Does concomitant gout in septic arthritis affect surgical outcomes?

BACKGROUND: We aim to review and describe the proportion of patients with co-existing gout amongst patients with surgical treated septic arthritis, characterize their clinical presentation, outcomes and complications compared to patients with native joint septic arthritis. METHODS: Sixty-one patients with surgically treated primary joint septic arthritis were identified from the period of January 2011 to December 2016. There were 13 (21.3%) patients with co-existing septic arthritis and crystal proven gout. Pertinent details such as demographics, comorbidities, clinical features on presentation, infection markers, number of surgeries, length of stay (LOS) in general and individual LOS in supportive care units, limb amputations, readmissions and mortality were reviewed. Multiple linear and logistic regression models were used to control for confounders during analysis. RESULTS: The average age of patients was 60.8 years (range: 23-87 years). The patients with gout are associated with comorbidities such as being hypertensive, hyperlipidemia and renal impaired. They tend to present with ankle joint involvement (46.2% vs 8.3%; p = 0.004) while septic arthritis patients without gout tend to present with knee joint involvement (75% vs 46.2%; p = 0.046). In terms of complications, up to two thirds of them require supportive care in the High Dependency Unit and/or Intensive Care Unit during treatment (61.5% vs 29.2%; p = 0.031) and having gout with septic arthritis independently predicted a significant increase in LOS by an additional 12.6 days on average (95% CI: 2.11 - 23.03; p = 0.019). They are also more likely to end up with limb amputation (23.1% vs 0%; p = 0.008) on univariate analysis. CONCLUSION: Gout accompanying septic arthritis in the same joint is potentially associated with major systemic and joint related sequela, complications in terms of prolonged hospital stay, need for complex care and risk for limb amputation. Our findings further indicate the value and need for well-designed prospective controlled cohort studies to explore the relationship between gout and septic arthritis.

p53-NEIL1 co-abnormalities induce genomic instability and promote synthetic lethality with Chk1 inhibition in multiple myeloma having concomitant 17p13(del) and 1q21(gain).

Recurrent cytogenetic abnormalities are the main hallmark of multiple myeloma (MM) and patients having 2 or more high-risk prognostic events are associated with extremely poor outcome. 17p13(del) and 1q21(gain) are critical and independent high-risk cytogenetic markers, however, the biological significance underlying the poor outcome in MM patients having co-occurrence of both these chromosomal aberrations has never been interrogated. Herein, we identified that patients harbouring concomitant 17p13(del) with 1q21(gain) demonstrated the worst prognosis as compared to patients with single- (either 17p13(del) or 1q21(gain)) and with no chromosomal events (WT for both chromosomal loci); and they are highly enriched for genomic instability (GI) signature. We discovered that the GI feature in the patients with concomitant 17p13(del)-1q21(gain) was recapitulating the biological properties of myeloma cells with co-existing p53-deficiency and NEIL1 mRNA-hyper-editing (associated with chromosome 17p and 1q, respectively) that have inherent DNA damage response (DDR) and persistent activation of Chk1 pathway. Importantly, this became a vulnerable point for therapeutic targeting whereby the cells with this co-abnormalities demonstrated hyper-sensitivity to siRNA- and pharmacological-mediated-Chk1 inhibition, as observed at both the in vitro and in vivo levels. Mechanistically, this was attributable to the synthetic lethal relationship between p53-NEIL1-Chk1 abnormalities. The Chk1 inhibitor (AZD7762) tested showed good synergism with standard-of-care myeloma drugs, velcade and melphalan, thus further reinforcing the translational potential of this therapeutic approach. In summary, combination of NEIL1-p53 abnormalities with an ensuing Chk1 activation could serve as an Achilles heel and predispose MM cells with co-existing 1q21(gain) and 17p13(del) to therapeutic vulnerability for Chk1 inhibition.

Macrophages protect mycoplasma-infected chronic myeloid leukemia cells from natural killer cell killing.

Macrophages (Mϕ) have been reported to downmodulate the cytotoxicity of natural killer (NK) cell against solid tumor cells. However, the collaborative role between NK cells and Mϕ remains underappreciated, especially in hematological cancers, such as chronic myeloid leukemia (CML). We observed a higher ratio of innate immune cells (Mϕ and NK) to adaptive immune cells (T and B cells) in CML bone marrow aspirates, prompting us to investigate the roles of NK and Mϕ in CML. Using coculture models simulating the tumor inflammatory environment, we observed that Mϕ protects CML from NK attack only when CML was itself mycoplasma-infected and under chronic infection-inflammation condition. We found that the Mϕ-protective effect on CML was associated with the maintenance of CD16 level on the NK cell membrane. Although the NK membrane CD16 (mCD16) was actively shed in Mϕ + NK + CML trioculture, the NK mCD16 level was maintained, and this was independent of the modulation of sheddase by tissue inhibitor of metalloproteinase 1 or inhibitory cytokine transforming growth factor beta. Instead, we found that this process of NK mCD16 maintenance was conferred by Mϕ in a contact-dependent manner. We propose a new perspective on anti-CML strategy through abrogating Mϕ-mediated retention of NK surface CD16.

Ilizarov reconstruction of chronic bilateral calcaneovalgus deformities.

Calcaneovalgus foot deformities are present in up to 35% of patients with lumbar spina bifida. Resultant heel weight bearing causes complications include those associated with pressure ulcers. Early surgical reconstruction is advocated to prevent deformity progression and rigidity. Several surgical techniques in paediatric populations have been described, but there remains a paucity of literature regarding reconstruction of chronic calcaneovalgus feet in adults. This case report describes our experience using the Ilizarov technique in the reconstruction of an adult presenting with chronic calcaneovalgus feet. This is a 34-year-old lady with myelomeningocoele spina bifida of lumbar level 5 who presented with a history of multiple admissions for cellulitis and infections of bilateral heel pressure sores. Rigid calcaneovalgus deformities of both feet (45° on the right, 40° on the left) were noted on clinical examination and radiological investigations. Reconstruction with an Ilizarov frame allowed for gradual correction of both soft tissue and bone, correcting heel weight bearing ambulation, with the aim of preventing further complications from infected heel ulcers. While the correction of bony deformities is crucial, management of chronically contracted soft tissue must not be overlooked. An Ilizarov frame requires both an experienced surgeon and a motivated patient, but it allows for accurate reconstruction of bony deformities, while allowing management of surrounding chronic soft tissue contractures with good functional outcome.