condition currently focus on controlling disease progression and limiting tumour-induced damage to bone, thereby playing a valuable role in increasing quality of life. However, limited understanding of the interplay between tumour cells and their environment during bone metastasis has impeded the development of curative treatments. To unravel the complex genetic and phenotypic alterations that occur during this process, it would be helpful to have a model in which tumours develop spontaneously at the primary site, spread to bone, undergo a dormancy phase and then, after a fixed timeframe, become re-activated to form osteolytic/mixed lesions in the skeleton. Unlike humans, spontaneous metastasis of primary mammary tumours to bone is rare in mice and no syngeneic models of oestrogen receptor positive disease have been reported. As there is no single model that authentically reproduces all of the genetic and phenotypic changes representative of human bone metastasis, this review discusses the traditional and novel mouse models that are used to study bone metastasis from breast cancer. Additionally, this review focuses on advances that have been made towards making these models more closely related to human disease in an attempt to help researchers select the correct model(s) for their experimental needs with the aim of improving translational efficacy between the laboratory and the clinic.

Oral squamous cell carcinoma (OSCC) is one of the common lethal malignancies which is increasing rapidly in the world. Increasing risks from alcohol and tobacco habits, lack of early detection markers, lack of effective chemotherapeutic agents, recurrence and distant metastasis make the disease more complicated to manage. Laboratory-based studies and epidemiological studies indicate important roles of nutraceuticals to manage different cancers. The plant bitter melon (Momordica charantia) is a good source of nutrients and bio-active phytochemicals such as triterpenoids, triterpene glycosides, phenolic acids, flavonoids, lectins, sterols and proteins. The plant is widely grown in Asia, Africa, and South America. Bitter melon has traditionally been used as a folk medicine and Ayurvedic medicine in Asian culture to treat diseases such as diabetes, since ancient times. The crude extract and some of the isolated pure compounds of bitter melon show potential anticancer effects against different cancers. In this review, we shed light on its effect on OSCC. Bitter melon extract has been found to inhibit cell proliferation and metabolism, induce cell death and enhance the immune defense system in the prevention of OSCC in vitro and in vivo. Thus, bitter melon may be used as an attractive chemopreventive agent in progression towards OSCC clinical study.

Seaweeds have been a food source since ancient times (600 BC) and are still widely used in Asia, mainly in traditional Chinese medicine and Japanese folk medicine. Nowadays, seaweed compounds and extracts have been gaining interest from the biomedical and pharmaceutical market sectors. Seaweeds have been referenced as feasible solutions in finding new potential compounds and therapies in prevention, control, and reduction of cancer development due to the multirole of some bioactive components (e.g, phenolic compounds and sulphated polysaccharides). Moreover, seaweeds are rich in important health-promoting molecules [such as poly and highly unsaturated fatty acids (PUFAs and HUFAs), essential amino acids, vitamins, and dietary fibers] and minerals (calcium, iron, iodine, magnesium, phosphorus, potassium, zinc, copper, manganese, selenium, and fluoride). In this review, the potential therapeutic effects of seaweed in the prevention and treatment of cancer are approached, as well as nutraceutical properties of seaweed to promote cell homeostasis.

The aim of this study was to collect the evidence on the performance of 2-deoxy-2-[18F]fluoro-D-glucose (¹⁸F-FDG) Positron Emission Tomography/Computed Tomography (PET/CT) in terms of detection rate (DR) and diagnostic accuracy in identifying hematogenous metastases in patients with differentiated thyroid cancer and compare its performance with that of other imaging techniques. A comprehensive PubMed/MEDLINE database research was carried out to retrieve studies documenting the performance of ¹⁸F-FDG PET/CT in depicting hematogenous metastases in patients with differentiated thyroid cancer. Statistical analysis was performed on a per-patient and per-lesion basis. The literature search yielded 15 articles to be included in the systematic review. ¹⁸F-FDG PET/CT showed a pooled DR of 85.08% on a per-patient analysis and 89.70% on a per-lesion analysis. For bone lesions, a high DR (81.78%) was found for ¹⁸F-FDG PET/CT. For the sub-group analysis of lung lesions, pooled DR was 92.77% for ¹⁸F-FDG PET/CT, 95.02% for CT, and 64.93% for magnetic resonance imaging (MRI). On a per-patient analysis, ¹⁸F-FDG PET/CT demonstrated a pooled sensitivity (SS) of 87.3% [95% confidence interval (CI): 77.3%-94%] and a pooled specificity (SP) of 95.6% (95%CI: 87.6-99.1). On a per-lesion analysis (328 metastases), PET/CT showed a pooled SS and SP of 86.3% (95%CI: 73.5%-93.5%) and 93.4% (95%CI: 71.7%-98.8%) in the detection of hematogenous metastases. The presented systematic review and meta-analysis favor the use of ¹⁸F-FDG PET/CT in the detection of hematogenous metastases in patients with differentiated thyroid cancer. The limited literature warrants further studies to confirm our findings.

Soft tissue sarcomas (STS) are a heterogenous group of rare malignancies of mesenchymal origin, affecting both children and adults. The majority of STS have a poor prognosis and advanced stage at the time of diagnosis. Standard treatments for STS largely constitute tumour resection with chemotherapy and/or radiotherapy, and there has been little significant advancement in the application of novel therapies for treatment of these tumours. The current multimodal approach to therapy often leads to long-term side effects, and for some patients, resistance to cytotoxic agents is associated with local recurrence and/or metastasis. There is, therefore, a need for novel therapeutic strategies for the treatment of STS. Recent advances in epigenetics have implicated the histone methyltransferase, EZH2, in the development and progression of diseases such as breast cancer, lymphoma and more recently STS. Here we will review the current literature for EZH2 in STS, including high expression of EZH2 in STS and correlation of this with specific features of malignancy (metastasis, histological grade, and prognosis). The effects of targeting EZH2 using RNA interference and small molecule inhibitors will also be reviewed and the potential for the use of EZH2 inhibition in therapeutic strategies for STS patients will be discussed.

Aim: Leelamine (LLM) inhibits the growth of human prostate cancer cells but the underlying mechanism is not fully understood. The present study was undertaken to determine the effect of LLM on cMyc, which is overexpressed in a subset of human prostate cancers.

Methods: The effect of LLM on cMyc expression and activity was determined by western blotting/confocal microscopy and luciferase reporter assay, respectively. A transgenic mouse model of prostate cancer (Hi-Myc) was used to determine the chemopreventive efficacy of LLM.

Results: Exposure of androgen-sensitive (LNCaP) and castration-resistant (22Rv1) human prostate cancer cells to LLM resulted in downregulation of protein and mRNA levels of cMyc. Overexpression of cMyc partially attenuated LLM-mediated inhibition of colony formation, cell viability, and cell migration in 22Rv1 and/or PC-3 cells. LLM treatment decreased protein levels of cMyc targets (e.g., lactate dehydrogenase), however, overexpression of cMyc did not attenuate these effects. A trend for a decrease in the expression level of cMyc protein was discernible in 22Rv1 xenografts from LLM-treated mice compared with control mice. LLM treatment (10 mg/kg body weight, 5 times/week) was well-tolerated by Hi-Myc transgenic mice. The incidence of high-grade prostatic intraepithelial neoplasia, adenocarcinoma in situ, and microinvasion were lower in LLM-treated Hi-Myc mice but the difference was not statistically significant.

Conclusion: The present study reveals that LLM inhibits cMyc expression in human prostate cancer cells in vitro but concentrations higher than 10 mg/kg may be required to achieve chemoprevention of prostate cancer.

Aim: Estrogen receptor α-positive (ER+) subtypes of breast cancer have the greatest predilection for forming osteolytic bone metastases (BMETs). Because tumor-derived factors mediate osteolysis, a possible role for tumoral ERα signaling in driving ER+ BMET osteolysis was queried using an estrogen (E₂)-dependent ER+ breast cancer BMET model.

Methods: Female athymic Foxn1^nu mice were inoculated with human ER+ MCF-7 breast cancer cells via the left cardiac ventricle post-E₂ pellet placement, and age- and dose-dependent E₂ effects on osteolytic ER+ BMET progression, as well as direct bone effects of E₂, were determined.

Results: Osteolytic BMETs, which did not form in the absence of E₂ supplementation, occurred with the same frequency in young (5-week-old) vs. skeletally mature (16-week-old) E₂ (0.72 mg)-treated mice, but were larger in young mice where anabolic bone effects of E₂ were greater. However, in mice of a single age and across a range of E₂ doses, anabolic E₂ bone effects were constant, while osteolytic ER+ BMET lesion incidence and size increased in an E₂ dose-dependent fashion. Osteoclasts in ER+ tumor-bearing (but not tumor-naive) mice increased in an E₂-dose dependent fashion at the bone-tumor interface, while histologic tumor size and proliferation did not vary with E₂ dose. E₂-inducible tumoral secretion of the osteolytic factor parathyroid hormone-related protein (PTHrP) was dose-dependent and mediated by ERα, with significantly greater levels of secretion from ER+ BMET-derived tumor cells.

Conclusion: These results suggest that tumoral ERα signaling may contribute to ER+ BMET-associated osteolysis, potentially explaining the greater predilection for ER+ tumors to form clinically-evident osteolytic BMETs.

Aim: In this study, our goal was to study the inhibition of nicotine metabolism by P450 2A6, as a means for reduction in tobacco use and consequently the prevention of smoking-related cancers. Nicotine, a phytochemical, is an addictive stimulant, responsible for the tobacco-dependence in smokers. Many of the other phytochemicals in tobacco, including polycyclic aromatic hydrocarbons, N-nitrosamines, and aromatic amines, are potent systemic carcinogens. Tobacco smoking causes about one of every five deaths in the United States annually. Nicotine plasma concentration is maintained by the smokers’ smoking behavior within a small range. Nicotine is metabolized by cytochrome P450s 2A6 and 2A13 to cotinine. This metabolism causes a decrease in nicotine plasma levels, which in turn leads to increased tobacco smoking, and increased exposure to the tobacco carcinogens.

Methods: Using the phytochemical nicotine as a lead structure, and taking its interactions with the P450 2A6 binding pocket into consideration, new pyridine derivatives were designed and synthesized as potential selective mechanism-based inhibitors for this enzyme.

Results: The design and synthesis of two series of novel pyridine-based compounds, with varying substituents and substitution locations on the pyridine ring, as well as their inhibitory activities on cytochrome P450 2A6 and their interactions with its active site are discussed here. Substitutions at position 3 of the pyridine ring with an imidazole or propargyl ether containing group showed the most optimal interactions with the P4502A6 active site.

Conclusion: The pyridine compounds with an imidazole or propargyl ether containing substituent on position 3 were found to be promising lead compounds for further development. Hydrogen-bonding interactions were determined to be crucial for effective binding of these molecules within the P450 2A6 active site.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with limited therapeutic options. Despite extensive clinical research over the past several decades, meaningful improvements in care standards have been challenging to achieve. Research efforts are underway on several fronts, including cytotoxic chemotherapy combinations, immunotherapy, and targeted therapy. In this review, we chose to focus less on mainstream avenues of clinical research in PDAC and highlight some novel and innovative research efforts that are typically outside the spotlight of therapies. Examples of these novel approaches include pharmacologic vitamin C and electromagnetic fields. This review’s scope is to present the biological basis of the anti-cancer potential and the early clinical data, as well as the future landscape of these agents, including ongoing clinical trials in these therapeutic avenues.

Multiple myeloma (MM) is a hematologic cancer characterized by uncontrolled growth of malignant plasma cells in the bone marrow and currently is incurable. The bone marrow microenvironment plays a critical role in MM. MM cells reside in specialized niches where they interact with multiple marrow cell types, transforming the bone/bone marrow compartment into an ideal microenvironment for the migration, proliferation, and survival of MM cells. In addition, MM cells interact with bone cells to stimulate bone destruction and promote the development of bone lesions that rarely heal. In this review, we discuss how Notch signals facilitate the communication between adjacent MM cells and between MM cells and bone/bone marrow cells and shape the microenvironment to favor MM progression and bone disease. We also address the potential and therapeutic approaches used to target Notch signaling in MM.

Metastatic triple negative breast cancer (mTNBC) is an aggressive disease associated with a poor prognosis as compared to other subtypes of breast cancer. Significant advances have been made in recent years with new approvals for PARP inhibitors for those patients who harbor germline BRCA mutations and immune checkpoint inhibitors for patients with programmed death ligand-1 (PD-L1) expressing tumors. These therapies are associated with favorable toxicity profiles and improved health-related quality of life when compared with chemotherapy. Maintenance therapy, now recognized as the mainstay for patients with ovarian malignancies, takes advantage of the benefit of low-intensity therapies to suppress a disease over a prolonged period of time following maximal response to induction therapy. This strategy has been little explored in the treatment of mTNBC. Here, we briefly discuss the evidence to date lending credence to this treatment paradigm and examine the potential role of immunotherapy as maintenance in the management of mTNBC.

Medullary thyroid carcinoma (MTC) is a rare endocrine tumor, which arises from thyroid parafollicular C cells. Through its ability to metastasize by blood and lymphatic vessels, it can show a more aggressive clinical behavior than differentiated thyroid cancers. Mutation of RET gene is the main molecular alteration involved in MTC origin. In the case of germline RET mutation, MTC can be inherited in an autosomal dominant way and show three different phenotypes: familial medullary thyroid carcinoma and multiple endocrine neoplasia types IIA and IIB. In addition, in sporadic cases, somatic RET mutation remains the key molecular alteration in most of cases. Total thyroidectomy with prophylactic or therapeutic central compartment lymph nodes dissection is the surgical treatment of choice. Further surgical treatments and local therapies should be used in the case of single or few local or distant metastasis. However, in cases with large metastatic spread of the disease, particularly in those with significant tumor progression, additional systemic treatments are needed. In this review, we discuss the key points of systemic treatment in advanced, metastatic MTC. We provide an update on the main aspects (from biological rationale to clinical experience) of each treatment, focusing our attention on the drugs used in clinical practice in the last years. Finally, we give insights about the emerging treatments from highly selective RET inhibitors to new radionuclide therapy.

Thyroid cancer (TC) constitutes more than 95% of all endocrine tumors. Differentiated thyroid carcinoma (DTC), which includes the papillary and follicular types, constitutes about 90% of all TCs and 2.1% of all cancers. The incidence of DTC has increased significantly worldwide, with papillary cancer leading this trend and being the most prevalent. Whereas the prognosis of patients with DTC is generally favorable, with the overall 5-year survival rate reaching up to 95%, long-term follow-up also discloses increased propensity for cardiovascular and cerebrovascular risk factors, morbidity, and mortality. Cardiovascular events are linked to TC particularly in subjects aged 45 years or more. The present review and analysis seek to highlight the significance of cardiovascular disease in the overall prognosis among TC survivors and explore potential mechanisms which might link treatment choices in DTC to cardiovascular risk and disease outcome.

The use of positron emission tomography with fluor-18-fluorodeoxyglucose (FDG-PET) in clinical practice for patients with head and neck squamous cell carcinoma (HNSCC) has expanded rapidly, with implications for diagnostic staging, radiotherapy planning, adaptive radiotherapy, and post-therapy evaluation. The implementation of FDG-PET/CT in radiation treatment planning not only has consequences for target volume definition and dose prescription but is also associated with an increased overall survival in patients with HNSCC. FDG-PET/CT-guided gradient dose prescription provides a window of opportunity for treatment de-intensification of the neck in order to decrease treatment-related toxicity without compromising oncological outcome. Further, interim FDG-PET/CT during radiotherapy can be useful to assess metabolic tumor response and enables opportunities for adaptive treatment strategies. The goals are to increase treatment effectivity in poor responders and reduce unnecessary toxicity in patients with good early tumor response. Further prospective trials investigating adaptive radiotherapy based on interim PET-evaluation are needed, especially regarding human papilloma virus-negative HNSCC and patients treated with primary radiotherapy.

The RAS gene family, responsible for signal transduction within the mitogen activated protein kinase (MAPK) and phosphatidylinositol 3 kinase (PI3K) pathways, is frequently involved in carcinogenesis, and alterations in its member genes can be detected, with variable frequency, in a wide variety of solid and hematological cancers. These alterations may behave as prognostic-predictive biomarkers and driver mutations, making them an interesting therapeutic target. Since their discovery, many strategies have been pursued to act on their signaling pathways. Indeed, in clinical practice, KRAS, the most prominent member of the RAS gene family, represents an especially elusive target in most malignancies; pathway inhibition is carried out upstream, on the EGFR receptor, or downstream, most frequently on the BRAF/MEK/ERK cascade. Recently, clinically relevant direct RAS inhibition has been successfully achieved with the development of potent and selective covalent inhibitors of KRAS c.34G>T (p.G12C). These latest-generation drugs represent both a new and interesting tool in the therapeutic armamentarium and a symbolic end to the myth of KRAS undruggability. However, their clinical relevance and appropriate place in treatment strategies remain to be determined.

Dysregulation of genes perpetuates cancer progression. During carcinogenesis, cancer cells acquire dependency of aberrant transcriptional programs (known as “transcription addiction”) to meet the high demands for uncontrolled proliferation. The needs for particular transcription programs for cancer growth could be cancer-type-selective. The dependencies of certain transcription regulators could be exploited for therapeutic benefits. Anaplastic thyroid cancer (ATC) is an extremely aggressive human cancer for which new treatment modalities are urgently needed. Its resistance to conventional treatments and the lack of therapeutic options for improving survival might have been attributed to extensive genetic heterogeneity due to subsequent evolving genetic alterations and clonal selections during carcinogenesis. Despite this genetic complexity, mounting evidence has revealed a characteristic transcriptional addiction of ATC cells resulting in evolving diverse oncogenic signaling for cancer cell survival. The transcriptional addiction has presented a huge challenge for effective targeting as shown by the failure of previous targeted therapies. However, an emerging notion is that many different oncogenic signaling pathways activated by multiple upstream driver mutations might ultimately converge on the transcriptional responses, which would provide an opportunity to target transcriptional regulators for treatment of ATC. Here, we review the current understanding of how genetic alterations in cancer distorted the transcription program, leading to acquisition of transcriptional addiction. We also highlight recent findings from studies aiming to exploit the opportunity for targeting transcription regulators as potential therapeutics for ATC.

Aim: Gliomatosis cerebri (GC) is defined as a rare pattern of growth of diffuse gliomas involving three or more cerebral lobes. Given its rarity, it is difficult to define prognostic factors and standard of treatment. We retrospectively analyzed patients (PT) with GC from a single institution with the aim of identifying the main prognostic factors and to assess optimal management.

Methods: Medical records were reviewed of patients ≥ 18 years with a histological and/or radiological diagnosis of GC (with no contrast enhancement) occurring between 2006 and 2017. Median progression free survival (PFS) and overall survival (OS) were calculated by the Kaplan-Meier method.

Results: We analyzed 33 PT, 22 males and 11 females; Eastern Cooperative Oncology Group (ECOG) performance status (PS) was 0-1 in 21 of the patients. Twenty-two PT underwent biopsy: 16 were astrocytomas and 6 oligodendrogliomas. O6-methylguanin-DNA-methyltransferase (MGMT) was detected in 14 cases, and it was methylated in eight cases. Isocitrate dehydrogenase 1 (IDH1) was analyzed in 16 PT, and it had mutated in 10 of them. Nine PT (27%) were treated with radiation therapy (RT) plus concurrent temozolomide (TMZ), 22 PT (67%) received TMZ alone, and 2 PT (6%) underwent RT alone. We reported “complete response” in 1 patient (3%), partial response in 9 PT (27%), and stable disease in 15 PT (45%), while 8 PT (25%) had a progressive disease. For all PT, PFS and OS were 19.1 and 30.7 months, respectively. For ECOG PS 0-1 and ≥ 2, PFS was 34.6 months vs. 3.4 months (P < 0.0001) and OS was 42 months vs. 8.9 months (P < 0.0001), respectively. Methylated MGMT was associated with longer PFS (41.6 months vs. 8.9 months, P = 0.05) and OS (52.7 months vs. 14.6 months, P = 0.009); PFS for IDH1 mutation and IDH wild-type was 52.7 months vs. 8.9 months (P = 0.006) and OS was 52.7 months vs. 41.7 months (P = 0.02), respectively. No significant difference was detected as regards treatments. With regard to histological subtype, OS was 42.0 months vs. 52.7 months (P = 0.8) and PFS was 41.6 months vs. 28.6 months (P = 0.7) for astrocytoma vs. oligodendroglioma, respectively. PT with treatment response showed a longer OS. PT receiving second-line treatment had a longer OS of 30.7 months vs. 6.5 months (P = 0.04).

Conclusion: ECOG PS, MGMT methylation, and IDH1 mutational status seem to have an important prognostic significance, while the type of treatment does not seem to affect survival. Treatment response could be a surrogate marker for survival.

Aim: To clarify the significance of surgical resection for pulmonary recurrence after curative esophagectomy for esophageal cancer.

Methods: Clinical details, such as the recurrence site, timing, and contents of therapies for recurrence, and the prognosis, were examined in 14 patients who underwent surgical resection for pulmonary recurrence that developed after curative esophagectomy.

Results: The median disease-free interval after esophagectomy was 17.2 months. Two patients underwent pulmonary resection two times, and in one patient, three times. All pulmonary resections were performed when other extra-pulmonary recurrences had been controlled, and R0 resection was achieved. Chemotherapy and/or radiotherapy were additionally performed for pulmonary metastasis in 13 patients. The median survival time after initial pulmonary resection was 45.5 months, and the 1-, 3-, and 5-year overall survival rates were 93%, 68%, and 43%, respectively. The 5-year overall survival rate after initial pulmonary resection was 13% in patients with Stage III or IV esophageal cancer and 100% in those with Stage I or II disease (P = 0.010). The rate was 56% in patients with tumors < 20 mm in size, while all 5 patients with lesions ≥ 20 mm in size died within 3 years (P = 0.005).

Conclusion: Surgical resection along with systemic therapy is a promising treatment strategy for pulmonary recurrence after curative esophagectomy when it is solitary and localized. Clinical factors, such as the esophageal cancer stage and the size of the pulmonary metastasis, are useful for deciding on the surgical indication.

The World Health Organization declared coronavirus infectious disease-2019 (COVID-19) linked to the severe acute respiratory syndrome (SARS-CoV-2), a global pandemic in March 2020. The pandemic outbreak has led to the most unprecedented and catastrophic loss of human life in the recent history. As of January 2021, there were more than 100 million cases of COVID-19 and more than two million deaths worldwide. Compared to the general population, patients with cancer are at a higher risk of poor outcomes from COVID-19. In large cohort studies, mortality from COVID-19 in patients with cancer can be as high as 40%. In addition to clinical variables (older age, male sex, and co-morbidities) that are associated with mortality in general population, cancer patients are uniquely vulnerable to severe COVID-19 due to immunosuppression from cancer and its therapy, and disruption of routine clinical care. Among patients with cancer, the lung cancer population is at a higher risk of poor outcomes and mortality from COVID-19 for several reasons. For instance, lung is the main target organ in COVID-19 that can lead to respiratory failure, patients with lung cancer have baseline poor lung function from chronic obstructive pulmonary disorder and smoking. In addition, some of the lung cancer treatment side-effects like pneumonitis, may obscure the diagnosis of COVID-19. In this article, we systematically review the most impactful cohort studies published to date in patients with cancer and COVID-19. We describe the rates of mortality in patients with cancer and COVID-19 with a special focus on the lung cancer population. We also summarize the factors associated with poor outcomes and mortality in patients with lung cancer and COVID-19.

Intraductal papillary mucinous neoplasm (IPMN) is a pre-malignant, mucin-producing epithelial lesion arising from pancreatic ducts. Observational reports define IPMN behavior as ranging from indolent, asymptomatic lesions to dysplasia that sometimes degenerate into pancreatic adenocarcinoma. The goal of IPMN management is risk-reducing surgery for high-risk cysts and observation of the remainder. Discriminating high- from low-risk IPMN disease still relies on imaging and clinical cyst characteristics. Here, we review the accepted classification of IPMN including the most common histological subtypes, their clinical features, and currently-accepted high-risk phenotypes. We then deeply examine the known molecular landscape of IPMN, which has largely been derived from post-resection analysis. This includes those gene variants unique to IPMN, chiefly GNAS and RNF43, but also examines the overlap between IPMN and conventional pancreatic adenocarcinoma. Utilizing molecular markers in the clinical setting relies on endoscopically-obtained cyst fluid and presumes that it accurately represents the molecular characteristics of the cystic epithelium. We synthesize existing data on mutational analysis from IPMN cyst fluid and consider the benefits and proper role of current commercially-available cyst fluid molecular analysis kits. We conclude that carefully interpreted molecular analysis of resected IPMN tissue reveals insights into its biology and natural history while cyst fluid analysis offers prognostication and data to guide treatment decisions. However, knowledge gaps remain, especially in characterizing IPMN molecular heterogeneity, time to progression, and correlating cyst fluid genotype data with surveillance strategies. As such, substantial additional research is required before the promise of true molecular guidance of IPMN management can be realized.

Pancreatic ductal adenocarcinoma (PDAC) remains a leading cause of cancer-related mortality, with cytotoxic chemotherapy still the mainstay of treatment. Beyond effective therapeutic agents alone, successful drug delivery is paramount. In PDAC, the tumor microenvironment represents a physical barrier that limits in vivo drug delivery and efficacy. In this review, we highlight therapeutic targets in the tumor microenvironment, focusing on past challenges and opportunities for the future. Targets discussed include the Hedgehog pathway, angiogenesis, hyaluronic acid, cancer-associated fibroblasts and associated cytokines, among others. Despite the obstacles in successfully recapitulating promising lab results to practice-changing clinical results, many important lessons have been learned to improve clinical trial design within a highly engaged and motivated scientific community. These collaborative efforts and the collective optimism will continue to propel the momentum forward to overcome these barriers and ultimately improve patient outcomes.

Aim: Neuroblastoma is the most common extracranial solid tumor in children. Recent advances in immunotherapy Approaches, including in neuroblastoma, have shown the important role of the immune system in mounting an effective anti-tumor response. In this study, we aimed to provide a comprehensive investigation of immune cell infiltration in neuroblastoma utilizing a large number of gene expression datasets.

Methods: We inferred immune cell infiltration using an established immune inference method and evaluated the association between immune cell abundance and patient prognosis as well as common chromosomal abnormalities found in neuroblastoma. In addition, we evaluated co-infiltration patterns among distinct immune cell types.

Results: The infiltration of naïve B cells, NK cells, and CD8+ T cells was associated with improved patient prognosis. Naïve B cells were the most consistent indicator of prognosis and associated with an active immune tumor microenvironment. Patients with high B cell infiltration showed high co-infiltration of other immune cell types and the enrichment of immune-related pathways. The presence of high B cell infiltration was associated with both recurrence-free and overall survival, even after adjusting for clinical variables.

Conclusion: In this study, we have provided a comprehensive evaluation of immune cell infiltration in neuroblastoma using gene expression data. We propose an important role for B cells in the neuroblastoma tumor microenvironment and suggest that B cells can be used as a prognostic biomarker to predict recurrence-free and overall survival independently of currently utilized prognostic variables.

Cancer is one of the leading causes of death in women and men worldwide. The fatal outcome usually occurs after metastatic dissemination, and bone is by far the most common site of metastasis for breast and prostate cancer, the highest incidence neoplasia in women and men, respectively. However, while this is clear, the mechanisms through which the metastatic preference is established is not. An emerging concept in this regard is the pre-metastatic niche (PMN) establishment, i.e., the process through which tumors can influence the bone microenvironment from the primary site and make it permissive for their engraftment, before they migrate to the blood flow and metastasize. In this review, we discuss key microenvironmental players in the bone/bone marrow PMN, including osteoblasts, osteoclasts, and bone marrow adipocytes. We also describe the known PMN-educating factors, as well as the role of extracellular vesicles as emerging players in the bone/bone marrow PMN. An overview of current therapeutic developments aimed at targeting the bone PMN is also provided.

Chimeric antigen receptor (CAR) T-cell therapy has significantly improved outcomes for patients with relapsed/refractory large B-cell lymphoma, mantle cell lymphoma, and follicular lymphoma, with multiple FDA-approved CAR T products now commercially available. Ongoing studies seek to move CAR T-cells to earlier lines of therapy and to characterize the efficacy and safety of CAR T-cell approaches in additional lymphoma histologies including relapsed/refractory follicular lymphoma and chronic lymphocytic leukemia. Other areas of active research address CAR T in combination with other lymphoma-directed therapies, and mechanisms of CAR T resistance. This review focuses on the FDA-approved anti-CD19 CAR T products for B-cell lymphomas, management of CAR T-cell-associated toxicities, approaches to bridging therapy, and ongoing clinical trials and future research directions across a broad range of lymphoma histologies.

Aim: Patients with prostate cancer frequently develop osteoblastic bone metastases. Canine models are important because dogs are the only mammal to develop spontaneous prostate cancer with osteoblastic bone metastases similar to men. The mechanism by which prostate cancer induces bone formation is unclear; however, it depends on the complex interaction between prostate cancer cells and bone microenvironment. This study investigated the effects of three canine prostate cancer cell lines (Ace-1, LuMa, and Probasco) on bone formation and resorption in vitro.

Methods: Mouse calvaria were treated with conditioned medium (CM) from cell lines. Calvaria were evaluated by histology, fluorescent calcein uptake at sites of bone mineralization, medium calcium assay, and alkaline phosphatase activity. The expression of bone-related genes was measured using quantitative reverse transcription-PCR.

Results: A novel calcein uptake assay was developed to measure bone formation and mineralization in vitro. Ace-1 CM induced predominantly bone resorption in calvaria, while Probasco CM induced marked bone formation, mineralization, and healing of calvaria defects. The expression of osteoblast-related genes in calvaria showed that Probasco CM stimulated the maturation and differentiation of osteoblasts and inhibited osteoclastogenesis. Both bone modeling and remodeling were involved in Probasco CM-induced bone formation and mineralization by inhibiting remodeling with zoledronic acid. Inhibition of WNT activity by DKK-1 decreased the osteoblastic activity of Probasco cells.

Conclusion: Probasco cells induced bone formation and mineralization in vitro that depended on the WNT signaling pathway. Probasco cells will serve as a valuable model for studying the mechanisms of osteoblastic bone metastasis in prostate cancer.

Aim: Murine tumour cell lines have been used in thousands of studies. Strikingly, it is rather the rule than exception for most of them that not much is known about their genetic characteristics. The squamous cell carcinoma (SCC) cell line KLN 205 is such an example. KLN 205 cells have not been studied yet for karyotype or acquired copy number variations (CNVs), but they have been used as models for (metastatic) lung cancer, lung-SCC, non-small cell lung cancer, tongue cancer and subcutaneous SCC. Here, it was characterised cytogenomically for the first time.

Methods: The cell line KLN 205 was characterised comprehensively by molecular cytogenetics using multicolour banding as well as molecular karyotyping. Based on these results, a map of the imbalances and breakpoints determined in the murine genome was translated to the human genome.

Results: Here, it could be shown that this > 40-year-old cell line has a stable, approximately tetraploid karyotype comprising 77-82 chromosomes. However, there are few structural chromosomal aberrations: only six derivatives involving chromosomes 2, 3, 5, 9, 10 and/or 19 could be found. According to the literature, SCCs derived from different human tissues, as well as lung SCC and non-small cell lung cancer, display overall similar CNV patterns.

Conclusion: Thus, according to the genetic profile found here, KLN 205 can be applied as a general model for human SCC; it is also suited as a model for lung cancer in general. Further molecular genetic characterisation of KLN 205 cell line may find more lung- and/or SCC-specific alterations.

The therapeutic landscape for advanced clear cell renal cell carcinoma (ccRCC) is rapidly evolving with improved knowledge of the biology of disease leading to the incorporation of a variety of antiangiogenic agents and immunotherapies. In this review, we discuss historical, current, and emerging first line treatment options for patients with advanced ccRCC. These include data with single agent vascular endothelial growth factor receptor tyrosine kinase inhibitors (TKIs): sunitinib, pazopanib and cabozantinib as well as the recently reported results for the combination of lenvatinib and everolimus (mTOR inhibitor). We also discuss results of the nivolumab anti-programmed cell death (PD-1)/ipilimumab (anti-cytotoxic T lymphocyte-associated antigen 4) combination as well as emerging front-line data with nivolumab and pembrolizumab (anti-PD-1) monotherapy. Finally, we review data supporting recent approvals of TKI and anti-PD-1 or anti-PD-Ligand 1 (PD-L1) combinations (e.g., axitinib/pembrolizumab, axitinib/avelumab and cabozantinib/nivolumab) and initial outcomes of lenvatinib (multi-kinase inhibitor) and pembrolizumab. With many individual and combination treatment options and the lack of head-to-head comparisons, treatment selection will depend on the goals of therapy (endpoints) and the identification and validation of clinical and tumor-based predictive biomarkers that are linked to the desired treatment endpoints.

Metastatic disease is the cause for 90% of breast cancer mortalities. For those 10%-20% of patients whose breast cancer metastasizes to the central nervous system, the one-year survival rate is just 20%. Both histology and molecular subtype have a correlation with the site of tumor metastasis, indicating an inherent preferential aspect to metastatic colony formation. The molecular differences between breast cancers may determine the site of metastasis through priming of the premetastatic niche in that site: cell surface molecules, exosomes released from the primary tumor, and soluble factors secreted from both the primary tumor and resident cells within the premetastatic niche all contribute to altering the premetastatic niche to be more favorable for the circulating tumor cells, allowing for cell invasion and growth. Here, we review breast to brain metastasis with a focus on the premetastatic niche. We discuss the secreted factors and exosomes that prime the premetastatic niche within the brain by instigating crosstalk between the resident cells of the brain microenvironment. We report on the individual roles that microglia, astrocytes, pericytes, neurons, and endothelial cells may have in the formation and maintenance of the premetastatic niche.

Incidental lesions of the thyroid are increasingly discovered as the prevalence of medical imaging escalates. The likelihood of malignancy must be assessed for each of these incidentalomas. The utility of the metabolic data derived from the identification of these lesions on PET/CT imaging is unclear. The overall rate of detection of thyroid incidentalomas on PET/CT is estimated at 1.5%-4.2%. However, this rate varies by the pattern of uptake. Several studies have evaluated predictive measures such as maximal standardized uptake value (SUV_max) and radiomics. However, no definitive conclusion has been reached. Given that the majority of PET/CT scans are performed in the context of malignancy, we recommend first assessing the general condition and life expectancy of patients when PET-detected thyroid incidentalomas are unveiled. We also recommend considering observation versus diagnostic workup with further imaging and/or fine-needle aspiration and cytology.

Aim: Angiogenesis is observed in acute myeloid leukemia (AML). AML cells abnormally proliferate and are resistant to death. Positive regulators of angiogenesis, VEGF-A and matrix metalloproteinases (MMPs) 2 and 9 are markers of disease status in AML. The natural phloroglucinol hyperforin (HF) displays antitumoral properties of potential pharmacological interest. Herein, we investigated the effects of HF on MMP-2/9 and VEGF-A expression and survival of primary AML cells.

Methods: Blood and bone marrow samples were collected in 45 patients with distinct subtypes defined by French American British classification, i.e., M0, M1, M2, M3, M4, and M5. Levels of MMPs and VEGF-A in leukemic blood cells and culture supernatants were determined by RT-PCR, ELISA, and gelatin zymography (MMPs). The balance between cell death and survival was assessed by flow cytometry with analysis of phosphatidylserine externalization and caspase-3 activation.

Results: The administration of HF promoted a caspase-associated apoptosis in primary AML blasts (from blood and bone marrow), but not normal blood cells and monocytes. In addition, HF inhibited the levels of secreted proMMP-2, proMMP-9, and VEGF-A without altering transcripts. The induction of apoptosis by HF significantly paralleled the inhibition of MMP-2/9 and VEGF-A release by HF. No differences were seen in response to the deleterious effects of HF between AML cells of distinct subtypes.

Conclusion: Our results suggest that HF, through its proapoptotic and potential antiangiogenic properties (by inhibiting MMP-2/9 and VEGF-A) on primary AML cells, might be a useful experimental agent, in combination with existing drugs, for new therapeutic approaches in the treatment of this incurable disease.

Bioactive lipids constitute a large family of molecules considered as inflammatory mediators. Among them, lysophosphatidic acid (LPA), sphingosine 1-phosphate (S1P), and eicosanoids (prostanoids such as PGE2 and leukotrienes such as LTB4, LTC4, and LTD4) play a central role in the pathophysiology of several inflammatory diseases. However, it has long been known that these bioactive lipids are also involved in cancer, mainly because of their ability to control the pro-inflammatory microenvironment of tumors as well as their ability to act directly on tumor cells promoting cell proliferation, migration, and survival. Recently, there has been increased interest in determining how these lipid mediators orchestrate tumor development and metastasis. Bone metastases result from a complex dialogue between tumor cells and bone cells. Recent findings demonstrate that all these bioactive lipids can profoundly affect bone metabolism by acting positively or negatively on both osteoblasts and osteoclasts. This review gives an overview of previous findings demonstrating direct involvement of LPA, S1P, and PGE2 in bone metastasis. This review also emphasizes the recent findings that characterize the activity of these bioactive lipids directly on bone cells and how these activities could be integrated into the complex molecular mechanisms leading to bone metastasis formation and progression.

Metastatic renal cell carcinoma (mRCC) presents with bone metastases in around 20%-30% of patients enrolled in the most recent first-line clinical trials. Emergence of several new agents in first line, in both monotherapy and combination, has significantly improved patient outcomes. However, the activity of such agents on bone metastases is unclear and management of these patients is complex, due to potential complications that can significantly impair quality of life. This review addresses mRCC diagnosis and monitoring and summarizes the current evidence on systemic therapy, ablative therapies such as stereotactic ablative radiotherapy and surgery, and supportive therapy with bone-targeting agents for these patients, with the goal of improving their outcomes.

Thyroid cancer (TC) is the most common malignancy of the endocrine system and has been rapidly increasing in incidence over the past few decades. Aggressive TCs metastasize quickly and often levy poor prognoses, as they are frequently resistant to first-line treatment options. Patients diagnosed with aggressive, dedifferentiated TC have a prognosis of under a year with the most current treatment modalities. Like many cancers, TCs also exhibit altered cell metabolism, which enhances the cell’s ability to generate energy, protect against reactive oxygen species, and synthesize macromolecules such as lipids, proteins, and nucleotides for proliferation. Genetic and enzyme profiling of TC tissues and cell lines have uncovered several dysregulated metabolic pathways such as glycolysis, the pentose phosphate pathway, glutamine metabolism, and pyrimidine synthesis. These aberrations are most often due to overexpression of rate-limiting enzymes or metabolite transporters. Metabolic pathways pose attractive therapeutic targets in aggressive TC and may serve to work in tandem with standard therapeutics such as kinase inhibitors depending on the genetic, metabolic, and signaling backgrounds of individual tumors. Further studies are needed to clearly delineate altered metabolic targets across TC subtypes for implementing therapeutic metabolic inhibitors that have shown success in other aggressive tumors.

Several prognostic models incorporating serum biomarkers to estimate patient survival have been established for metastatic renal cell carcinoma. Interim advancements in biomarker research have highlighted much additional serum, gene mutation, genetic expression signatures, and histologic biomarkers that predict clinical outcomes and response to treatments. We, therefore, reviewed biomarkers associated with overall, cancer-specific, progression-free, and disease-free survival, overall response, and time to treatment failure rate in adult populations with metastatic renal cell carcinoma. We reviewed human studies reporting associations between biomarkers and clinical outcomes. Data were abstracted via standardized form, then reported with hazard ratios and confidence intervals where appropriate, subdivided by biomarker type (serum, gene mutation, genetic expression, and histologic). We identified a range of newer biomarkers that have clinical associations with prognostic and predictive outcomes. Beyond biomarkers used in modern risk models, those consistently associated with prognosis included serum levels of CAIX, COP-NLR, CRP, s-TATI, and VEGF, gene mutations in BAP1, CDKN2A, CIMP/FH, and TERT, gene expression of ERV and NQO1, and histologic macrophage infiltration and expression of CAIX and PDL1. Biomarkers consistently associated with the response to targeted antiangiogenic therapy included serum CRP, mutations in MET, PBRM-1, BAP1, and the mTOR pathway, TERT promoter mutations, and expression of PTEN and angiogenic gene signatures. Gene expression of hERV, T-effector, and immunogenic signatures have been associated with improved response to immune checkpoint inhibition. Future models should incorporate well-studied biomarkers to help clinicians predict outcomes and treatment responses for patients with metastatic renal cell carcinoma.

Metastatic Renal Cell Carcinoma (mRCC) is a highly heterogeneous disease that is notoriously difficult to treat successfully. However, the discovery of novel, targeted therapies over the last decade has revolutionized its management. As the therapeutic options continue to evolve, developing a more individualized treatment strategy is of paramount importance. The International mRCC Database Consortium (IMDC) is a prognostic model that is commonly used in trials and clinical settings to risk stratify patients. This allows for optimal therapy selection on a more individual basis. However, the distinct lack of validated predictive biomarkers in mRCC renders it difficult to assess therapy response. An improved understanding of tumor biology and genetics has prompted a shift from cytokine therapy to the use of vascular endothelial growth factor (VEGF) inhibitors, tyrosine kinase Inhibitors, immune checkpoint inhibitors or combination strategies. Studies have identified some putative markers and genetic mutations as potential predictors of therapy response. Early results are promising, and there are many ongoing trials further assessing their suitability for clinical use. This review will evaluate the current treatment landscape and molecular biology of mRCC, with a specific focus on the prognostic and predictive markers available to guide treatment options and further improve patient outcomes.

Recent advances in the treatment of metastatic renal cell carcinoma expose a gap in the treatment of less advanced, localized disease. Tyrosine kinase inhibitors, which revolutionized the treatment of metastatic disease, have not provided a similar survival benefit in the adjuvant setting and currently only sunitinib is approved by the Food and Drug Administration for adjuvant treatment in patients with high-risk of recurrence based on S-TRAC disease-free survival data. The advent of immune checkpoint inhibitors has offered a fresh hope in the field of adjuvant treatment after encouraging results are seen with combination of immune checkpoint inhibitors as well as with targeted therapy in the metastatic setting. Several studies are investigating these combinations in the adjuvant setting, and it is hoped that they will bring about a better outcome for a largely unmet need in kidney cancer treatment.

We aim to describe the most recent advances in the upfront treatment of metastatic renal cell carcinoma, and to provide criteria - though often subjective - which could be used for treatment selection, by means of a critical review of the results of novel trials of immune-based combinations, coupled with personal considerations and experiences. To date, 5 immune-based combinations have been tested within large phase III trials; four of them yielded a significant overall survival benefit (Ipilimumab + Nivolumab, Pembrolizumab + Axitinib, Nivolumab + Cabozantinib and Pembrolizumab + Lenvatinib), while the combination of Avelumab + Axitinib, although reaching study primary endpoint, determined just a significant progression-free survival benefit. In terms of safety, the excess of adverse events is overall counterbalanced to the higher activity of the combinations. Overall, all the discussed immune-based combinations were ultimately approved by different regulatory authorities, and are indeed included in the most important international guidelines. Waiting for longer follow-ups and more mature trial data, as well as for real-world experiences, in the absence of validated biomarkers, our 1st line treatment choice cannot but rely on methodologically incorrect treatment comparisons, personal preferences, and experience.

Genetic and epigenetic lesions within hematopoietic cell populations drive diverse hematological malignancies. Myelodysplastic syndromes (MDS) are a group of myeloid neoplasms affecting the hematopoietic stem cells characterized by recurrent genetic abnormalities, myelodysplasia (a pathological definition of abnormal bone marrow structure), ineffective hematopoiesis resulting in blood cytopenia, and a propensity to evolve into acute myelogenous leukemia. Although there is evidence that the accumulation of a set of genetic mutations is an essential event in MDS, there is an increased appreciation of the contribution of specific microenvironments, niches, in the pathogenesis of MDS and response to treatment. In physiologic hematopoiesis, niches are critical functional units that maintain hematopoietic stem and progenitor cells and regulate their maturation into mature blood cells. In MDS and other hematological malignancies, altered bone marrow niches can promote the survival and expansion of mutant hematopoietic clones and provide a shield from therapy. In this review, we focus on our understanding of the composition and function of hematopoietic niches and their role in the evolution of myeloid malignancies, with an emphasis on MDS.

The incidence of esophagogastric junction (EGJ) adenocarcinoma has been increasing in Asian countries. Despite the recent advances in multidisciplinary treatments, EGJ adenocarcinoma remains aggressive with unfavorable outcomes. Regarding surgical strategy, EGJ adenocarcinoma arises between the esophagus and the stomach, and thus tumor cells spread through the lymphatic system both upward to the mediastinum and downward to the abdomen. Nevertheless, an optimal extent of lymphadenectomy remains controversial. Regarding drug therapy, the latest topic in gastric and EGJ adenocarcinoma is trastuzumab deruxtecan, which is an antibody-drug conjugate consisting of an anti-HER2 antibody. In addition, many clinical trials have recently demonstrated the efficacy of immune checkpoint inhibitors. Meanwhile, recent advances in sequencing technology have revealed that gastroesophageal adenocarcinoma could be categorized into four molecular subtypes: epstein-Barr virus-associated, high-level microsatellite instability, genomically stable, and chromosomal instability tumors. Furthermore, these subtypes show distinct clinical phenotypes and molecular alterations. We review the current surgical strategy and drug treatment such as molecular-targeted agents, immune checkpoint inhibitors, and molecular-subtype-based therapeutic strategies in EGJ adenocarcinoma. Clinical and molecular characteristics and response to immune checkpoint inhibitors differ among molecular subtypes. Treatment strategies based on molecular subtypes may be clinically beneficial for patients with EGJ adenocarcinoma.

Patients with unresectable malignant pleural mesothelioma (MPM) have historically poor outcomes and treatment, and their treatments have been limited to palliative chemotherapy. Recent efforts to improve prognosis for these patients by adding angiogenesis inhibitors to chemotherapy led to significant benefits. However, the emergence of immunotherapy combinations for the front-line treatment has upended the standard of care and has led to the first new FDA approvals for the treatment of MPM in nearly two decades. This review aims to cover the main clinical trials in unresectable MPM with VEGF inhibitors and immunotherapy which have led to paradigm shifts in current practice. Ongoing clinical trials exploring the combination of chemo and immunotherapies show a great deal of promise, and continued support for ambitious, large-scale well-designed trials remain vital for defining the future outcomes of patients diagnosed with MPM.

Cytoreductive nephrectomy has been a mainstay in treating patients with synchronous metastatic renal cell carcinoma (mRCC) for over two decades. It was supported in part by level 1 evidence that showed improved survival for patients undergoing radical nephrectomy before initiation of systemic therapy dating back almost 20 years. Since that time, the landscape of systemic therapy for mRCC has shifted mainly from IL-2 based therapy to tyrosine kinase inhibitors (TKIs) targeting the vascular endothelial growth factor pathway, and now to immunotherapy with PD-L1 inhibitors. Given the significant advancements in systemic therapy for patients with mRCC, the role of cytoreductive nephrectomy and sequencing of treatment has been questioned. Recent randomized studies appear to disprove the theory that upfront cytoreduction improves overall survival, particularly in the TKI era, and thus treating physicians are faced with conflicting data to guide treatment decisions. The role of cytoreductive nephrectomy is in evolution, and so is the timing of surgery in selected patients. Familiarity with available evidence coupled with patient selection and targeted therapy should help to inform decision-making. Currently, an initial course of systemic therapy followed by consideration of nephrectomy in those with a favorable response may be the most prudent algorithm outside the context of a clinical trial.

The prognosis of patients with head and neck squamous cell cancer (HNSCC) decreases with the presence of extranodal extension (ENE) in lymph node metastases. Therefore, ENE was introduced in the 8th Edition TNM Classification (TNM8) for Head and Neck Cancer as a staging variable in all HPV-negative HNSCC. Patients with ENE may benefit from adjuvant or even primary chemotherapy and/or radiotherapy. There is a clear discrepancy between the definition of clinical ENE and pathological ENE. In TNM8, the radiological evaluation of ENE only plays a supportive role. Since not all patients with advanced disease will undergo a neck dissection, histologic proof of ENE will not always be available. In these cases, it would be of great help to be able to accurately determine ENE with radiological imaging. In this review, an update is given of the ability of radiological imaging to identify and grade ENE.

Despite intense research and the development of several new chemotherapeutics, the prognosis for specific subsets of acute myeloid leukemia (AML) has not improved significantly. Thus, the investigation of signaling pathways associated with the pathogenesis and progression of AML has become a source for the discovery of more effective treatments. The epidermal growth factor receptor (EGFR) belongs to the HER family of tyrosine kinase (TK) receptors and is involved in the progression of a variety of solid tumors. Although the expression of members of the HER family appears to be limited to epithelial tissues and derived neoplasms, there is evidence demonstrating their role in hematopoiesis and hematological neoplasms. In AML, preclinical studies and two anecdotal cases of response to EGFR TK inhibitors (TKI) supported the EGFR signaling pathway as a potential therapeutic target. Indeed, the presence of EGFR ligands in the bone marrow microenvironment has been shown to play pathological and regenerative/protective roles in AML. However, data reporting the expression of EGFR in AML remain controversial and the EGFR pathway inhibition in AML patients has demonstrated limited clinical significance. Further studies are required to determine the relevance of the EGFR pathway in AML biology and which patients may benefit from using EGFR TKI or other drugs that target TK receptors.

For both primary and metastatic renal cell carcinoma (RCC), treatment with stereotactic body radiotherapy (SBRT) has found its way into clinical practice. Being a non-invasive outpatient procedure, SBRT requires only a few visits to the radiation department and may be of interest for the elderly or, in the case of primary RCC, for patients who are not considered surgical candidates due to technical limitations, medical comorbidities, or in the event that the maintenance of kidney function is compromised. In the treatment landscape of oligometastatic RCC, SBRT shows promise in eradicating metastatic disease and delaying the initiation of systemic treatment. Technical advancements in the planning and administration of radiation treatment and improvements in movement management allow irradiating the tumor and/or metastatic lesions with very high doses in few fractions while maximally sparing the surrounding organs at risk, thus minimizing toxicity. In that context, the increasing availability of particle therapy, such as proton beam radiotherapy or carbon ion radiotherapy, could further optimize the delivery of radiation treatment in order to reduce toxicity and improve outcome.

Aim: Many therapeutic means have emerged to treat esophageal cancer. Factors relating to nutritional status such as body weight maintenance are important to the continuation of these treatments. In this study, we investigated methods to extend the administration of diversified treatments for patients with esophageal cancer, especially regarding measures to suppress body weight loss after surgery.

Methods: We retrospectively evaluated a strategy for preventing postoperative body weight loss which can hinder the continuation of treatment via a reconstruction method aimed at safety and comfort combined with postoperative dietary intake and nutritional support for esophageal cancer patients.

Results: The subjects comprised 386 patients who underwent subtotal stomach reconstruction during esophageal cancer surgery performed from January 2008 to January 2021 at Gifu University Hospital. The anastomotic leakage rate was 0.5%. By administering oral nutritional supplementation under strict rules using ENSURE® H during the perioperative period, the percentage of body weight loss after 5 years could be limited to 4.78% compared to that before treatment. Scores assessing early feeling of fullness measured using the EORTC QLQ-OES18 at postoperative months 3, 12, 24, 36, 48, and 60 were 1.7 ± 0.3, 2.0 ± 0.2, 1.2 ± 0.3, 1.3 ± 0.2, 1.5 ± 0.2, and 1.4 ± 0.1, respectively.

Conclusion: Considering methods to eliminate the factors that prevent continuation of treatment may lead to sustainable treatment against esophageal cancer. Proper surgical reconstruction and nutritional management will allow maintenance of body weight and good quality of life.

Pancreatic cancer is a deadly disease and the third-highest cause of cancer-related deaths in the United States. It has a very low five-year survival rate (< 5%) in the United States as well as in the world (about 9%). The current gemcitabine-based therapy soon becomes ineffective because treatment resistance and surgical resection also provides only selective benefit. Signature mutations in pancreatic cancer confer chemoresistance by deregulating the cell cycle and promoting anti-apoptotic mechanisms. The stroma-rich tumor microenvironment impairs drug delivery and promotes tumor-specific immune escape. All these factors render the current treatment incompetent and prompt an urgent need for new, improved therapy. In this review, we have discussed the genetics of pancreatic cancer and its role in tumor evolution and treatment resistance. We have also evaluated new treatment strategies for pancreatic cancer, like targeted therapy and immunotherapy.

POEMS syndrome is a rare paraneoplastic disorder due to an underlying clone of aberrant plasma cells. The name POEMS is an acronym for some of the major disease manifestations, namely polyneuropathy, organomegaly, endocrinopathy, presence of monoclonal component, and skin changes. The clinical presentation can be various and could lead to delayed diagnosis and treatment. Little is known about the pathogenic mechanism, although the neoangiogenesis due to overproduction of vascular endothelial growth factor (VEGF) by plasma cells seems to play a key role. The latest evidence suggests that the blood concentration of this cytokine correlates with the activity of the syndrome: VEGF could then be used as a therapeutic target and a marker to monitor response. Several case reports have shown the efficacy of this approach, but extended studies are required to better define the use of anti-VEGF in patients affected by POEMS syndrome.

Progression of chronic lymphocytic leukemia (CLL) is determined by the localization of malignant cells in lymphoid tissues, where they receive growth and survival signals. CLL cells produce angiogenic factors that are regulated by internal and external stimuli and whose levels vary according to the clinical stage of the disease. Stromal cellular and molecular components in CLL niches disturb the balance of pro- and antiangiogenic molecules in CLL cells and induce an angiogenic switch. Additionally, CLL cells also influence the behavior of microenvironmental cells, inducing endothelial cell proliferation and increasing the angiogenic capacity of macrophages, neutrophils, and other cells present in CLL niches. As a result of these reciprocal functional interactions, bone marrow angiogenesis is frequently increased in CLL and has been proposed as a prognostic marker in early disease. Besides their role in regulating angiogenesis, angiogenic factors are also involved in CLL cell migration and survival, all contributing to disease progression. Angiogenic factors, particularly vascular endothelial growth factor, have therefore been attractive therapeutic targets in CLL and many clinical trials were established in the past years. However, the results of these trials reveal that anti-angiogenic therapies alone are not as efficient as expected and should rather be used in combination with other treatments.

Triple-negative breast cancer (TNBC) represents the subtype of breast cancer with the most aggressive biological behavior and the worst prognosis compared to other breast cancers. Metastatic TNBC is characterized by a high proliferative index, rapid progression with metastases to the viscera and central nervous system, and generally an unfavorable prognosis with a survival of about one year. It is, therefore, necessary to identify specific targets and more effective treatments for patients with TNBC. Evidence of the effect of the tumor immune microenvironment on clinical outcomes is considered a significant issue in breast cancer therapeutics. Compared to other subtypes of breast cancer, TNBC is characterized by a higher mutational burden and is recognized as the most immunogenic among them. Based on these findings, immune checkpoint inhibition was evaluated in TNBC with encouraging results. Indeed, enhancing antitumor immunity in TNBC by blocking the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) axis or the programmed cell death-1 (PD-1) receptor/programmed death-ligand 1 (PD-L1) pathway is a promising treatment option. In this review, we examine the role of monoclonal antibodies targeting CTLA-4 and PD-1/PD-L1 in this breast cancer subtype and discuss combination approaches for early and advanced disease.

As the current standard, surgery is applied to treat early-stage cervical cancer and selected post-irradiation pelvic relapses. Surgical therapy for local disease is based on a model of unlimited isotropic cancer cell propagation and dissection artifacts such as subperitoneal “ligaments” and “spaces”. For regional disease, the role of traditional surgery is diagnostic and eventually cytoreductive. However, the isotropic local tumor propagation model has to be rejected due to numerous inconsistencies with clinical facts. Likewise, the “ligament and space” approach to the subperitoneum is too crude and variable to accurately cover both local spread and intercalated lymph node metastases of cervical cancer. The ontogenetic cancer field model is fully in line with the locoregional spread patterns of carcinoma of the female genital tract. Developmentally derived (ontogenetic) anatomy enables unbiased and accurate dissection of the complex tissue structures within the subperitoneum. Cancer field surgery founded on these insights has a high potential to improve the treatment outcome of cervical carcinoma.

Aim: The aim of this study was to evaluate the impact of MRI performed three months after treatment on further follow-up interventions and outcome in patients with uterine cervical carcinoma treated with definitive chemoradiotherapy.

Methods: Sixty consecutive women diagnosed with uterine cervical cancer FIGO 2009 stage IB1-IVA during 2011-2012 treated with definitive chemoradiotherapy/radiotherapy with curative intent at the Department of Gynaecological Oncology at Karolinska University Hospital were retrospectively included. A review of MRI reports and medical records with focus on follow-up interventions associated to imaging was performed.

Results: On follow-up MRI three months post treatment, 29/60 women had complete remission (mrCR), 24/60 women had partial remission (mrPR) and 7/60 had progressive disease (mrPD). In patients with mrCR, no additional procedures were performed. The group with mrPR had 27 additional MRIs, 3 PET/CT examinations and 9 biopsy procedures, none leading to diagnosis of residual tumour. Locoregional control rate was 96% after 6.5 months (median). No patient had cervical relapse only; 2/53 had cervical relapse in combination with non-regional lymph nodes and distant relapse. There was no statistically significant difference in overall survival between patients with mrCR and mrPR (HR = 2.2, P = 0.21).

Conclusion: Patients with residual changes on MRI at three months post treatment have a low risk for locoregional recurrence. If this is not recognised, follow-up MRI results in unnecessary additional procedures with low impact on treatment outcome. Further studies are needed regarding the most appropriate imaging modality and timing of post-treatment evaluation.

Natural killer (NK)/T cell lymphoma includes two major subtypes of disease, specifically extranodal NK/T cell lymphoma, nasal type (ENKL) and aggressive NK cell leukemia (ANKL). Both are strongly associated with Epstein-Barr virus and are prevalent in East Asia and Latin America. Except for that of limited-stage ENKL, the prognosis of both diseases was poor in the previous decade. The advent of non-anthracycline-based chemoradiotherapy has contributed to an improvement in ENKL prognosis, but there is still room for further treatment progress. Recently, the high efficacy of PD-1 antibody was reported in relapsed or refractory ENKL patients. This was later supported by the finding that PD-L1/PD-L2 genetic alterations are frequently observed in ENKL and ANKL patients. Due to the rarity of the disease, a standard treatment for ANKL remains to be established. Currently, allogeneic stem cell transplantation is the only curative treatment, and this is even applicable to chemo-resistant ANKL patients. In this review, we focus on recent treatment approaches for NK/T cell lymphomas including novel agents.

The last decade has brought about major advances in systemic therapy for patients with advanced clear cell renal cell carcinoma. The introduction of angiogenesis targeting agents, immune checkpoint inhibitors, and combinations thereof has resulted in a multitude of therapeutic standards for patients with newly diagnosed advanced disease. With the rapid adoption and increasing number of available options for patients, selection amongst treatment regimens has become complex. Further, a new balance is also being sought to optimize treatment outcomes and limit treatment-related toxicities. With a rising bar against which novel therapeutics are being measured, the field looks toward an evolved understanding of tumor biology to help pave new ways forward for individualized therapy. Here, we review pivotal studies that led to regulatory approvals and ongoing clinical trials conducted in patients with systemically untreated clear cell renal cell carcinoma and provide perspective on how newly emerging data can be integrated into this rapidly changing landscape.

Metastasectomy was initially described in the 1970s as a therapeutic strategy for patients with metastatic renal cell carcinoma. Since that time, systemic therapy options have grown exponentially, most recently with the introduction of immunotherapy. We aimed to review the contemporary literature regarding the role of metastasectomy in the era of targeted therapy and immunotherapy. Historically, metastasectomy has benefited patients with small volume, single-organ metastases, with favorable outcomes amongst younger, healthier patients with metastases to specific sites. The interplay between the employment of metastasectomy and systemic therapy has been limited to small, retrospective series with significant patient selection bias. More recently, investigators have conducted randomized controlled trials exploring the use of targeted therapies in the adjuvant setting after metastasectomy. Initial randomized data suggested no benefit in using sorafenib in this setting, and a subsequent study demonstrated possible harm in using pazopanib after metastasectomy. However, the role of other novel systemic therapies, including immunotherapy, nor the timing of use, have been meaningfully explored. Metastasectomy appears to be a valuable therapeutic option in the properly selected patient, requiring a multi-disciplinary management strategy and, pending future trials, a multimodal treatment approach.

Malignant pleural mesothelioma (MPM) is a primary solid malignancy related to inhalational asbestos exposure. Despite advances in therapy, MPM remains challenging to treat with a post-treatment survival of only 15% at 5-year. In recent years, extra-pleural pneumonectomy has decreased in popularity due to a high morbidity rate and mortality compared to pleurectomy/decortication and other therapeutic alternatives. In this review, we will discuss both procedures, outcomes, ongoing studies, and the roles of surgery in the future treatment of this disease.

Intraoperative nerve monitoring (IONM) has evolved into an objective tool not only for the identification but also for the preservation and prognostication of function of the recurrent laryngeal nerve in thyroid surgeries. Technical improvements have resulted in the increasing incorporation of IONM into operating rooms around the world. The importance of adherence to recommended standards is also recognized as being vital in optimizing the efficacy of IONM. The advent of continuous IONM has made real-time nerve monitoring possible, thus providing the surgeon with an ally in difficult surgeries. Additionally, as thyroid surgeries are evolving into remote access and minimally invasive procedures, so also is the applicability of IONM. This review focuses on the use of IONM for nerve monitoring in thyroidectomies for neoplastic conditions while discussing the rationale, technique, and interpretation of findings and their implications.