Aim: To investigate the frequencies and trends of brain metastases (BMs) as exclusion criteria in extensive-stage small cell lung cancer (ES-SCLC) trials.

Methods: We conducted a comprehensive search to identify prospective clinical trials in patients with ES-SCLC. PubMed searches were conducted with the key words “small cell lung cancer” and “extensive”. The online archives of 20 oncology journals were also searched. Recent review articles in ES-SCLC were also investigated for additional articles. Eligible studies must have enrolled primarily ES-SCLC and been published in English. Studies involving brain/chest radiation and brain metastasis-specific trials were excluded. Studies were categorized into allowed/undefined, conditional, or complete exclusion of BM.

Results: In total, 491 published studies were identified by PubMed (240), journal websites (198), and review articles (53). Early publication year (1970-1999) and first-line/maintenance setting were associated with higher incidence of complete exclusion of cases with BMs (P < 0.0001 and 0.0233, respectively). Incidence of complete exclusion was 27% in the 1990s, and then decreased to 12% in the 2000s and 8% in the 2010s.

Conclusion: A significant number of ES-SCLC trials continues to exclude patients with BM. Future studies need to ease eligibility regarding BM according to ASCO/Friends recommendations.

Hyponatremia is a common disorder among cancer patients and is associated with a poor prognosis in several malignancies. It is classified by volemic status into hypovolemic, euvolemic, and hypervolemic hyponatremia. Clinical history, physical examination, and blood and urine tests are important for a correct classification and diagnosis of hyponatremia, to assure correct management. Treatment of hyponatremia in cancer patients depends on the etiology of hyponatremia, as well as on the chosen therapy for the tumor. Supportive care is also a factor to be taken into account.

Aim: Neuroblastoma is a pediatric cancer of the sympathetic nervous system. Using various parameters including stage of the disease, amplification status of N-Myc, DNA index and histopathology, neuroblastoma can be stratified into low- and high-risk groups. Recent advances in treatment have significantly improved the survival rate of low-risk neuroblastoma patients. However, the overall survival rate of high-risk neuroblastoma group, especially N-Myc amplified patients, is poor. Moreover, the survivors of both low- and high-risk neuroblastoma manifest adverse side effects to chemotherapy and thus their quality of life is impaired. Considering all these factors, there is an urgent need to develop therapeutic strategies with natural compounds to improve the survival rate and to reduce the side effects. In this study, we hypothesised that the mesenchymal nature of neuroblastoma cells is a reason, at least in part, for the aggressive and treatment resistant phenotype.

Methods: In order to validate our hypothesis, we used publicaly available RNA-Seq data, in vitro assays and xenograft mouse models.

Results: Using a combinatorial treatment of mesenchymal-to-epithelial inducers (curcumin or silibinin) with doxorubicin significantly increased the cell death in a panel of neuroblastoma cells in vitro. Follow up analysis in vivo, confirmed the therapeutic benefit of utilising the combination of curcumin with doxorubicin. The combinatorial therapy significantly reduced the tumor burden and increased the survival of mice implanted with high-risk neuroblastoma cells.

Conclusion: Taken together, this study shows the efficacy of using curcumin in combination with doxorubicin to improve the survival rate and has the potential to enhance the quality of life of neuroblastoma patients.

Aim: To develop a comprehensive item library of patient-reported, immunotherapy-related adverse events (irAEs) that draws from and expands on the Functional Assessment of Chronic Illness Therapy (FACIT) Measurement System.

Methods: Literature review and iterative expert input. Based on a literature review of irAEs, we developed a framework of immunotherapy classes and their associated symptoms. Clinical experts then reviewed iterations of symptom summaries and item maps linked to the immunotherapy framework. Experts provided content review and feedback was shared across experts until consensus was reached. The iterative process facilitated creation of a Primary Symptom List associated with immune checkpoint modulators (ICMs), drawn from the larger set of symptoms. Existing FACIT items were mapped to the symptom list, and new items were written as needed to create the item library.

Results: The full item library of irAEs is comprised of 239 items, covering 142 unique symptoms across 75 inflammatory reactions/immune conditions. A subset of 66 items comprises a Primary Symptom List considered most common/relevant to ICM treatment. This includes gastrointestinal, skin, pulmonary, neurologic, musculoskeletal, and multiple miscellaneous and constitutional symptoms.

Conclusion: The FACIT Immunotherapy Item Library is a compilation of 239 self-report items that capture the wide range of AEs experienced by people receiving immune treatments. A subset of 66 items comprises a Primary Symptom List meant for ICM therapy. Use of items selected from this library is encouraged in clinical research and clinical practice evaluation.

Systemic chemotherapy for peritoneal disease in ovarian carcinoma is associated with a recurrence rate of more than 75%, and most of the cases are confined to the peritoneal cavity. The propensity of locoregional treatment failure has paved the way for the discovery of cytoreductive surgery with intra-cavitary chemotherapy. Cytoreductive surgery (CRS) is the present-day treatment modality for a variety of peritoneal carcinomatosis including ovarian cancer, and multi-visceral resection is critical for completion of CRS. In cases of diaphragmatic infiltration by tumor deposits, partial resection leads to a diaphragmatic rent, which can be used for the perfusion of chemotherapeutic drugs into the pleural cavity. Disease transmission from the peritoneal to pleural cavity is a poor prognostic factor however. Hence, intrathoracic hyperthermic chemotherapy may be a reasonable treatment option for ovarian carcinoma with malignant pleural effusion or pleural deposits. Hyperthermic intraperitoneal chemotherapy (HIPEC) is added to the treatment plan in cases of complete CRS but this is a technically demanding procedure. Therefore, performing hyperthermic intrathoracic chemotherapy on top of CRS and HIPEC may be even more complicated for such advanced cancers. The technique of combining HIPEC and hyperthermic intrathoracic chemotherapy is also commonly known as hyperthermic thoracoabdominal chemotherapy (HITAC). The perioperative morbidity and mortality may be remarkably high in such scenarios. We describe our CRS technique with HITAC, which was performed in three FIGO stage IVA ovarian carcinoma patients with metastatic pleural effusion after complete CRS. The patients were retrospectively identified from a prospectively maintained database. All had partial diaphragmatic resection followed by HITAC as part of CRS treatment. Surgical techniques are outlined along with accompanying intra-operative images. Patient demographics, clinical and follow-up details were also described briefly. No comparative analysis with control patients was done. Adjustments in chemotherapy dose are not mandatory for HITAC. Of three patients, one had intrathoracic recurrence on follow-up; no mortality was recorded HITAC is a complex and potentially harmful procedure whose toxicity profile is still poorly known. Morbidity was not life-threatening and survival was acceptable.

Reliance on glycolysis for energy production is considered a hallmark of cancer and the glycolytic enzyme α-enolase is overexpressed in a range of cancer types. However, recent studies have revealed that α-enolase is involved in a variety of unrelated physiological processes and can be found in multiple unexpected cellular locations. This review focuses on the unlikely role of α-enolase as an extracellular plasminogen-binding receptor localised to the plasma membrane. Conversion of plasminogen to plasmin on the surface of cancer cells enhances their ability to invade through stroma by activating collagenases and degrading fibrin as well as extracellular matrix proteins. Increased expression of α-enolase is associated with increased migration and invasion of cancer cells, and decreased metastasis-free survival in patients with several cancer types, including non-small cell lung, pancreatic, breast and colorectal cancers. Due to its overexpression in a range of cancer types and multi-functional roles in key areas of tumour metabolism and metastasis, α-enolase may be useful as a universal cancer prognostic biomarker or therapeutic target.

Gastric cancer (GC) is the fifth most common cancer worldwide. In approximately 10% of GC cases, cancer cells show ubiquitous and monoclonal Epstein-Barr virus (EBV) infection. A significant feature of EBV-associated GC (EBVaGC) is high lymphocytic infiltration and high expression of immune checkpoint proteins, including programmed death-ligand 1 (PD-L1). This highlights EBVaGC as a strong candidate for immune checkpoint blockade therapy. Indeed, several recent studies have shown that EBV positivity in GC correlates with positive response to programmed cell death protein 1 (PD-1)/PD-L1 blockade therapy. Understanding the mechanisms that control PD-L1 expression in EBVaGC can indicate new predictive biomarkers for immunotherapy, as well as therapeutic targets for combination therapy. Various mechanisms have been implicated in PD-L1 expression regulation, including structural variations, post-transcriptional control, oncogenic activation of intrinsic signaling pathways, and increased sensitivity to extrinsic signals. This review provides the most recent updates on the multi-layered control of PD-L1 expression in EBVaGC.

The rapid advances in the understanding of oncogenic process and the maturation of affordable precision diagnostic tools have enabled the development of targeted therapeutic agents, such as those targeting BCR-ABL, epithelial growth factor receptor L858R, EML4-anaplastic lymphoma kinase, and BRAF V600E, to treat cancers that harbor specific molecular alterations. Traditionally, each targeted drug has been developed for a particular tumor type where such alteration is most frequently found. Recently, the widespread adoption of next generation sequencing has led to an increase in the identification of rare and ultra-rare alterations, and, in some cases, the same rare alterations are found across multiple tumor types. The rarity of these alterations makes clinical trials traditionally designed for specific tumor types infeasible. As a result, tissue-agnostic trials have been developed to study the efficacy of these treatments and increase patient access. This review summarizes current successful cases of tissue-agnostic development, such as drugs targeting tropomyosin receptor kinase fusions, and proposes the next wave of potential tissue-agnostic targets, including fusions of ROS1, anaplastic lymphoma kinase, fibroblast growth factor receptor, and rearranged during transfection. In addition, the advantages and the challenges of such approach are discussed in the context of clinical development and approval.

Aim: Human stem cell-derived extracellular vesicles (EV) provide many advantages over cell-based therapies for the treatment of functionally compromised tissue beds and organ sites. Here we aimed to highlight multiple administration routes for the potential treatment of various forms of brain injury.

Methods: Human neural stem cell-derived EV were isolated from conditioned media and administered via three distinct routes: intrahippocampal transplantation, retro-orbital vein injection, and intranasal. EV were administered after which brains were evaluated to determine the capability of EV to translocate into normal tissue.

Results: Data showed no significant differences in the amount of EV able to translocate across the brain, indicating the functional equivalence of each administration route to effectively deliver EV to the brain parenchyma.

Conclusion: Findings show that both systemic administration routes (retro-orbital vein or intranasal delivery) afforded effective penetrance and perfusion of EV throughout the brain in a minimally invasive manner, and point to a translationally tractable option for treating certain neurological disorders including those resulting from cranial irradiation procedures.

Prostate cancer (PCa) is the leading cause of cancer death in men. With more therapeutic modalities available, the overall survival in PCa has increased significantly in recent years. Patients with relapses after advanced second-generation anti-androgen therapy however, often show poor disease prognosis. This group of patients often die from cancer-related complicacies. Multiple approaches have been taken to understand disease recurrence and to correlate the gene expression profile. In one such study, an 11-gene signature was identified to be associated with PCa recurrence and poor survival. Amongst them, a specific deubiquitinase called ubiquitin-specific peptidase 22 (USP22) was selectively and progressively overexpressed with PCa progression. Subsequently, it was shown to regulate androgen receptors and Myc, the two most important regulators of PCa progression. Furthermore, USP22 has been shown to be associated with the development of therapy resistant PCa. Inhibiting USP22 was also found to be therapeutically advantageous, especially in clinically challenging and advanced PCa. This review provides an update of USP22 related functions and challenges associated with PCa research and explains why targeting this axis is beneficial for PCa relapse cases.

A 70-year-old female with metastatic cutaneous squamous cell carcinoma (cSCC) and low-grade non-Hodgkin’s lymphoma, not amenable to cisplatin combination therapy, was treated with cyclophoshamide (Cyc)-fluorouracil (FU)-interleukin-2 (IL-2) in light of high tumor immunogenicity and the potential activity of this regimen. Cyc 300 mg/m² and FU 500 mg/m² intravenously on day 1 and IL-2 4.5 MIU/day on days 3-6 and 17-20 subcutaneously every 4 weeks; Carboplatin (C) AUC 2 and paclitaxel (P) 85 mg/m² on days 1, 8 and 15 ± capecitabine (Cape) every 4 weeks. After partial remission (PR) of lung metastases and local control with two cycles of first therapy followed by PR with five cycles of CP ± Cape, right mastectomy was performed with evidence of viable tumor. Subsequently, the patient underwent 3 cycles of chlorambucil and is alive after 13 months of follow-up. Safety and activity of chemo-immunotherapy and salvage treatment can be achieved in cSCC.

Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related deaths in the Western world. Despite progress made with targeted therapies and immune checkpoint inhibitors, the vast majority of patients have to undergo chemotherapy with platinum-based drugs. To increase efficacy and reduce potential side effects, a more comprehensive understanding of the mechanisms of the DNA damage response (DDR) is required. We have shown that overexpression of the scaffold protein RAN binding protein 9 (RANBP9) is pervasive in NSCLC. More importantly, patients with higher levels of RANBP9 exhibit a worse outcome from treatment with platinum-based drugs. Mechanistically, RANBP9 exists as a target and an enabler of the ataxia telangiectasia mutated (ATM) kinase signaling. Indeed, the depletion of RANBP9 in NSCLC cells abates ATM activation and its downstream targets such as p53 signaling. RANBP9 knockout cells are more sensitive than controls to the inhibition of the ataxia and telangiectasia-related (ATR) kinase but not to ATM inhibition. The absence of RANBP9 renders cells more sensitive to drugs inhibiting the Poly(ADP-ribose)-Polymerase (PARP) resulting in a “BRCAness-like” phenotype. In summary, as a result of increased sensitivity to DNA damaging drugs conferred by its ablation in vitro and in vivo, RANBP9 may be considered as a potential target for the treatment of NSCLC. This article aims to report the results from past and ongoing investigations focused on the role of RANBP9 in the response to DNA damage, particularly in the context of NSCLC. This review concludes with future directions and speculative remarks which will need to be addressed in the coming years.

Liquid biopsy has become an emerging technology in the detection of cancer related biomarkers as well as the continuous monitoring of cancer treatment. There has been extensive research on the applications of magnetic nanotechnologies in liquid biopsies from the separation of target analytes to the detection of cancer biomarkers. Magnetic separation plays an important role in increasing both the efficiency and sensitivity of the liquid biopsy process. The detection of cancer biomarkers through magnetic nanosensors also possesses many advantages such as low background noise, high sensitivity, short assay time, and the ability to detect multiple biomarkers at the same time. This review focuses on the recent advances of magnetic nanotechnologies in liquid biopsies for cancer detection and its future potential in comparison with other technologies.

Although prostate epithelium concentrates zinc for the purpose of promoting citrate secretion, it loses its capacity to import zinc while undergoing malignant transformation. This exclusion of zinc may be necessary for the viability of prostate cancer, as measures which increase the intracellular zinc content of prostate cancers lead to cell death, oxidative stress, and a marked reduction in ATP, suggestive of mitochondrial damage. The anti-fungal drug clioquinol, which can act as a zinc ionophore, can markedly slow the growth of human prostate cancer in nude mice, and has been proposed as a clinical therapy for prostate cancer. However, clioquinol is currently only available as a topical agent, as it was linked to subacute myelo-optic neuropathy with oral use. A more practical option for promoting zinc transport may be offered by the nutraceutical zinc dipicolinate, a stable chelate in which four coordination positions of zinc are occupied by two molecules of the tryptophan metabolite picolinic acid. Zinc dipicolinate is a highly effective supplemental source of zinc that has been shown to be more potent than soluble zinc salts for alleviating the symptoms of acrodermatitis enteropathica, a genetic zinc deficiency disorder reflecting homozygous loss of functional ZIP4 zinc importers in enterocytes. This suggests that the zinc dipicolinate complex is sufficiently stable and lipophilic to transfer zinc across cellular membranes. If so, it may have potential for “smuggling” zinc into prostate cancer cells. Hence, cell culture and rodent studies to evaluate the impact of zinc dipicolinate on human prostate cancer are warranted.

Long-term genetic studies utilizing backcross and congenic strain analyses coupled with positional cloning strategies and functional studies identified Cdkn2a, Mtor, and Mndal as mouse plasmacytoma susceptibility/resistance genes. Tumor incidence data in congenic strains carrying the resistance alleles of Cdkn2a and Mtor led us to hypothesize that drug combinations affecting these pathways are likely to have an additive, if not synergistic effect in inhibiting tumor cell growth. Traditional and novel systems-level genomic approaches were used to assess combination activity, disease specificity, and clinical potential of a drug combination involving rapamycin/everolimus, an Mtor inhibitor, with entinostat, an histone deacetylase inhibitor. The combination synergistically repressed oncogenic MYC and activated the Cdkn2a tumor suppressor. The identification of MYC as a primary upstream regulator led to the identification of small molecule binders of the G-quadruplex structure that forms in the NHEIII region of the MYC promoter. These studies highlight the importance of identifying drug combinations which simultaneously upregulate tumor suppressors and downregulate oncogenes.

Glioblastoma multiforme is considered one of the most common malignant primary intracranial tumors. Despite treatment with a combination of surgery, chemotherapy and radiotherapy, patients with glioblastoma multiform have poor prognosis. It has been widely accepted that the occurrence, progression, and even recurrence of glioblastoma multiforme strictly depends on the presence of glioma cancer stem cells. The presence of glioma stem cells reduces the efficacy of standard therapies, thus increasing the imperative to identify new targets and therapeutic strategies in glioblastoma patients. In this regard, the p21^Cip1 pathway has been found to play an important role in the maintenance of the glioma stem cells. It has been shown that this pathway regulates cancer stem cell pool by preventing hyperproliferation and exhaustion. MicroRNAs, endogenous small non-coding RNAs, and long non-coding RNAs, regulate post-transcription gene expression. These are not only altered in glioma, but also in other cancer types, and are involved in tumor development and progression. Notably, they have also been shown to modulate the expression of proteins in the p21^Cip1 signaling pathway. This review highlights the extent and complexity of cross-talk between microRNAs, long non-coding RNAs and the p21^Cip1 pathway, and demonstrates how such interplay orchestrates the regulation of protein expression and functions in glioma and glioma stem cells.

Aim: Nephrilin peptide modulates systemic immune responses to trauma in contexts characterized by simultaneous inflammation and immunosuppression. This study explores the possibility that nephrilin peptide may modulate lung metastasis, which also occurs in an environment of concurrent inflammation and immunosuppression.

Methods: B16MET melanoma cells were injected via the tail vein of mice and the development of lung metastases was recorded in animals treated with nephrilin peptide or vehicle by subcutaneous bolus injection daily for three weeks. In a separate experiment, nephrilin was administered by subcutaneous bolus injection for seven days to study the biodistribution of peptide and possible changes to plasma cytokine levels.

Results: Nephrilin significantly suppressed B16MET lung metastases. Suppression was more effective in deep lobes with the poorest access to circulation: accessory > inferior > middle > superior. In a separate biodistribution study in mice, nephrilin showed similar biodistribution levels in kidney, liver, brain, and left lung, but significantly higher accumulation in the lobes of the right lung in a gradient that matched its effectiveness in suppressing metastases (accessory > inferior > middle). The latter environments were also characterized by significantly higher local concentrations of succinate, a proxy for lower levels of oxygenation.

Conclusion: Nephrilin accumulates preferentially in the deep lobes of the right lung in mice and inhibits B16MET right lung metastases in a lobe-specific manner.

Aim: Cardiovascular disease is a leading cause of mortality among long-term cancer survivors treated with large total doses of doxorubicin. An increase in coronary artery disease (CAD) among childhood cancer survivors by age 45 has been observed and is driven by primarily anthracycline chemotherapy and to a lesser extent chest radiation that includes the heart in the radiation field. The risk factors and associated chronic diseases (hypertension, etc.) are well known for CAD and can be often prevented or treated, thus reducing the risk of CAD in these patients. We piloted a risk-based survivorship clinic in an academic medical center to characterize the distribution of risk factors for CAD and improve the quality of life in a population of sarcoma survivors treated with doxorubicin.

Methods: We followed a prospective cohort of sixty-one survivors of bone and soft tissue sarcoma treated with doxorubicin chemotherapy (> 400 mg/m²) and at least 2 years post-therapy attending the sarcoma survivorship clinic. We collected clinical, demographic data, and patient reported outcomes via PROMIS questionnaires annually.

Results: We demonstrated a high burden of chronic diseases in this population. Among six chronic conditions that are known risk factors for CAD (hypertension, diabetes, obesity, chronic inflammation, kidney disease and dyslipidemia), more than one-fourth (26%, 16/61) of patients had three or more of these risk factors at baseline visit, and 49% (30/61) had two or more.

Conclusion: The results of this pilot study support the presence of modifiable CAD risk factors in this population of sarcoma survivors. Evidence-based guidelines for high-risk survivors of rare cancers are needed.

Aim: A significant fraction of mortalities from non-small cell lung cancer could be prevented, if the cancer would be diagnosed earlier. Nanobiosensors for the ultrasensitive detection of active proteases in serum were designed to detect a significant protease activity signature of non-small cell lung cancer (stage I and higher).

Methods: We determined the activity of nine protease biomarkers in the sera of non-small cell lung cancer patients and compared them with the protease activities of a control group of healthy human subjects using optical nanobiosensors. They consist of a central Fe/Fe₃O₄ core/shell nanoparticle with an attached Fluorescence resonance energy transfer-pair [tetrakis-carboxyphenyl porphyrin (TCPP) and cyanine 5.5]. TCPP is attached to the central nanoparticle via a protease-cleavable tether, whereas cyanine 5.5 is tethered permanently to the dopamine-layer surrounding the nanoparticle.

Results: Based on the activity pattern of urokinase plasminogen activator, matrix metalloproteinases 1, 2, 3, 7, 9, and 13, and cathepsins B and L as well, non-small cell lung cancer could be detected at stage I by means of a liquid biopsy.

Conclusion: This feasibility study, comprising 33 non-small cell lung cancer patients and 20 apparently healthy subjects, clearly demonstrated the feasibility of minimally invasive early diagnosis of non-small cell lung cancer, starting with stage I.

Epidemiological evidence has highlighted the association of specific diets and a lower incidence of cancer. Foremost, the Mediterranean diet provides high levels of polyphenolics and a high consumption of healthier fats, e.g., as from olive oil. In the Mediterranean region the consumption of vegetables is elevated providing a class of compounds, the isothiocyanates (ITCs) as found in the cabbage family. The ITCs have raised great interest for their health benefits over the past few decades. Some of the key ITC compounds, sulforaphane, phenethylisothiocyanate and benzyl isothiocyanate, have been studied in vitro and in vivo and the data support their promise for cancer chemoprevention, as anti-tumor agents, and for chemoprotection of normal tissues and organs. Along with other polyphenolic compounds in the diet, in general, they also possess key anti-inflammatory properties thus satisfying the criteria for compounds that could intervene in cancer initiation and progression. In this review we provide a larger overview of the advantages of including ITCs in the diet as food or as supplements and speculate on what could constitute a valuable therapeutic strategy for improving and sustaining good health and countering cancer disease in humans.

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.

Epithelial-mesenchymal transition (EMT) is a natural phenomenon thatoccurs during embryodevelopment. It is a phenomenon involving the transition of adherence-dependent stationary epithelial cells to adherence-independent migratory mesenchymal cells. Tumours reactivate this machinery and evade anti-tumour immunity and inhibition by cancer-specific drugs. EMT harnesses complex crosstalk among cancer cell signalling pathways that make it difficult to tackle therapeutically, and it plays a pivotal role in cancer metastasis. Most screening platforms and approved drugs are limited by their applicability to epithelial cancers. There is a significant need for developing new strategies targeting metastatic cancers. Here, we review the challenges with the current methods of screening and available drugs for EMT and shed some light on the key essentials needed for next-generation drug discovery attempts.

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.

Aim: Small-cell lung cancer (SCLC) disseminates aggressively and may exhibit high chemoresistance and poor survival rates. In this study, we aimed to investigate a new mechanism of drug resistance for SCLC circulating tumor cells (CTCs).

Methods: SCLC CTC cell lines (n = 4) which shed cellular fragments (MAT), as demonstrated by light and scanning electron microscopy, are compared to permanent SCLC lines. Selected proteins are detected by proteome arrays and the functional impact of MAT is studied using cytotoxicity tests involving cisplatin and Topotecan.

Results: The SCLC CTC lines revealed layers of attached cellular fragments with a range of decreasing sizes from intact cells (approximately 12 µm) down to small debris (approximately 2 µm) which are not detectable in permanent SCLC lines. Intact SCLC CTC clusters represent cores of these fragment-coated spheroids. Proteome profiling of MAT revealed a protein pattern similar to intact cells. Chemosensitivity tests employing SCLC and SCLC CTC lines with chemotherapeutics used in therapy of SCLC demonstrated an inhibitory activity of MAT on the resulting cytotoxicity.

Conclusion: Generation of cell-associated debris by SCLC CTCs offers protective effects against cytotoxic drugs, representing a novel mechanism allowing survival of SCLC CTCs in patients.

Pancreatic ductal adenocarcinoma (PDAC) is currently the fourth most common cause of cancer-related deaths in the United States. It has a poor prognosis and remains a difficulty to treat malignancy. Over the past several decades, significant efforts have been directed towards developing new approaches to enhance the efficacy of therapeutic regimens for PDAC treatment. In recent years, the measurement of serum carbohydrate antigen 19-9 (CA 19-9) has become one of the most validated and extensively used tumour biomarkers for PDAC. In particular, serum CA 19-9 levels have been explored as a validated tool to predict either the signs of disease progression or the response to treatment. However, despite its clinical relevance, the implications on diagnosis or accurately predicting tumour resectability, and monitoring disease symptoms in PDAC patients remains limited. This current review highlights the recent updates on the applicability of CA 19-9, its exploitation, and challenges in predicting the treatment efficacy and responses in PDAC patients.

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.

Phytochemicals derived from dietary sources and natural products have gained significant attention in the scientific community due to their ability to modulate various pharmacological and biological activities. Understanding the molecular mechanisms by which natural products protect against various diseases including cancer will provide the basis for both clinical use and further chemical modification to develop targeted therapy. Autophagy, an evolutionarily conserved self-digestion process that employs lysosomal-mediated enzymatic degradation has a functional role in a wide range of pathological disorders, and has attracted oncology scientists over the past two decades. Studies employing natural products have shown that induction of autophagy may be either cytoprotective or cytotoxic governed by different molecular pathways. In this review, we summarize four major phytochemicals namely phenethyl isothiocyanate, capsaicin, withaferin A, genistein and their association with autophagy in cancer chemoprevention. We also discuss ideas for further investigation essential to understanding their mechanisms, which will guide their clinical applications for cancer prevention and treatment.

Liquid biopsy (LB) is an emerging tool for the evaluation of relapse in several cancers and nowadays is used in lung cancer for primary detection and molecular characterization when tumoral tissue is not available. It can represent an innovative biospecimen for the screening, diagnosis, and monitoring of all types of cancer and for monitoring of therapeutic efficacy. LB includes several biofluids such as blood, urine, peritoneal fluid/lavage, and analytes (circulating tumor cells, circulating tumor DNA, long noncoding RNA, microRNA, vesicles, mRNA, and protein) that can play different roles in diagnosis, prognosis, and patient management as well as in the improvement of the knowledge of cancer evolution. Endometrial cancer (EC) is a tumor usually detected at low stage with a good prognosis, but few low risk cases, unexpectedly, can evolve to bad prognosis. Up to now, no molecular target exists to treat advanced stage or to define the evolution of low stage EC. This review focuses on how the LB may help in the management and characterization of patients affected by EC.

Exosomes, nanovesicles of endocytic origin, are secreted by most cell types; cancer cells representing no exception. Exosomes facilitate intercellular communication as they deliver diverse proteins, mRNA, miRNA and lipids. In this review, we discuss how exosomes represent one of the main risks associated with cancer but also one of the most promising new tools to fight it. Exosomes appear to function as signalling molecules between the tumour microenvironment, i.e., the complex of both cancer and stromal cells, and the rest of the body. Cancer-derived exosomes have been shown to drive the initiation and progression of metastasis, by transporting their cargoes to target tissues. In this respect, exosomes are implicated in cancer progression, dissemination and therapy resistance. However, exosomes are also emerging as a key tool in precision medicine, pivotal for cancer liquid biopsy in early diagnosis and for assessing when there is a recurrence. Profiling exosomal cancer-derived nucleic acids by ultrasensitive next-generation sequencing along with mapping the protein profile utilizing high-throughput proteomics will allow earlier cancer detection, therapeutic stratification and monitoring of response to therapy. Exosomes are also a promising new tool for cancer immunotherapy. Clinically utilizing exosomes for these applications in cancer diagnosis and therapeutics will be the next challenge.

Metastasis, tumor progression, and chemoresistance are the major causes of death in patients with pancreatic ductal adenocarcinoma (PDAC). Tumor dissemination is associated with the activation of an epithelial-to-mesenchymal transition (EMT) process, a program by which epithelial cells lose their cell polarity and cell-to-cell adhesion, and acquire migratory and invasive abilities to become mesenchymal stem cells (MSC). These MSCs are multipotent stromal cells capable of differentiating into various cell types and trigger the phenotypic transition from an epithelial to a mesenchymal state. Therefore, EMT promotes migration and survival during cancer metastasis and confers stemness features to particular subsets of cells. Furthermore, a major problem limiting our ability to treat PDAC is the existence of rare populations of pancreatic cancer stem cells (PCSCs) or cancer-initiating cells in pancreatic tumors. PCSCs may represent sub-populations of tumor cells resistant to therapy which are most crucial for driving invasive tumor growth. These cells are capable of regenerating the cellular heterogeneity associated with the primary tumor when xenografted into mice. Therefore, the presence of PCSCs has prognostic relevance and influences the therapeutic response of tumors. PCSCs express markers of cancer stem cells (CSCs) including CD24, CD133, CD44, and epithelial specific antigen as well as the drug transporter ABCG2 grow as spheroids in a defined growth medium. A major difficulty in studying tumor cell dissemination and metastasis has been the identification of markers that distinguish metastatic cancer cells from cells that are normally circulating in the bloodstream or at sites where these cells metastasize. Evidence highlights a linkage between CSC and EMT. In this review, The current understanding of the PCSCs, signaling pathways regulating these cells, PDAC heterogeneity, EMT mechanism, and links between EMT and metastasis in PCSCs are summarised. This information may provide potential therapeutic strategies to prevent EMT and trigger CSC growth inhibition and cell death.

Melanoma and non-melanoma cutaneous malignancies are some of the leading causes of cancer-related death in the United States. Though melanoma is more known to have a high mortality rate, the total mortality per year is nearly equal for between melanoma and non-melanoma skin cancer. Moreover, the non-melanoma types of cutaneous malignancies have potential to become locally invasive and even metastasize with very little to no treatment options when advanced. The development of these malignancies involves various genetic pathways through the four hallmarks of cancer development: malignant cell growth, apoptosis evasion, the use of supporting stroma and vascularization, and modulating and promoting an inadequate immune response. The genetic signaling pathways of basal cell carcinoma, squamous cell carcinoma, verrucous carcinoma, basosquamous cell carcinoma, melanoma, and cutaneous T-cell lymphoma interact with each other through genetic predisposition as well as with environmental exposures. Furthermore, solar ultraviolet radiation and chronic inflammatory states are found to initiate the progression of many of these cutaneous malignancies. This paper includes validated models of genetic pathways, emerging pathways, and crosstalk between genetic pathways through the four hallmarks of cancer development. Moreover, unlike most reviews addressing oncogenetics of the well-recognized, as well as newly discovered, genetic pathway mutations, this review stresses that these pathways are not fixed but rather exist in dynamic, interrelated, interactive, complex, and adaptive flux states.

Head and neck squamous cell carcinoma (HNSCC) is the 6th most frequently diagnosed malignancy and accounts for about 5% of all malignancies worldwide. There is a lack of biomarkers to monitor the status and progress of the disease. Therefore, it is of great importance to develop non-invasive diagnostic tools such as exosomes that monitor tumor changes and provide molecular information about the malignancy to identify the metastatic disease earlier and allow better therapeutic management. Thus, we aimed to review whether tumor-derived exosomes can predict disease progression in HNSCC and if and especially how they can be used as a diagnostic tool.

With the widespread use of immunotherapy in numerous solid tumours, immunotherapy-related adverse events (irAEs) have started to emerge and bring new challenges for clinicians to manage. Among established irAEs, dermatologic toxicity is one of the most common toxicities; it is often mild but can be severe and potentially life-threatening, such as bullous pemphigoid. Here, we report a case of nivolumab-mediated severe, extensive, refractory bullous pemphigoid involving both skin and oral mucosa in a patient with metastatic renal cancer. We also summarise a list of selected case reports of immunotherapy-induced bullous pemphigoid by literature review. We highlight various presentations, investigations and managements of this type of skin irAEs. Meantime, we would like to discuss the correlation of skin irAEs incidence rate with immunotherapy drug benefit and resistance.

Patients with leptomeningeal metastases (LM) from non-small cell lung cancer (NSCLC) have a poor outcome with survival of less than 1 year regardless of advancements in treatment strategy. In the past, some randomized clinical trials have been conducted with heterogeneous inclusion criteria, diagnostic parameters, response evaluation and primary endpoints. Efforts to develop a standardized magnetic resonance imaging (MRI) assessment and liquid biopsy techniques to monitor disease evolution in plasma or cerebrospinal fluid (CSF) are underway. This review aims to cover the main clinical and diagnostic challenges of LM from NSCLC, in particular the role of MRI, CSF cytology and liquid biopsy for the diagnosis and monitoring of the disease, as well as the most recent clinical trials on targeted therapies. Targeted therapy, such as epidermal growth factor receptor tyrosine kinase inhibitors and anaplastic lymphoma kinase rearranged inhibitors, represent a feasible treatment with encouraging results in terms of disease control and survival. For ineligible patients, immune checkpoint inhibitors could represent a therapeutic option with acceptable tolerance, although clinical trials focused on LM from NSCLC are lacking and represent a research focus for the future.

Cancer is one of the leading causes of mortality and morbidity globally. Many types of cancer treatments have been developed, such as chemotherapy, surgery, radiotherapy, and immunotherapy. However, these therapies can also kill healthy cells and lead to severe side effects. Therefore, scientists are looking for new strategies to eliminate cancerous cells specifically. Exosomes, nanometer-sized lipid bilayer-enclosed vesicles secreted from various cell types, exist in nearly all body fluids, including blood, breast milk, saliva, urine, bile, pancreatic juice, cerebrospinal, and peritoneal fluids. They carry myriad donor cell-derived bioactive molecules such as proteins, lipids, and RNAs (including microRNA and lncRNA) and can deliver them to both nearby and distant recipient cells. Due to these characteristics, exosomes have attracted great interest in cancer treatment (especially serving as a biological carrier for some drugs, microRNA, lncRNA, inhibitors, and antibodies). In this paper, we will review the current knowledge of exosome therapeutic applications in cancer.

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.

It is estimated that approximately 80%-90% of pancreatic ductal adenocarcinoma (PDAC) will present with unresectable disease with about half of patients presenting with distant metastases. The prognosis of these patients is generally poor with an average life expectancy of approximately 6 months and a median 5-year survival of 1%. The current standard of care for metastatic PDAC patients is palliative chemotherapy, as surgery in this setting does not lead to better survival. More recently, some centers have utilized very specific patient selection to perform resection of oligometastatic disease with reported improvement in survival - with many centers using response to systemic therapy as a sign of favorable biology. We performed a literature review investigating the role of surgical resection of oligometastatic disease of the lung and liver in PDAC.

Mammalian cells have the ability to respond to a myriad of diverse extracellular stimuli that modulate cell function. This often involves ligands binding to cell surface receptors and subsequent activation of intracellular signaling pathways. These pathways can lead to changes in gene expression patterns that in turn regulate cell growth, differentiation, migration, and function. One important type of cell surface receptor is the receptor tyrosine kinase (RTK). In response to in response to ligand binding, RTKs dimerize, then trans-phosphorylate each other, leading to activation of downstream pathways. While the signaling proteins in these pathways are important for normal cell growth control, when improperly regulated they can lead to uncontrolled growth and sometimes cancer. For this reason, they are often considered to be good candidates for drug targets for chemotherapeutic drugs. RTKs can activate multiple different signaling pathways. Some of the signaling proteins in these pathways can have crosstalk with other RTK activated pathways, and some of them can be activated by multiple mechanisms in addition to activation by RTKs. While there is a wide array of different signaling proteins and pathways activated by RTKs, in this review we will discuss components of several key pathways including the MAPK pathway, the Her2/Neu pathway, mTOR, and Pak kinases. We provide an overview of the roles for these pathways in cell signaling and discuss how different components of these pathways are being considered as targets for cancer treatment.

The unending morbidity and mortality that results from cancer, as well as adverse reactions due to chemotherapy and the enormous economic burden of treatment and hospitalization, advocates for the necessity of chemopreventive measures. Cancer chemoprevention refers to the use of agents capable of reversing, reducing, or slowing down the pathology of cancer at various stages. Fortunately, a few therapeutic drugs with relatively low toxicity (e.g., tamoxifen, finasteride), and a sparse number of vaccines (hepatitis B, HPV), are used to prevent specific cancers. In the general population, however, therapeutic options for cancer prevention are not common. Nonetheless, it is generally agreed that diet affects the genesis of cancer, and phytochemicals have the capacity of functioning as cancer chemoprevention agents. This is supported by epidemiological studies and clearly documented with animal models designed to mimic human carcinogenesis. Additionally, some public health strategies, such as recommendations for greater consumption of fruits and vegetables, reflect the merits of cancer chemoprevention. Here, we focus on some well-established natural product cancer chemopreventive agents, including resveratrol (grapes), epigallocatechin-3-gallate (green tea), sulforaphane (cruciferous vegetables), anthocyanins (grapes and berries), curcumin (turmeric), silibinin (milk thistle), and lycopene (tomatoes). As aptly demonstrated by genomic analysis and other methods, the mechanistic underpinning is variable and complex. In addition, responses may be mediated through indirect mechanisms, such as interaction with the microbiome. Furthermore, ancillary applications of chemopreventive agents are worthy of consideration, such as management of sequelae induced by chemotherapy. Recognizing the loss of millions of cancer patients every year, it is obvious that negating malignant metastatic conditions remains of paramount importance. In meeting this objective, cancer chemoprevention offers great promise.

Aim: Lung metastasis is a leading cause of death in patients with osteosarcoma (OS). No effective therapy exists that improves the five-year overall survival rate of OS patients with metastasis. Therefore, finding novel therapeutic targets will help develop new treatment strategies for OS patients with lung metastasis.

Methods: Based on analysis of gene expression profiles between sublines of the Dunn OS LM8 cell line with high (LM8-H) and low (LM8-L) metastatic ability, we have identified Wnt signal-related genes that play an important role in lung metastasis of OS. Function of the genes was investigated by establishing sublines of gene knockout and assessing their metastatic ability using a mouse lung metastasis model. The molecular mechanism underlying the function of the genes was further investigated by in vitro experiments.

Results: We have identified that receptor tyrosine kinase-like orphan receptor 2 (ROR2), a receptor of the non-canonical Wnt signaling pathway, was involved in OS cell survival in lung capillaries during metastasis. LM8-H knocked out of Ror2 (H/Ror2-KO) significantly reduced lung metastasis by decreasing the viability in lung capillaries 48 h after intravenous injection. In vitro study revealed that ROR2 increased anoikis resistance through AKT activation. Reconstitution of ROR2 expression in H/Ror2-KO cells restored their metastatic ability and viability in lung capillaries.

Conclusion: The results demonstrate a novel ROR2 function in OS lung metastasis and may inform new treatment strategies for OS patients.

A survey of the current literature on natural isoflavones and their biological activity is presented. This subcategory of a large group of plant polyphenolics has particular characteristics, structural as well as pharmacological, which makes it suitable for discussion of pleiotropic activities of phytochemicals and their exploitation in healthcare, beyond the concept of selectively targeted new drugs for narrow therapeutic indication.

Surface tumors of the bone are broadly defined as a diverse group of osteogenic and chondrogenic benign and malignant neoplasms that arise adjacent to the outer surface of cortical bone. They may be a cause of diagnostic difficulty due to a degree of histological overlap, rarity, and nomenclature. In this review we summarize the different histological types of primary malignant tumors of bone surface, namely, secondary peripheral chondrosarcoma, periosteal chondrosarcoma, parosteal osteosarcoma, dedifferentiated parosteal osteosarcoma, periosteal osteosarcoma, and high-grade surface osteosarcoma. We provide a comprehensive updated review of their pathogenesis and highlight radiological, macroscopic, and histopathological features and recently available ancillary diagnostic tools that may aid in the differential diagnosis.

Small cell lung cancer (SCLC) is an aggressive subtype of neuroendocrine tumor. It is characterized by a rapid doubling time and early development of metastatic disease. Despite being responsive to initial chemotherapy, most of the patients will have relapse of the disease within a few months. The prognosis of SCLC is dismal with a 5-year survival rate of less than 5%. For that reason, management of SCLC has been an active area of research. The utilization of immunotherapy has provided promising results in treatment of SCLC in the front-line setting. Therefore, utilization of immunotherapy and targeted therapy is being studied in the setting of relapsed/refractory disease, and currently, different clinical trials are exploring new drugs and further options. In this review, we will explore the latest updates in management of relapsed/refractory SCLC.

Bone and soft tissue sarcomas are malignant neoplasms probably originating from musculoskeletal and mesenchymal progenitor cells. More than 80 different histopathological subtypes are encountered in orthopedics. The standard of care for sarcoma patients involves a multidisciplinary combination of surgery, anthracycline-based multiagent chemotherapy and radiation. Unfortunately, these are associated with adverse events and occasionally disappointing outcomes. Various genomic-, biologically-, and immunologically-based therapies are still under evaluation in early-phase clinical trials. However, there are strong barriers to the development and clinical translation of new therapeutic modalities. This is due to the rarity of these diseases, the broad spectrum of tumor subtypes with genetic and biological heterogeneity, and the wide variability in clinical manifestation, response to treatment and prognosis. A potential approach toward overcoming this barrier is to identify therapeutic targets that cover multiple sarcoma types. Glycogen synthase kinase 3β (GSK3β) has emerged as a common therapeutic target in more than 25 different cancer types. Here we review the evidence for tumor-promoting roles of GSK3β in the major types of bone and soft tissue sarcomas including osteosarcoma, rhabdomyosarcoma, synovial sarcoma, and fibrosarcoma. In this review, we describe the therapeutic effects of inhibiting GSK3β in these sarcoma types, while also protecting healthy cells and tissues from detrimental effects associated with conventional therapies, such as doxorubicin-induced cardiotoxicity. Consequently, we highlight GSK3β as a potential therapeutic target spanning multiple sarcoma types.

Glioblastomas are highly aggressive brain tumors that can persist after exposure to conventional chemotherapy or radiotherapy. Nitric oxide (NO) produced by inducible NO synthase (iNOS/NOS2) in these tumors is known to foster malignant cell proliferation, migration, and invasion as well as resistance to chemo- and radiotherapy. Minimally invasive photodynamic therapy (PDT) sensitized by 5-aminolevulinic acid (ALA)-induced protoporphyrin IX (PpIX) is a highly effective anti-glioblastoma modality, but it is also subject to NO-mediated resistance. Studies by the authors have revealed that glioblastoma U87 and U251 cells use endogenous iNOS/NO to not only resist photokilling after an ALA/light challenge, but also to promote proliferation and migration/invasion of surviving cells. Stress-upregulated iNOS/NO was found to play a major role in these negative responses to PDT-like treatment. Our studies have revealed a tight network of upstream signaling events leading to iNOS induction in photostressed cells and transition to a more aggressive phenotype. These events include activation or upregulation of pro-survival/pro-expansion effector proteins such as NF-κB, phosphoinositide-3-kinase (PI3K), protein kinase-B (Akt), p300, Survivin, and Brd4. In addition to this upstream signaling and its regulation, pharmacologic approaches for directly suppressing iNOS at its activity vs. transcriptional level are discussed. One highly effective agent in the latter category is bromodomain and extra-terminal (BET) inhibitor, JQ1, which was found to minimize iNOS upregulation in photostressed U87 cells. By acting similarly at the clinical level, a BET inhibitor such as JQ1 should markedly improve the efficacy of anti-glioblastoma PDT.

Angiogenesis is a word that refers to new blood vessel formation, and this process is of fundamental importance for physiological development and tissue homeostasis, as well as the genesis of several diseases, including tumors. Thus, studies carried out in the last years have shown that angiogenesis is essential for the growth of many solid tumors. Angiogenesis is also important for the growth of many hematological malignancies, including acute myeloid leukemia (AML). Endothelial cells are essential constituents of the bone marrow vascular niches, structures essential for the survival and maintenance of normal hematopoietic stem/progenitor cells. Bone marrow endothelial cells play an essential role in leukemia development and there is growing evidence that a targeting of both leukemic and endothelial cells of the leukemic vascular niche may improve the efficacy of antileukemic therapies. Bone marrow angiogenesis is frequently increased in AML, is morphologically evidenced as increased microvascular density, and is typically associated with some AML subtypes. The molecular mechanisms underlying the increased angiogenesis in some AML subtypes have been defined. In conclusion, a better understanding of angiogenesis as well as the fundamental interactions between bone marrow endothelial cells and leukemic stem cells may contribute to improve antileukemia treatments.

Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was declared a pandemic by the World Health Organisation (WHO) on 11 March 2020. The pandemic has had profound effects on healthcare systems across the world, and also poses unique challenges for oncology services. Singapore saw its first imported case of COVID-19 on 23 January 2020, and there has since been 52,000 confirmed cases and 27 deaths as of early August 2020 locally. Oncologists have a special duty to our patients to ensure patient safety and provide optimum care without undue disruption which may compromise long-term cancer-specific outcomes. We herein examine the impact that the COVID-19 pandemic has had on our clinical services, and share our experience with regards to manpower reconfiguration, infection control measures, diagnostic evaluation of patients with suspected COVID-19, oncological management of lung cancer patients, as well as changes in the education and training of juniors, from our unique position as a Medical Oncology department in Tan Tock Seng Hospital, a tertiary hospital affiliated with the National Centre of Infectious Diseases in Singapore.

Aim: Primary tumors can be divided into oncogene-addicted (e.g., lung) and non-oncogene addicted (e.g., breast). Only the former group has an Achilles-heel single gene for successful target therapy, whereas the latter has mutations of multiple causative genes. Currently, tissue biopsy used for genetic surveys do not give a complete picture of the molecular profile and clonal evolution, but only provide static information over time.

Methods: A series of 133 patients with 16 different solid tumors were enrolled. Blood samples were collected and cell-free DNA (cfDNA) was extracted. cfDNA libraries were analyzed using AVENIO circulating tumor DNA (ctDNA) Expanded Kit and Illumina NextSeq 550 for sequencing was used. In order to evaluate the clinical evolution over time, a second cfDNA analysis was performed after a mean interval of 2 months.

Results: Through the cfDNA liquid biopsy, we found 89 pathogenic variants in 54 genes. Breast, lung, and prostate cancers showed the largest number of mutated genes. TP53, PIK3CA, FGFR3, KRAS, and ERBB2 were the most frequently mutated genes among 16 different tumors. Gene distribution didn’t show any type of prevalence. In particular, every patient with disease progression seems to have a “private” combination of gene pair mutations, with TP53 as the most frequently mutated gene.

Conclusion: We showed that the clonal evolution of tumors includes a private combination of genes, regardless of tumor type. In the future, the cancer treatment can be the targeted therapy against specific tumor mutation(s). The present approach seems promising to both identify key cancer genes and follow clonal evolution over time.