Histone deacetylase (HDAC) inhibitors are an emerging class of therapeutics with potential as anticancer drugs. The rationale for developing HDAC inhibitors (and other chromatin-modifying agents) as anticancer therapies arose from the understanding that in addition to genetic mutations, epigenetic changes such as dysregulation of HDAC enzymes can alter phenotype and gene expression, disturb homeostasis, and contribute to neoplastic growth. The family of HDAC inhibitors is large and diverse. It includes a range of naturally occurring and synthetic compounds that differ in terms of structure, function, and specificity. HDAC inhibitors have multiple cell type-specific effects in vitro and in vivo, such as growth arrest, cell differentiation, and apoptosis in malignant cells. HDAC inhibitors have the potential to be used as monotherapies or in combination with other anticancer therapies. Currently, there are two HDAC inhibitors that have received approval from the US FDA for the treatment of cutaneous T-cell lymphoma: vorinostat (suberoylanilide hydroxamic acid, Zolinza) and depsipeptide (romidepsin, Istodax). More recently, depsipeptide has also gained FDA approval for the treatment of peripheral T-cell lymphoma. Many more clinical trials assessing the effects of various HDAC inhibitors on hematological and solid malignancies are currently being conducted. Despite the proven anticancer effects of particular HDAC inhibitors against certain cancers, many aspects of HDAC enzymes and HDAC inhibitors are still not fully understood. Increasing our understanding of the effects of HDAC inhibitors, their targets and mechanisms of action will be critical for the advancement of these drugs, especially to facilitate the rational design of HDAC inhibitors that are effective as antineoplastic agents. This review will discuss the use of HDAC inhibitors as multitargeted therapies for malignancy. Further, we outline the pharmacology and mechanisms of action of HDAC inhibitors while discussing the safety and efficacy of these compounds in clinical studies to date.

Infection and sepsis are common problems in cancer management affecting up to 45% of patients and are associated with significant morbidity, mortality and healthcare utilisation.ObjectiveTo develop and implement a whole of hospital clinical pathway for the management of sepsis (SP) in a specialised cancer hospital and to measure the impact on patient outcomes and healthcare utilisation.MethodsA multidisciplinary sepsis working party was established. Process mapping of practices for recognition and management of sepsis was undertaken across all clinical areas. A clinical pathway document that supported nurse-initiated sepsis care, prompt antibiotic and fluid resuscitation was implemented. Process and outcome measures for patients with sepsis were collected preimplementation (April–December 2012), postimplementation cohorts (April–December 2013), and from January to December 2014.Results323 patients were evaluated (111 preimplementation, 212 postimplementation). More patients with sepsis had lactate measured (75.0% vs 17.2%) and appropriate first dose antibiotic (90.1% vs 76.1%) (all p<0.05). Time to antibiotics was halved (55 vs 110 min, p<0.05). Patients with sepsis had lower rates of intensive care unit admission (17.1% vs 35.5%), postsepsis length of stay (7.5 vs 9.9 days), and sepsis-related mortality (5.0% vs 16.2%) (all p<0.05). Mean total hospital admission costs were lower in the SP cohort, with a significant difference in admission costs between historical and SP non-surgical groups of $A8363 (95% CI 81.02 to 16645.32, p=0.048) per patient on the pathway. A second cohort of 449 patients with sepsis from January to December 2014 demonstrated sustained improvement.ConclusionsThe SP was associated with significant improvement in patient outcomes and reduced costs. The SP has been sustained since 2013, and has been successfully implemented in another hospital with further implementations underway in Victoria.

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Despite the implementation of multimodal bundles of care in hospitalised patients, post-operative sepsis in patients with cancer still accounts for a significant burden of illness and substantial healthcare costs. Patients undergoing surgery for cancer are at particular risk of sepsis due to underlying malignancy, being immunocompromised associated with cancer management and the complexity of surgical procedures performed. In this review, we evaluate the burden of illness and risks for sepsis following surgery for cancer. Current evidence supporting standardised strategies for sepsis management (including early recognition and resuscitation) is examined together with challenges in implementing quality improvement programs.

A woman with metastatic melanoma was treated with immunotherapy induction with ipilimumab and nivolumab and radiotherapy to liver metastases. The patient deteriorated shortly thereafter, becoming febrile and hypotensive and requiring admission to the intensie care unit (ICU) for inotrope support. Failure to respond to antibiotics and a negative septic screen prompted further investigation, which ultimately led to a diagnosis of haemophagocytic lymphohistiocytosis (HLH). The patient improved on high dose steroids and was discharged home. Months later, in the context of progressive melanoma, the patient was re-challenged with nivolumab monotherapy and subsequently experienced recurrence of HLH, confirming the aetiology as being immunotherapy related. This case serves as a reminder to consider HLH where there are fevers of unknown origin in an unwell patient receiving immune checkpoint inhibitor therapy and also highlights immunotherapy as a potential cause for HLH, which has rarely been reported in the literature to date.