Proliferating macrophages in human tumours show characteristics of monocytes responding to myelopoietic growth factors.

Macrophages play essential roles in maintaining tissue homeostasis and immune defence. However, their extensive infiltration into tumours has been linked to adverse outcomes in multiple human cancers. Within the tumour microenvironment (TME), tumour-associated macrophages (TAMs) promote tumour growth and metastasis, making them prime targets for cancer immunotherapy. Recent single-cell analysis suggest that proliferating TAMs accumulate in human cancers, yet their origins and differentiation pathways remain uncertain. Here, we show that a subpopulation of CD163+ TAMs proliferates in situ within the TME of melanoma, lung cancer, and breast cancer. Consistent with their potential role in suppressing anti-tumour activities of T cells, CD163+ TAMs express a range of potent immunosuppressive molecules, including PD-L1, PD-L2, IL-10, and TGF-ß. Other phenotypic markers strongly suggested that these cells originate from CD14+ CCR2+ monocytes, a cell population believed to have minimal capacity for proliferation. However, we demonstrate in vitro that certain myelopoietic cytokines commonly available within the TME induce robust proliferation of human monocytes, especially the combination of interleukin 3 (IL-3) and Macrophage Colony-Stimulating Factor 1 (M-CSF). Monocytic cells cultured with these cytokines efficiently modulate T cell proliferation, and their molecular phenotype recapitulates that of CD163+ TAMs. IL-3-driven proliferation of monocytic cells can be completely blocked by IL-4, associated with the induction of CDKN1A, alongside the upregulation of transcription factors linked to dendritic cell function, such as BATF3 and IRF4. Taken together, our work suggests several novel therapeutic routes to reducing immunosuppressive TAMs in human tumours, from blocking chemokine-mediated recruitment of monocytes to blocking their proliferation.

Exploring melanoma shifts: a two-decade analysis in New Zealand.

AIMS: New Zealand melanoma incidence rates are amongst the highest in the world. The study aims to provide information on the incidence of cutaneous melanoma in New Zealand from 2000 to 2022. METHODS: De-identified data were extracted from the New Zealand Cancer Registry using the ICD-10 code for malignant melanoma (C34) and melanoma in situ (MIS) (D03) from 2000 to 2022. Statistical analysis was performed to calculate melanoma incidence rates. RESULTS: Invasive melanoma (IM) incidence rates demonstrated an increasing trend from 2000 to 2008 (+1.10 per 100,000 person-years per year), followed by an inflection point at 2008 and then a decreasing trend from 2008 to 2022 (-0.28 per 100,000 person-years per year), which was not statistically different from zero/no change. MIS incidence increased from 30.3 to 72.1 per 100,000 person-years between 2000 and 2022. CONCLUSIONS: The incidence of IM in New Zealand has plateaued in the last decade and was associated with an increase in MIS incidence over the same period. While this trend is encouraging, further research is required to investigate whether there is an actual decline in IM incidence.

A Rare Case of a Basomelanocytic Tumor.

ABSTRACT: Basal cell carcinomas and melanoma are common cutaneous malignancies. However, the development of a basomelanocytic tumor that simultaneously includes elements of melanoma and basal cell carcinoma is extremely rare. We present the case of an 84-year-old man who presented with a nonpigmented, nonulcerated pink nodule of his left upper back and discuss the current management recommendations for basomelanocytic tumors.

Seven-colour multiplex immunochemistry/immunofluorescence and whole slide imaging of frozen sections.

Multiplex Immunochemistry/Immunofluorescence (mIHC/IF) aims to visualise multiple biomarkers in a single tissue section and is especially powerful when used on slide scanners coupled with digital analysis tools. mIHC/IF is commonly employed in immuno-oncology to characterise features of the tumour microenvironment (TME) and correlate them with clinical parameters to guide prognostication and therapy. However, mIHC/IF can be applied to a wide range of organisms in any physiological or disease context. Recent innovation has extended the number of markers that can be detected using slide scanners well beyond the 3-4 markers typically reported in traditional fluorescence microscopy. However, these methods often require sequential antibody staining and stripping, and are not compatible with frozen tissue sections. Using fluorophore-conjugated antibodies, we have established a simple mIHC/IF imaging workflow that enables simultaneous staining and detection of seven markers in a single section of frozen tissue. Coupled with automated whole slide imaging and digital quantification, our data efficiently revealed the tumour-immune complexity in metastatic melanoma. Computational image analysis quantified the immune and stromal cell populations present in the TME as well as their spatial interactions. This imaging workflow can also be performed with an indirect labelling panel consisting of primary and secondary antibodies. Our new methods, combined with digital quantification, will provide a valuable tool for high-quality mIHC/IF assays in immuno-oncology research and other translational studies, especially in circumstances where frozen sections are required for detection of particular markers, or for applications where frozen sections may be preferred, such as spatial transcriptomics.

Utility of Elective Neck Dissection in Clinically Node-Negative Parotid Malignancy.

OBJECTIVE: We sought to investigate the utility of elective neck dissection (END) in clinically node-negative parotid malignancy through the evaluation of factors that are associated with receiving END and survival analysis of patients who received END. STUDY DESIGN: Retrospective cohort database study. SETTING: The National Cancer Database (NCDB). METHODS: The NCDB was used to extract patients with clinically node-negative parotid malignancy. END was defined as having 5 or more lymph nodes examined pathologically, as previously defined in the literature. Univariate and multivariate analyses were used to compare predictors of receiving END, rates of occult metastasis, and survival. RESULTS: Of the 9405 included patients, 3396 (36.1%) underwent an END. END was most frequently performed for squamous cell carcinoma (SCC) and salivary duct histology. All other histologies were significantly less likely to undergo END compared to SCC (p < .05). Salivary ductal carcinoma and adenocarcinoma had the greatest rates of occult node disease (39.8% and 30.0%, respectively), followed by SCC (29.8%). Kaplan-Meier survival analysis showed a statistically significant increase in 5-year overall survival in patients who received END with poorly differentiated mucoepidermoid (56.2% vs 48.5%, p = .004) along with moderately and poorly differentiated SCC (43.2% vs 34.9%, p = .002; 48.9% vs 36.2%, p < .001, respectively). CONCLUSION: Histological classification is a benchmark for determining which patients should receive an END. We demonstrated an increase in overall survival in patients who undergo END with poorly differentiated tumors of mucoepidermoid and SCC histology. As such, histology should be considered along with clinical T-stage and rate of occult nodal metastasis to determine eligibility for END.

Extent of Surgery for Follicular Thyroid Carcinoma.

OBJECTIVES: To examine the association between the extent of surgery and overall survival in follicular thyroid cancer (FTC) patients. STUDY DESIGN: Retrospective analysis of the National Cancer Database (NCDB). METHODS: Patients who underwent surgical intervention for FTC from 2004 to 2015 were selected. Patients were >18 years old, with tumor size 1-4 cm, no other malignancies, and >0 follow up time. Patients were divided into two cohorts based on extent of surgery: lobectomy (≥1 lobe resected) and thyroidectomy (total or near total resection). Pearson's chi-squared analysis was used to compare cohorts. Kaplan-Meier survival and Cox hazards models were utilized to determine overall survival between two cohorts with p < 0.05 used for significance. RESULTS: A total of 6871 patients were identified with FTC, of which 1507 patients underwent lobectomy and 5364 patients underwent total thyroidectomy. There were no significant differences in patient demographics, comorbidity index, local spread, or tumor grade. Patients undergoing lobectomy had mean survival of 12.94 versus 12.71 years for those undergoing thyroidectomy. Extent of surgery was not associated with a significant difference in survival (5 years OS = 96% in lobectomy and 95.5% in total thyroidectomy, p = 0.08). Stratification by tumor grade resulted in no significant difference in survival between lobectomy and thyroidectomy. CONCLUSION: Survival time was not significantly different in patients with more extensive resection of FTC. LEVEL OF EVIDENCE: 3 Laryngoscope, 133:993-999, 2023.

Morbidity following thyroid and parathyroid surgery: Results from key performance indicator assessment at a high-volume centre in New Zealand.

BACKGROUND: Complications following thyroid/parathyroid surgery include recurrent laryngeal nerve (RLN) injury, hypocalcaemia and return to theatre for haematoma evacuation. Rates of these form the basis of key performance indicators (KPI). An endocrine database, containing results from 1997, was established at the North Shore Hospital in Auckland, New Zealand. We aimed to measure complication rates by procedure (thyroid and parathyroid), explore a temporal change in our unit and compare our results against international literature. METHODS: A retrospective review of the database between July 1997 and February 2020 was performed. The results for each KPI were analysed in total and over consecutive time periods. A review of the literature was carried out to find international complication rates for comparison. A cumulative sum (CUSUM) analysis was performed to give visual feedback on performance. RESULTS: There were 1062 thyroidectomies and 336 parathyroidectomies from July 1997 to February 2020. Thyroid surgery results found rates of temporary/permanent RLN injury of 1.9%/0.3%, temporary/permanent hypocalcaemia of 22.3/2.5%, and return to theatre for haematoma evacuation of 1.1%. Parathyroid surgery results were, temporary RLN injury of 0.8% (no permanent injury), temporary/permanent hypocalcaemia of 1.7%/0.4%, and return to theatre for haematoma evacuation of 0.3%. CUSUM analysis found KPI results to be comparable with international literature. CONCLUSION: Our unit's KPI results are comparable to published results in the literature. The use of this clinical database will help in future monitoring of performance and help drive improvement in the service. Embedding prospective data collection as routine practice allows for continuous improvement for the unit.

Contemporary management of locoregionally advanced melanoma in Australia and New Zealand and the role of adjuvant systemic therapy.

Australia and New Zealand have the highest incidence and mortality rates for melanoma in the world. Local surgery is still the standard treatment of primary cutaneous melanoma, and it is therefore important that surgeons understand the optimal care pathways for patients with melanoma. Accurate staging is critical to ensure a reliable assessment of prognosis and to guide treatment selection. Sentinel node biopsy (SNB) plays an important role in staging and the provision of reliable prognostic estimates for patients with cutaneous melanoma. Patients with stage III melanoma have a substantial risk of disease recurrence following surgery, leading to poor long-term outcomes. Systemic immunotherapies and targeted therapies, known to be effective for stage IV melanoma, have now also been shown to be effective as adjuvant post-surgical treatments for resected stage III melanoma. These patients should be made aware of this and preferably managed in an integrated multidisciplinary model of care, involving the surgeon, medical oncologists and radiation oncologists. This review considers the impact of a recent update to the American Joint Committee on Cancer (AJCC) staging system, the role of SNB for patients with high-risk primary melanoma and recent advances in adjuvant systemic therapies for high-risk patients.

Proposed quality performance indicators of sentinel lymph node biopsy for cutaneous melanoma.

BACKGROUND: Melanoma is a leading cause of morbidity and mortality in Australia and New Zealand. New Zealand has the highest melanoma incidence in the world alongside Australia at 54 per 100 000 persons. The aim of this study is to conduct a retrospective quality audit of sentinel lymph nodal biopsy (SLNB) practices from 2007 to 2019 of a high-volume melanoma surgeon. Primary outcome was false negative rate (FNR). Secondary outcomes were sentinel node (SN) identification and removal rate, and complication rates. METHODS: A database was maintained, containing n = 553 consecutive SLNB's for cutaneous melanoma from 31 August 2007 to 31 August 2019. Patient characteristics and details of the primary lesion, sentinel lymph node biopsy, recurrence and complications were recorded. RESULTS: SN's were successfully identified in 444 (99.6%) out of 446 patients with an FNR of 9.1%. Positive SN's were identified in 70 (12.7%) SLNB's. Complications occurred in 76 out of 553 (13.7%) SLNB's. A review of internationally published literature reveals an SN identification rate of 94.4-99.5% with an FNR of 4.0-37.5%. SLNB is the best staging tool for melanoma and gives potential access to adjuvant systemic treatment if >1 mm deposits are found. It is a day-stay procedure with a low-complication rate. CONCLUSION: SLNB is a safe and reliable procedure utilized for cutaneous melanoma. We propose our data should be used alongside international SN series to establish Quality Performance Indicators to improve melanoma management.

Radiological imaging of melanoma: a review to guide clinical practice in New Zealand.

The aim of this review is to propose guidelines for initial radiological staging and the follow-up imaging regime for melanoma. This will provide consistency in the access and delivery of quality melanoma care. Radiological imaging plays an important role in assessing the extent of disease, guiding individual treatment and evaluating treatment response. However, there exists limited literature addressing the optimal radiological staging and surveillance imaging regimes for melanoma. The lack of consensus on imaging for melanoma can generate inconsistency in the standard of skin cancer care provided. This review considers the appropriate imaging techniques for both initial melanoma staging and follow-up specifically in the New Zealand clinical environment. The recommendations in this article are based on evaluation of the currently available literature and consensus of feedback from consultation with a working group of New Zealand clinicians involved in providing care to patients with melanoma. The proposed guidelines are considered the standard of care, but regional practice may differ based on access to imaging technology, cost limitations and the clinical experience of healthcare professionals.

E-referrals and teledermatoscopy grading for melanoma: a successful model of care.

BACKGROUND/OBJECTIVES: An e-referral system was developed at a tertiary care hospital in Auckland, New Zealand in 2014 for suspected cutaneous malignancy. E-referrals include patient information, a description of the lesion(s), biopsy results and/or attached photograph(s). Experienced surgical oncologists prioritised the referrals and selected a management option or referred them for a teledermatoscopy opinion. Our aim was to review the efficacy of e-referrals for improving diagnostic accuracy for melanoma. METHODS: Referrals received in 2016 including images and categorisation as confirmed, likely or suspected melanoma by the triage specialist were evaluated. Concordance of the pathological diagnosis with the triage diagnosis and teledermatoscopy diagnosis was determined for each referral. RESULTS: 809 of 3470 e-referrals for skin cancer were categorised as confirmed, likely or suspected melanoma. 230 (28.4%) of these included a referral histopathology confirming melanoma/melanoma in situ. Of the remaining 579 referrals, 315 were sent for urgent diagnostic excision and 264 were referred for teledermatoscopy. 120 of the 315 sent for urgent excision were confirmed as melanoma (53) or melanoma in situ (67) on histopathology: a positive predictive value (PPV) of 38.1% and number needed to excise (NNE) of 2.6. Less than 10% of referrals triaged for teledermatoscopy were confirmed as melanoma (24/264). Almost half of all referrals (374/809, 45.6%) included melanoma/melanoma in situ. The melanoma: melanoma in situ ratio was 1: 1.18. CONCLUSIONS: The e-referral and teledermatoscopy service for suspected melanoma has proven fewer unnecessary excisions of benign lesions than previously reported.

Sentinel Node Biopsy in 105 High-Risk Cutaneous SCCs of the Head and Neck: Results of a Multicenter Prospective Study.

BACKGROUND: Regional nodal metastases from cutaneous squamous cell carcinoma (cSCC) is strongly associated with a poor prognosis, but these metastases are difficult to predict clinically. Sentinel node biopsy (SNB) has been used for a wide range of malignancies to assess for regional nodal metastasis, but is not widely used for cSCC. METHODS: Patients presenting with high-risk cSCC of the head and neck with clinically N0 necks were offered SNB at the time of primary cSCC excision or secondary wide local excision. Patients with positive sentinel nodes were offered completion lymph node dissection, and all the patients were followed up at regular intervals for up to 5 years. RESULTS: In this study, 105 lesions underwent SNB, and 10 sentinel nodes (9.5%) were positive. In an additional five patients, regional recurrence developed after a negative sentinel node, with a total subclinical nodal metastasis rate of 14.3%. Nodal metastases were significantly associated with reduced disease-specific survival. The significant predictors of metastasis were four or more high-risk features or tumors with a concurrent invasion deeper than 5 mm and PNI. CONCLUSION: For high-risk cSCC, SNB is a safe and feasible staging technique. The total number of high risk features and certain combinations of high-risk features predicted metastasis better than individual high-risk features.

The prevalence and treatment outcomes of antineuronal antibody-positive patients admitted with first episode of psychosis.

BACKGROUND: Antineuronal antibodies are associated with psychosis, although their clinical significance in first episode of psychosis (FEP) is undetermined. AIMS: To examine all patients admitted for treatment of FEP for antineuronal antibodies and describe clinical presentations and treatment outcomes in those who were antibody positive. METHOD: Individuals admitted for FEP to six mental health units in Queensland, Australia, were prospectively tested for serum antineuronal antibodies. Antibody-positive patients were referred for neurological and immunological assessment and therapy. RESULTS: Of 113 consenting participants, six had antineuronal antibodies (anti-N-methyl-D-aspartate receptor antibodies [n = 4], voltage-gated potassium channel antibodies [n = 1] and antibodies against uncharacterised antigen [n = 1]). Five received immunotherapy, which prompted resolution of psychosis in four. CONCLUSIONS: A small subgroup of patients admitted to hospital with FEP have antineuronal antibodies detectable in serum and are responsive to immunotherapy. Early diagnosis and treatment is critical to optimise recovery. DECLARATION OF INTEREST: None.

Prospective study of sentinel node biopsy for high-risk cutaneous squamous cell carcinoma of the head and neck.

BACKGROUND: Nodal metastasis from cutaneous squamous cell carcinoma (SCC) is poorly predicted clinically and is associated with a high mortality rate. METHODS: From 2010 to 2013, patients with high-risk cutaneous SCC were assessed with sentinel node biopsy (SNB) either at the time of primary cutaneous tumor resection or at secondary wide local excision. RESULTS: Of 57 patients, 8 (14%) had nodal metastasis. Significant predictors of metastasis are the number of high-risk factors (p = .008), perineural invasion (PNI; p = .05), and lymphovascular invasion (LVI; p = .05). During a mean of 19.4 months, 9 patients developed recurrence and 6 died of cutaneous SCC, indicating that over 1300 patients would be required for a randomized controlled trial with 80% power to detect a significant difference in disease-free survival. CONCLUSION: Lymph node metastasis occurs in 14% of patients with high-risk cutaneous SCC. Larger studies will be required to identify which "high-risk" factors should be considered as an indication for surgical assessment of the nodal basin. © 2015 Wiley Periodicals, Inc. Head Neck 38: E884-E889, 2016.

Predicting lymph node metastases in cutaneous squamous cell carcinoma: use of a morphological scoring system.

BACKGROUND: Predicting which patients will develop nodal metastasis from cutaneous squamous cell carcinoma (cSCC) remains difficult. This study evaluates a recently described histological risk model validated for mucosal head and neck SCC (HNSCC) when applied to cutaneous tumours. In this model, morphologic variables including worst pattern of invasion, lymphocytic host response and perineural invasion were shown to predict disease recurrence, loco regional recurrence and overall survival in mucosal HNSCC. METHODS: Patients with cSCC and known metastatic spread were identified from the author's database over a 5-year period between July 2007 and July 2012. Histology specimens from the original primary tumour were separately analysed by 2 histopathologists. Scores were compared against T-Stage matched control specimens without metastatic spread. RESULTS: 27 patients with metastatic cSCC were identified. Scores for worst pattern of invasion (WPOI) were significantly higher in individuals with lymph node metastases (p=0.02). CONCLUSIONS: Adverse pattern of invasion, defined as presence of small tumour islands or tumour satellites may be an independent risk factor for developing nodal metastases in cSCC. These tumours are difficult to investigate histopathologically as it is difficult to be confident the correct primary is chosen for study.

Antiphospholipid antibody testing for the antiphospholipid syndrome: a comprehensive practical review including a synopsis of challenges and recent guidelines.

The antiphospholipid (antibody) syndrome (APS) is an autoimmune condition characterised by a wide range of clinical features, but primarily identified as thrombotic and/or obstetric related adverse events. APS is associated with the presence of antiphospholipid antibodies (aPL), including the so-called lupus anticoagulant (LA). These aPL are heterogeneous in nature, detected with varying sensitivity and specificity by a diverse range of laboratory tests. All these tests are unfortunately imperfect, suffer from poor assay reproducibility (inter-method and inter-laboratory) and a lack of standardisation and harmonisation. Clinicians and laboratory personnel may struggle to keep abreast of these factors, as well as the expanding range of available aPL tests, and consequent result interpretation. Therefore, APS remains a significant diagnostic challenge for many clinicians across a wide range of clinical specialities, due to these issues related to laboratory testing as well as the ever-expanding range of reported clinical manifestations. This review is primarily focussed on issues related to laboratory testing for APS in regards to the currently available assays, and summarises recent international consensus guidelines for aPL testing, both for the liquid phase functional LA assays and the solid phase assays (anticardiolipin and anti-beta-2-Glycoprotein-I).

Diagnostic value of distinguishing and reporting different perinuclear ANCA (P-ANCA) immunofluorescence patterns: a prospective study.

OBJECTIVES: To investigate whether discriminating the classic perinuclear antineutrophil cytoplasmic antibody (P-ANCA) pattern from atypical P-ANCA and uninterpretable patterns improves the diagnostic utility of ANCA testing. METHODS: All ANCA requests (n = 3,544) referred to Pathology Queensland were analyzed prospectively over 4 months for P-ANCA pattern subtypes and myeloperoxidase (MPO)-ANCA/PR3-ANCA results and correlated with clinical, laboratory, and radiologic evidence of necrotizing small vessel vasculitis. RESULTS: Of the 436 perinuclear immunofluorescence-positive samples, 45 were classic P-ANCA, 163 were atypical P-ANCA, and 228 were antinuclear antibodies/uninterpretable. The classic P-ANCA pattern had a significantly stronger association with vasculitis (30/45) than atypical P-ANCA (2/163) (P <.0001) or ANA/uninterpretable patterns (8/228) (P <.0001). The combination of a classic P-ANCA pattern and positive MPO-ANCA/PR3-ANCA result was also more strongly associated with vasculitis than a positive MPO-ANCA/PR3-ANCA result in isolation (P = .003). CONCLUSIONS: This study demonstrates that reporting different P-ANCA patterns (including ANA/uninterpretable patterns) provides additional diagnostic information to MPO-ANCA/PR3-ANCA results.

Compensation neurosis: a too quickly forgotten concept?

There has been great debate concerning the existence and meaning of compensation neurosis. It is included in the International Classification of Diseases (ICD)-9 and -10 but not listed in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR). On the eve of publication of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), we re-examine the history and concept of compensation neurosis and conceptually update the condition to reflect current psychiatric thought. We consider its utility as a diagnostic entity for forensic evaluations and its components as they relate to exaggeration in injury claims. We also discuss how compensation neurosis differs from malingering and factitious disorder.