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Patients with advanced-stage ovarian cancer are widely believed to have a dismal prognosis; however, around 20% of women with this disease survive beyond 12 years after treatment and are effectively cured. In this Perspectives, Steven Narod presents the case that this proportion could be substantially increased through the combination of maximal debulking surgery and intraperitoneal chemotherapy. Approximately 20% of women with advanced-stage ovarian cancer survive beyond 12 years after treatment and are effectively cured. Initial therapy for ovarian cancer comprises surgery and chemotherapy, and is given with the goal of eradicating as many cancer cells as possible. Indeed, the three phases of therapy are as follows: debulking surgery to remove as much of the cancer as possible, preferably to a state of no visible residual disease; chemotherapy to eradicate any microscopic disease that remains present after surgery; and second-line or maintenance therapy, which is given to delay disease progression among patients with tumour recurrence. If no cancer cells remain after initial therapy is completed, a cure is expected. By contrast, if residual cancer cells are present after initial treatment, then disease recurrence is likely. Thus, the probability of cure is contingent on the combination of surgery and chemotherapy effectively eliminating all cancer cells. In this Perspectives article, I present the case that the probability of achieving a cancer-free state is maximized through a combination of maximal debulking surgery and intraperitoneal chemotherapy. I discuss the evidence indicating that by taking this approach, cures could be achieved in up to 50% of women with advanced-stage ovarian cancer.

Key Points Metronomic chemotherapy relies on frequent administration of a low dose of chemotherapy Initially considered as an antiangiogenic therapy, metronomic chemotherapy is now regarded as a multi-target therapy with immunological properties, and direct effect on cancer stem cells Many clinical studies have demonstrated activity in relapsed and/or refractory disease and several randomized studies are ongoing Metronomic chemotherapy can be easily combined with drug repositioning and targeted therapies to generate more potent non-toxic regimens Combined with tumour molecular analysis, metronomic chemotherapy is poised to move towards personalized chemotherapy Metronomic therapy is a non-toxic, inexpensive strategy well-suited for global oncology Metronomic chemotherapy has undergone major advances as an antiangiogenic therapy. The discovery of the pro-immune properties of chemotherapy has established the intrinsic multitargeted nature of this therapeutic approach. André et al . describe the complex mechanisms of action of metronomic chemotherapy, and discuss the latest clinical data in both adult and paediatric populations, highlighting its potential role in the era of personalized medicine. Since its inception in 2000, metronomic chemotherapy has undergone major advances as an antiangiogenic therapy. The discovery of the pro-immune properties of chemotherapy and its direct effects on cancer cells has established the intrinsic multitargeted nature of this therapeutic approach. The past 10 years have seen a marked rise in clinical trials of metronomic chemotherapy, and it is increasingly combined in the clinic with conventional treatments, such as maximum-tolerated dose chemotherapy and radiotherapy, as well as with novel therapeutic strategies, such as drug repositioning, targeted agents and immunotherapy. We review the latest advances in understanding the complex mechanisms of action of metronomic chemotherapy, and the recently identified factors associated with disease resistance. We comprehensively discuss the latest clinical data obtained from studies performed in both adult and paediatric populations, and highlight ongoing clinical trials. In this Review, we foresee the future developments of metronomic chemotherapy and specifically its potential role in the era of personalized medicine.

As most of the population acquires access to the internet, protecting online identity from threats of confidentiality, integrity, and accessibility becomes an increasingly important problem to tackle. By definition, a network intrusion detection system (IDS) helps pinpoint and identify anomalous network traffic to bring forward and classify suspicious activity. It is a fundamental part of network security and provides the first line of defense against a potential attack by alerting an administrator or appropriate personnel of possible malicious network activity. Several academic publications propose various artificial intelligence (AI) methods for an accurate network intrusion detection system (IDS). This paper outlines and compares four AI methods to train two benchmark datasets- the KDD’99 and the NSL-KDD. Apart from model selection, data preprocessing plays a vital role in contributing to accurate solutions, and thus, we propose a simple yet effective data preprocessing method. We also evaluate and compare the accuracy and performance of four popular models- decision tree (DT), multi-layer perceptron (MLP), random forest (RF), and a stacked autoencoder (SAE) model. Of the four methods, the random forest classifier showed the most consistent and accurate results.

Response to first-line therapy is a primary determinant of outcome in patients with metastatic colorectal cancer (mCRC). In the past decade, the development of antiangiogenic and anti-EGFR biologic agents, doublet and triplet chemotherapy regimens, and combinations of these treatment modalities has created not only new first-line treatment options, but also new challenges for the management of this disease. In this Perspectives, these advances and the confusion surrounding their implications are discussed. The authors attempt to address some of the challenges in clinical decision-making and propose an algorithm for personalized allocation of first-line treatments in patients with mCRC. The response to first-line therapy is a primary determinant of outcome in patients with metastatic colorectal cancer (mCRC), for three main reasons: effective upfront therapy provides a unique opportunity to cure some patients; can be crucial in delaying disease progression and achieving symptom relief; and can improve patient eligibility for, and the effectiveness of, further treatments. In the past decade, decision-making regarding the choice of first-line therapy for mCRC has been complicated by the availability of many different options without a definitive consensus on a specific standard of care (despite major advances in categorizing predictive molecular disease subtypes). Most of the efforts of the scientific community have been directed at establishing the best biologic agent to be combined with a chemotherapy doublet, although a different branch of research has produced new data that underscore the importance of defining the optimal chemotherapy backbone. Herein, we review the key clinical trials completed in the past 10 years that have investigated and compared the use of chemotherapy doublets, triplets, and monotherapies, with or without molecularly targeted biologic agents, in the first-line treatment of patients with mCRC. Our examination of the literature led us to propose a new patient-oriented algorithm to guide clinicians' decisions on the best choice of upfront therapy for mCRC.

Patients with localized pancreatic ductal adenocarcinoma (PDAC) are best treated with surgical resection of the primary tumour and systemic chemotherapy, which provides considerably longer overall survival (OS) durations than either modality alone. Regardless, most patients will have disease relapse owing to micrometastatic disease. Although currently a matter of some debate, considerable research interest has been focused on the role of neoadjuvant therapy for all forms of resectable PDAC. Whilst adjuvant combination chemotherapy remains the standard of care for patients with resectable PDAC, neoadjuvant chemotherapy seems to improve OS without necessarily increasing the resection rate in those with borderline-resectable disease. Furthermore, around 20% of patients with unresectable non-metastatic PDAC might undergo resection following 4–6 months of induction combination chemotherapy with or without radiotherapy, even in the absence of a clear radiological response, leading to improved OS outcomes in this group. Distinct molecular and biological responses to different types of therapies need to be better understood in order to enable the optimal sequencing of specific treatment modalities to further improve OS. In this Review, we describe current treatment strategies for the various clinical stages of PDAC and discuss developments that are likely to determine the optimal sequence of multimodality therapies by integrating the fundamental clinical and molecular features of the cancer.Advances in surgical technique and chemotherapy regimens have improved the survival outcomes of patients with pancreatic cancer, although these remain dismal relative to most other solid tumours. Attempts to further improve outcomes have led to increasing research interest in neoadjuvant therapy, which is beginning to improve the outcomes of certain subgroups of patients. In this Review, the authors provide an overview of the various neoadjuvant therapy approaches for patients with pancreatic cancer, including discussions of several promising future research directions

Key Points Metronomic chemotherapy induces disease control in patients with advanced-stage breast cancer with a lower incidence of adverse events compared with conventional maximum tolerated dose chemotherapy Ideal agents to be used in metronomic chemotherapy regimens should be oral, inexpensive and well-tolerated, with no or minimal cumulative toxicity Several phase III trials on metronomic chemotherapy are ongoing and might demonstrate whether this approach will remain a niche option or assume a wider acceptance and application Most drugs used in a metronomic fashion have generic equivalents, are inexpensive, and available in oral form, which avoids costly hospital stays and intravenous injections Metronomic chemotherapy regimens combined with molecularly targeted agents might improve the therapeutic activity and avoid industry concerns regarding the use of off-patent or cheap chemotherapy drugs Metronomic protocols should be guided by molecular data as the genetic and epigenetic landscape of a given tumour can be markedly different at diagnosis, post-treatment and at relapse Metronomic chemotherapy has shown promising efficacy and minimal toxicity in patients with advanced-stage breast cancer. Moreover, the low cost of this regimen represents an opportunity for its expanded utilization, especially in developing countries. In this Review, the authors discuss the key clinical advances, including new trial design, appropriate patient and end point selection, and the evolving rationale for metronomic chemotherapy combinations. Over 15 years ago, low-dose metronomic chemotherapy was shown to induce disease control in patients with advanced-stage breast cancer with a lower incidence of adverse events compared with conventional maximum tolerated dose chemotherapy. Good response rates have been seen in heavily pre-treated patients for whom limited treatment options are available. Most patients prefer oral therapy and metronomic chemotherapy is a convenient alternative in patients with advanced-stage disease in which minimal toxicity and good tumour control are the overall aims of treatment. The addition of metronomic protocols to standard neoadjuvant chemotherapy regimens has produced promising pathological complete response rates. Ongoing trials including the SYSUCC-001 trial in patients with triple-negative breast cancer and the IBCSG 22-00 trial that is assessing a cyclophosphamide–methotrexate maintenance regimen after standard adjuvant therapy in hormone receptor-negative disease, will clarify the value of adding this approach to conventional therapies. The low cost associated with metronomic chemotherapy represents an opportunity for the utilization of this treatment option, especially in developing countries, and poses a challenge for the launch of large trials sponsored by industry. Using breast cancer as the principal example, we discuss the key clinical advances in this area, including new trial design, appropriate patient and end point selection, as well as the evolving rationale for metronomic chemotherapy combinations.

The past three decades have borne witness to many advances in the understanding of the molecular biology and treatment of nasopharyngeal carcinoma (NPC), an Epstein–Barr virus (EBV)-associated cancer endemic to southern China, southeast Asia and north Africa. In this Review, we provide a comprehensive, interdisciplinary overview of key research findings regarding NPC pathogenesis, treatment, screening and biomarker development. We describe how technological advances have led to the advent of proton therapy and other contemporary radiotherapy approaches, and emphasize the relentless efforts to identify the optimal sequencing of chemotherapy with radiotherapy through decades of clinical trials. Basic research into the pathogenic role of EBV and the genomic, epigenomic and immune landscape of NPC has laid the foundations of translational research. The latter, in turn, has led to the development of new biomarkers and therapeutic targets and of improved approaches for individualizing immunotherapy and targeted therapies for patients with NPC. We provide historical context to illustrate the effect of these advances on treatment outcomes at present. We describe current preclinical and clinical challenges and controversies in the hope of providing insights for future investigation.Nasopharyngeal carcinoma (NPC) is an Epstein–Barr virus (EBV)-associated malignancy endemic to southern China, southeast Asia and north Africa. The authors of this Review present a comprehensive overview of advances from the past three decades on the pathogenic role of EBV, and the genomic, epigenomic and immune landscape of NPC, which have led to the development of new biomarkers, therapeutic targets and improved treatment approaches for patients with NPC.

Platinum (Pt) compounds entered the clinic as anticancer agents when cisplatin was approved in 1978. More than 40 years later, even in the era of precision medicine and immunotherapy, Pt drugs remain among the most widely used anticancer drugs. As Pt drugs mainly target DNA, it is not surprising that recent insights into alterations of DNA repair mechanisms provide a useful explanation for their success. Many cancers have defective DNA repair, a feature that also sheds new light on the mechanisms of secondary drug resistance, such as the restoration of DNA repair pathways. In addition, genome-wide functional screening approaches have revealed interesting insights into Pt drug uptake. About half of cisplatin and carboplatin but not oxaliplatin may enter cells through the widely expressed volume-regulated anion channel (VRAC). The analysis of this heteromeric channel in tumour biopsies may therefore be a useful biomarker to stratify patients for initial Pt treatments. Moreover, Pt-based approaches may be improved in the future by the optimization of combinations with immunotherapy, management of side effects and use of nanodelivery devices. Hence, Pt drugs may still be part of the standard of care for several cancers in the coming years.Platinum chemotherapy agents remain among the most widely used anticancer drugs, but there is still room to maximize their efficacy. This Review discusses newer findings related to sensitivity and resistance to these drugs as well as recent advances in platinum drug development.

Human papillomavirus (HPV)-positive (HPV+) oropharyngeal squamous cell carcinoma (OPSCC) has one of the most rapidly increasing incidences of any cancer in high-income countries. The most recent (8th) edition of the UICC/AJCC staging system separates HPV+ OPSCC from its HPV-negative (HPV−) counterpart to account for the improved prognosis seen in the former. Indeed, owing to its improved prognosis and greater prevalence in younger individuals, numerous ongoing trials are examining the potential for treatment de-intensification as a means to improve quality of life while maintaining acceptable survival outcomes. In addition, owing to the distinct biology of HPV+ OPSCCs, targeted therapies and immunotherapies have become an area of particular interest. Importantly, OPSCC is often detected at an advanced stage owing to a lack of symptoms in the early stages; therefore, a need exists to identify and validate possible diagnostic biomarkers to aid in earlier detection. In this Review, we provide a summary of the epidemiology, molecular biology and clinical management of HPV+ OPSCC in an effort to highlight important advances in the field. Ultimately, a need exists for improved understanding of the molecular basis and clinical course of this disease to guide efforts towards early detection and precision care, and to improve patient outcomes.The incidence of human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) is increasing rapidly in most developed countries. In this Review, the authors provide an overview of the epidemiology, molecular biology and treatment of HPV-positive OPSCC, including discussions of the role of treatment de-escalation and emerging novel therapies.