Myeloma: A Lot of Progress, Still a Long Way to Go

Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase, which is an essential player in regulating cell migration, invasion, adhesion, proliferation, and survival. Its overexpression and activation have been identified in sixty-eight percent of epithelial ovarian cancer patients and this is significantly associated with higher tumor stage, metastasis, and shorter overall survival of these patients. Most recently, a new role has emerged for FAK in promoting resistance to taxane and platinum-based therapy in ovarian and other cancers. The development of resistance is a complex network of molecular processes that make the identification of a targetable biomarker in platinum and taxane-resistant ovarian cancer a major challenge. FAK overexpression upregulates ALDH and XIAP activity in platinum-resistant and increases CD44, YB1, and MDR-1 activity in taxaneresistant tumors. FAK is therefore now emerging as a prognostically significant candidate in this regard, with mounting evidence from recent successes in preclinical and clinical trials using small molecule FAK inhibitors. This review will summarize the significance and function of FAK in ovarian cancer, and its emerging role in chemotherapeutic resistance. We will discuss the current status of FAK inhibitors in ovarian cancers, their therapeutic competencies and limitations, and further propose that the combination of FAK inhibitors with platinum and taxane-based therapies could be an efficacious approach in chemotherapeutic resistant disease.

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Predicting clinical behaviour of breast phyllodes tumors: utility of Singapore nomogram

The Breast ◽

10.1016/s0960-9776(21)00204-6 ◽

2021 ◽

Vol 56 ◽

pp. S64

Author(s):

J. Gurawalia ◽

R. Arjunan

Keyword(s):

Phyllodes Tumors ◽

Clinical Behaviour

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Resistance to Antiandrogens in Prostate Cancer: Is It Inevitable, Intrinsic or Induced?

Cancers ◽

10.3390/cancers13020327 ◽

2021 ◽

Vol 13 (2) ◽

pp. 327

Author(s):

Norman J. Maitland

Keyword(s):

Prostate Cancer ◽

Locally Advanced ◽

Receptor Protein ◽

Cell Of Origin ◽

Resistant Disease ◽

Conflicting Evidence ◽

Androgen Receptor Protein ◽

Tumor Cell Heterogeneity ◽

Treatment Naïve ◽

Salvage Pathways

Increasingly sophisticated therapies for chemical castration dominate first-line treatments for locally advanced prostate cancer. However, androgen deprivation therapy (ADT) offers little prospect of a cure, as resistant tumors emerge rather rapidly, normally within 30 months. Cells have multiple mechanisms of resistance to even the most sophisticated drug regimes, and both tumor cell heterogeneity in prostate cancer and the multiple salvage pathways result in castration-resistant disease related genetically to the original hormone-naive cancer. The timing and mechanisms of cell death after ADT for prostate cancer are not well understood, and off-target effects after long-term ADT due to functional extra-prostatic expression of the androgen receptor protein are now increasingly being recorded. Our knowledge of how these widely used treatments fail at a biological level in patients is deficient. In this review, I will discuss whether there are pre-existing drug-resistant cells in a tumor mass, or whether resistance is induced/selected by the ADT. Equally, what is the cell of origin of this resistance, and does it differ from the treatment-naïve tumor cells by differentiation or dedifferentiation? Conflicting evidence also emerges from studies in the range of biological systems and species employed to answer this key question. It is only by improving our understanding of this aspect of treatment and not simply devising another new means of androgen inhibition that we can improve patient outcomes.

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Public Health Control Measures in Response to Global Pandemics and Drug Resistance

The Journal of Law Medicine & Ethics ◽

10.1111/jlme.12266 ◽

2015 ◽

Vol 43 (S2) ◽

pp. 49-56

Author(s):

Polly J. Price

Keyword(s):

Public Health ◽

Communicable Disease ◽

International Health ◽

Control Measures ◽

World Health ◽

Legal Authority ◽

List Type ◽

Resistant Disease ◽

Global Pandemic ◽

Health Organization

These teaching materials explore the specific powers of governments to implement control measures in response to communicable disease, in two different contexts:The first context concerns global pandemic diseases. Relevant legal authority includes international law, World Health Organization governance and the International Health Regulations, and regulatory authority of nations.The second context is centered on U.S. law and concerns control measures for drug-resistant disease, using tuberculosis as an example. In both contexts, international and domestic, the point is to understand legal authority to address public health emergencies.

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Differential methylation EPIC analysis discloses cisplatin-resistance related hypermethylation and tumor-specific heterogeneity within matched primary and metastatic testicular germ cell tumor patient tissue samples

Clinical Epigenetics ◽

10.1186/s13148-021-01048-y ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

João Lobo ◽

Vera Constâncio ◽

Pedro Leite-Silva ◽

Rita Guimarães ◽

Mariana Cantante ◽

...

Keyword(s):

Germ Cell ◽

Germ Cell Tumors ◽

Testicular Germ Cell Tumor ◽

Complete Response ◽

Differential Analysis ◽

Testicular Germ Cell ◽

Tissue Samples ◽

Tumor Patient ◽

Resistant Disease ◽

Response To Chemotherapy

AbstractTesticular germ cell tumors (TGCTs) are among the most common solid malignancies in young-adult men, and currently most mortality is due to metastatic disease and emergence of resistance to cisplatin. There is some evidence that increased methylation is one mechanism behind this resistance, stemming from individual studies, but approaches based on matched primary and metastatic patient samples are lacking. Herein, we provide an EPIC array-based study of matched primary and metastatic TGCT samples. Histology was the major determinant of overall methylation pattern, but some clustering of samples related to response to cisplatin was observed. Further differential analysis of patients with the same histological subtype (embryonal carcinoma) disclosed a remarkable increase in net methylation levels (at both promoter and CpG site level) in the patient with cisplatin-resistant disease and poor outcome compared to the patient with complete response to chemotherapy. This further confirms the recent results of another study performed on isogenic clones of sensitive and resistant TGCT cell lines. Differentially methylated promoters among groups of samples were mostly not shared, disclosing heterogeneity in patient tissue samples. Finally, gene ontology analysis of cisplatin-resistant samples indicated enrichment of differentially hypermethylated promoters on pathways related to regulation of immune microenvironment, and enrichment of differentially hypomethylated promoters on pathways related to DNA/chromatin binding and regulation. This data supports not only the use of hypomethylating agents for targeting cisplatin-resistant disease, but also their use in combination with immunotherapies and chromatin remodelers.

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Persistent seropositivity in oophorectomy-resistant anti-NMDA receptor encephalitis

BMJ Case Reports ◽

10.1136/bcr-2021-241878 ◽

2021 ◽

Vol 14 (9) ◽

pp. e241878

Author(s):

Susmit Tripathi ◽

Nara M Michaelson ◽

Alan Segal

Keyword(s):

Clinical Decision Making ◽

Serum Antibody ◽

Disease Patient ◽

Clinical Decision ◽

High Serum ◽

Nmda Receptor Encephalitis ◽

Resistant Disease ◽

Nmdar Encephalitis ◽

Antibody Titres ◽

Case Basis

To discuss (1) the significance of seropositivity in anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis and (2) clinical decision making in oophorectomy resistant disease. Patient A (a 35-year-old woman) had high CSF and serum anti-NMDA antibody titres, a complicated hospital course, little improvement with first and second-line therapies, and remained with high CSF and serum antibody titres despite unilateral oophorectomy, requiring a nearly 13-month long hospitalisation. Conversely, patient B (a 29-year-old woman) had low CSF titres, seronegative disease and quickly recovered to her baseline with first line therapies and oophorectomy. Anti-NMDAR antibodies are themselves pathological, causing signalling dysfunction and internalisation of the NMDAR. Seropositivity with anti-NMDAR antibodies likely reflects leakage from the blood–brain barrier, with high serum titres being a downstream effect of high CSF titres. Empiric bilateral oophorectomies is controversial but appropriate on a case-by-case basis in extremely treatment-resistant NMDAR encephalitis given the possibility of antigenic microteratomas, which may not be detected on imaging or even bilateral ovarian biopsies.

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