Pathlab (New Zealand)

Background: Despite the impressive outcomes seen with tyrosine kinase inhibitor (TKI) therapy in chronic myeloid leukaemia (CML), the optimal upfront therapy remains unclear. Second generation TKI (2G TKI) trials have shown significantly more rapid and deeper levels of molecular response with a lower incidence of progression to advanced stage disease, but no improvement in overall survival. 2G TKIs are however associated with long term side effects, including increased vascular events in patients receiving nilotinib and pulmonary toxicity in patients on dasatinib. In contrast, the innovator TKI imatinib has now been used in New Zealand for over 20 years, with side effects that are mild and manageable, and no emergent long term toxicity, making it an attractive option for safe, long term therapy. Aims: The objective of the KISS study (Kinase Inhibition with Sprycel Startup) is to investigate the efficacy and safety of de-escalating upfront 2G TKI therapy with dasatinib to imatinib in patients with chronic myeloid leukaemia (CML) who have reached a “safe haven” as defined by achieving MR3.0 after 12 months of therapy. Methods: This is a phase II trial of newly diagnosed adult patients with chronic phase CML (CP-CML) recruited from 9 New Zealand haematology centres, and treated upfront with dasatinib 100mg once daily. Patients achieving a confirmed MR3.0 at 12 months were transitioned to imatinib 400mg once daily and followed for 24 months. The primary objective is the proportion of patients who remain in MR3.0 for 2 years following the change of therapy from dasatinib to imatinib. Results: 96 patients with CP-CML were recruited between 17 July 2017 and 14 April 2022, with data cut off 31 December 2022. Currently 75 patients have at least 12 months of follow up and 10 patients continue on dasatinib but have not yet reached the 12 month assessment. During the first 12 months of the study, 19 patients have withdrawn (n=11, including 2 patients with variant transcripts not able to be monitored by quantitative PCR) or discontinued study treatment (n=8); toxicity was the cause of this in 11 out of 19 patients. To date, 44 of 67 patients have achieved a confirmed MR3.0 after 12 months of dasatinib treatment. Of the 44 patients with confirmed MR3.0 at 12 months, 38 have consented to transition to imatinib. Summary/Conclusion: Preliminary analysis of the KISS study suggests this is a feasible and well tolerated strategy. Longer term follow up, and molecular data will confirm whether this strategy can be used to rapidly induce a molecular response with initial 2G TKI therapy, followed by ongoing therapy with imatinib, avoiding the potential for significant off target side effects. Keywords: Molecular response, Tyrosine kinase inhibitor, Chronic myeloid leukemia, Toxicity

Within 30 years, the global number of deaths from AMR-associated infections is predicted to increase from ~700,000 to ~10 million people annually, if we do not act now.1 The Aotearoa New Zealand (NZ) response to the current COVID-19 pandemic has been lauded internationally-found-ed in science, responsive to expert advice, implemented with clear leadership and communication, and subject to ongoing critical evaluation and improvement. AMR-associated infections and related care (eg, time off work or school to travel to hospital for treatment) will disproportionately impact the most socioeconomically disadvantaged among us, those living in rural or remote settings, and Maori and Pacific populations who shoulder a greater infection and AMR burden and have increased reliance on antimicrobial therapy.6'7 One of the biggest drivers for AMR is antimicrobial use, which is high in human health in NZ compared with many developed countries.8'9 Most of our antimicrobial use (95%) is in the community9 and up to 50% may be inappropriate.2 The NZ community antibacterial consumption rate increased 49% between 2006 and 2014;in 2013, it exceeded that of 22 out of 29 European countries.8 A subsequent modest 14% decrease occurred across 2015 to 2018, mainly due to reductions in under 5 year olds,10 which is pleasing as antimicrobial use in childhood may create reservoirs of resistant pathogens impacting communities cross-generationally. In 2013, the Health Quality and Safety Commission (HQSC) published a scoping report that offered insight into what was needed to progress AMS in NZ.14 Key recommendations were to establish: * National leadership and coordination of AMS activities * National antimicrobial prescribing guidelines * Quality improvement tools and measures In the near decade that has followed this report, none of these recommendations have been achieved. The NCAMS should provide access to (and support use of) quality improvement tools (eg, auditing systems for between facility benchmarking), develop initiatives to improve antimicrobial use (including those involving consumers), monitor performance against quality markers, and establish clinical care standards with the oversight of NAMSEG.

Stargardt disease (STGD1) and ABCA4 retinopathies (ABCA4R) are caused by pathogenic variants in the ABCA4 gene inherited in an autosomal recessive manner. The gene encodes an importer flippase protein that prevents the build-up of vitamin A derivatives that are toxic to the RPE. Diagnosing ABCA4R is complex due to its phenotypic variability and the presence of other inherited retinal dystrophy phenocopies. ABCA4 is a large gene, comprising 50 exons; to date > 2000 variants have been described. These include missense, nonsense, splicing, structural, and deep intronic variants. Missense variants account for the majority of variants in ABCA4. However, in a significant proportion of patients with an ABCA4R phenotype, a second variant in ABCA4 is not identified. This could be due to the presence of yet unknown variants, or hypomorphic alleles being incorrectly classified as benign, or the possibility that the disease is caused by a variant in another gene. This underlines the importance of accurate genetic testing. The pathogenicity of novel variants can be predicted using in silico programs, but these rely on databases that are not ethnically diverse, thus highlighting the need for studies in differing populations. Functional studies in vitro are useful towards assessing protein function but do not directly measure the flippase activity. Obtaining an accurate molecular diagnosis is becoming increasingly more important as targeted therapeutic options become available; these include pharmacological, gene-based, and cell replacement-based therapies. The aim of this review is to provide an update on the current status of genotyping in ABCA4 and the status of the therapeutic approaches being investigated.

Psoriasis is a common, chronic skin eruption characterized by abnormal hyperproliferation of the epidermis. When assessing psoriasis histologically, it is historically considered a "dry" disease, with significant amounts of serum not expected within lesional stratum corneum. However, this specific feature is not often mentioned within the literature. A retrospective study was undertaken to assess prevalence of serum within stratum corneum in cases of non-palmoplantar psoriasis. We evaluated 27 specimens diagnosed histologically as psoriasis between January 2015 and June 2016. In addition to serum, we assessed for psoriasiform hyperplasia, hypogranulosis, suprapapillary thinning and parakeratosis with neutrophils. The cases were then categorized as either diagnostic for, or consistent with, psoriasis and were followed up with clinicians to assess whether the clinical course was consistent with psoriasis. A total of 27 hematoxylin and eosin (H&E)-stained biopsies were examined from 21 patients, with periodic acid-Schiff (PAS) performed on 20 of the biopsies. Of these, 12 biopsies had serum present (44.4%). Of the 12 lesions considered to clinically and histologically represent psoriasis, 5 (41.7%) had serum. Our results suggest serum within stratum corneum is possibly an acceptable feature within the spectrum of psoriasis histopathology and should not necessarily detract from the diagnosis.

Uterine smooth muscle tumours of uncertain malignant potential (STUMP) are diagnostically and clinically challenging. The alternative lengthening of telomeres (ALT) telomere maintenance mechanism is associated with poor survival in soft tissue leiomyosarcoma. Time to first recurrence and survival were known for 18 STUMP and 43 leiomyosarcomata (LMS). These were screened for ALT telomere maintenance by the presence of ALT‐associated PML bodies (APBs) and for changes associated with the ALT phenotype, namely aberrant p53 expression, isocitrate dehydrogenase 1 mutation (R132H substitution) expression, mutant ATRX (αthalassemia/mental retardation syndrome X‐linked) expression and mutant DAXX (death‐domain‐associated protein) expression by immunohistochemistry (IHC). Overexpression of p16INK4A was examined immunohistologically in a subset of cases. Many of the tumours associated with death or recurrence demonstrated APBs commensurate with ALT telomere maintenance. However, all uterine STUMP (4/4), and vaginal STUMP (2/2) patients, and almost all LMS patients (88.4%, 23/26, including 90% (9/10) of stage 1 LMS cases), who had died of disease or who had recurrent disease, displayed loss of ATRX or DAXX expression. Loss of ATRX or DAXX expression identified poor prognosis (95% CI 2.1 to 40.8, p < 0.003), in the LMS group. Thus, loss of ATRX or DAXX expression in uterine smooth muscle tumours identifies a clinically aggressive molecular subtype of early stage LMS and when histopathological features are problematic such as in STUMP. As ATRX and DAXX IHC is readily performed in diagnostic laboratories these are potentially useful for routine histopathological classification and management.

The recurrence rate of benign nevi has been infrequently reported and primarily as a rate of clinical recurrence. The aim of this study was to document the rate of recurrence leading to re-excision of previously biopsied nevi (the clinically significant recurrence rate). Nevi undergoing primary biopsy with a minimum 5 years follow-up were reviewed in a pathology database for recurrence requiring a further excision. A total of 1035 nevi were reviewed including 196 dysplastic nevi. Twenty six percent of nevi had a positive margin, more common in shave and punch than ellipse biopsied lesions. Three cases recurred requiring re-excision resulting in a pathology recurrence rate of 0.3%. These 3 cases showed benign changes and 2 were originally excised with clear margins. The rate of recurrence requiring re-excision is very low at 0.3%. This suggests that few cases of clinical recurrence are re-excised. Re-excision of benign nevi including mild and moderately dysplastic nevi may not be necessary.

We present an interesting case of a patient who developed an epidural abscess caused by Streptobacillus moniliformis. This is the first report in the medical literature of a spinal epidural abscess associated with this organism. Diagnosis of S. moniliformis infection requires a high degree of suspicion, and a delay may be inevitable when a relevant clinical history is lacking.