Publications by authors named "John F Thompson"

581 Publications

Road to Metastasis: The TWEAK Pathway as a Discriminant between Metastasizing and Non-Metastasizing Thick Melanomas.

Int J Mol Sci 2021 Sep 29;22(19). Epub 2021 Sep 29.

Department of Imaging and Pathology, Translational Cell and Tissue Research, University Hospitals Leuven, 3000 Leuven, Belgium.

Cutaneous melanoma (CM) is the most aggressive form of skin cancer, and its worldwide incidence is rapidly increasing. Early stages can be successfully treated by surgery, but once metastasis has occurred, the prognosis is poor. However, some 5-10% of thick (≥2 mm) melanomas do not follow this scenario and run an unpredictable course. Little is known about the factors that contribute to metastasis in some patient with thick melanomas and the lack thereof in thick melanoma patients who never develop metastatic disease. We were therefore interested to study differential gene expression and pathway analysis and compare non-metastatic and metastatic thick melanomas. We found that the TNF-like weak inducer of apoptosis (TWEAK) pathway was upregulated in thick non-metastasizing melanomas. MAP3K14 (NIK1), BIRC2 (cIAP1), RIPK1, CASP7, CASP8, and TNF play an important role in inhibiting proliferation and invasion of tumor cells via the activation of the non-canonical NF-κB signaling pathway. In particular, this pathway sensitizes melanoma cells to TNF-alpha and activates the apoptosis module of the TWEAK pathway in thick non-metastasizing melanomas. Hence, our study suggests a potential role of the TWEAK pathway in inhibiting thick melanoma from metastasis. Exploitation of these genes and the pathway they control may open future therapeutic avenues.
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http://dx.doi.org/10.3390/ijms221910568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8508767PMC
September 2021

Residual melanoma in wide local excision specimens after 'complete' excision of primary cutaneous in situ and invasive melanomas.

Pathology 2021 Aug 12. Epub 2021 Aug 12.

Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia; Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, NSW, Australia; NSW Health Pathology, Sydney, NSW, Australia. Electronic address:

Wide local excision (WLE) to achieve adequate clearance margins is the standard initial definitive treatment for patients with biopsy-proven primary cutaneous melanoma. Residual melanoma in WLE specimens after prior complete excision-biopsy (CEB) is reported in 0-6.3% of cases. However, studies evaluating the prevalence, clinicopathological features and relevance of persistent disease in WLE specimens are limited. This study sought to determine the frequency of and clinicopathological characteristics associated with residual melanoma in WLE specimens performed after a CEB of primary cutaneous or acral melanoma (in situ or invasive) with clinically and histologically tumour-free margins, and assess its relevance. A review of the research database and pathology archives of a large Australian tertiary referral melanoma treatment centre was performed. Eligible patients were those for whom a definitive WLE was performed after CEB of a primary melanoma (in situ or invasive) with negative clinical and histological margins, between May 2013 and May 2015. All partial biopsies were excluded. Of 640 eligible patients, 510 (79.7%) had invasive melanoma and 130 (20.3%) had melanoma in situ. Residual disease was identified in 20 cases (20/640, 3.1%), of which three (15%) were melanoma in situ on CEB and 17 (85%) were invasive melanoma. On univariate analysis, the presence of residual disease in WLE specimens was associated with lentigo maligna (LM)/LM melanoma (LMM) subtype [odds ratio (OR) 10.33; 95% confidence interval (CI) 2.84-37.54; p=0.004], nodular melanoma (NM) subtype (OR 4.92; 95% CI 1.53-15.85; p=0.0076) and, for invasive tumours, higher tumour mitotic rate (mean 7.7, SD 7.51 vs 3.4, SD 4.83; OR 1.11; 95% CI 1.04-1.18; p=0.0014). Breslow thickness >4 mm was associated with a higher risk of residual disease (OR 7.30; 95% CI 1.88, 28.26; p=0.004). Cases with residual disease had primary tumours with a significantly larger diameter (median 14 mm, range 4-25) than those without residual disease (median 9 mm, range 2-60), (OR 1.07; 95% CI 1.03-1.11; p≤0.001) and were also more likely to be amelanotic (38% vs 14%), (OR 3.69; 95% CI 1.17, 11.60; p=0.026). Residual disease was associated with assessment of >3 slides of tissue (OR 6.98; 95% CI 1.54-31.62; p=0.0118) and complete blocking of the scar (OR 31.69; 95% CI 3.98-252.21; p=0.0011). Residual melanoma in WLE specimens is an infrequent occurrence. Risk factors for residual disease are LM/LMM and NM melanoma subtypes, higher mitotic rate, larger lesion diameter and amelanosis. Tumours with these features warrant more extensive pathological sampling. WLE after CEB for melanoma remains an important procedure to reduce local recurrence; however, limited pathological sampling of the WLE scar is probably appropriate for cases lacking high risk features.
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http://dx.doi.org/10.1016/j.pathol.2021.05.094DOI Listing
August 2021

ASO Author Reflections: Surgical Resection May Improve the Outcome for Patients with Residual Metastatic Melanoma When Modern Systemic Therapies Have Not Achieved Complete Disease Control.

Ann Surg Oncol 2021 10 9;28(11):6124-6125. Epub 2021 Aug 9.

Melanoma Institute Australia, The University of Sydney, North Sydney, NSW, 2040, Australia.

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http://dx.doi.org/10.1245/s10434-021-10514-zDOI Listing
October 2021

In Sentinel Node-Positive Melanoma Patients, Does Omission of Completion Lymph Node Dissection Make More Intensive Follow-Up Necessary, and Does Adjuvant Systemic Therapy Permit Less Intensive Follow-Up?

Authors:
John F Thompson

Ann Surg Oncol 2021 Nov 7;28(12):6915-6917. Epub 2021 Aug 7.

Melanoma Institute Australia, The University of Sydney, North Sydney, NSW, Australia.

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http://dx.doi.org/10.1245/s10434-021-10572-3DOI Listing
November 2021

Survival Outcomes of Salvage Metastasectomy After Failure of Modern-Era Systemic Therapy for Melanoma.

Ann Surg Oncol 2021 Oct 4;28(11):6109-6123. Epub 2021 Aug 4.

Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia.

Background: Metastasectomy for selected patients with melanoma was associated with improved survival in the era before effective systemic therapy. Emerging evidence shows that these benefits persist even in this era of BRAF-targeted therapy and immune checkpoint inhibitor immunotherapy. This study aimed to evaluate the outcomes of salvage metastasectomy after failure of systemic therapy.

Methods: Stage 3 or 4 melanoma patients with extracranial disease progression after at least 4 weeks of systemic treatment between 2009 and 2020 were identified and categorized as resected to no evidence of disease (NED), non-progressive residual disease (NPRD), or progressive residual disease (PRD). Systemic therapy was stratified into BRAF-targeted therapy, immune checkpoint inhibitor immunotherapy, or both. The end points of overall survival (OS), progression-free survival (PFS), and locoregional disease control (LRC) were assessed using Kaplan-Meier curves. Uni- and multivariable Cox regression procedures were used to examine factors associated with OS, PFS and LRC.

Results: The study enrolled 190 patients. Among all the patients, the 5-year OS from metastatectomy was 52%, the 3-year PFS was 21%, and the 5-year LRC was 61%. After resection to NED, NPRD, and PRD, the 5-year OS values were 69%, 62% and 8%, respectively. Fewer lines of preoperative therapy, use of preoperative immunotherapy, and resection to NED were predictors of improved OS. After resection to NED, NPRD, and PRD, the 3-year PFS values were 23%, 24% and 10%, and the 5-year LRC values were 61%, 72% and 34%, respectively.

Conclusions: Salvage metastasectomy was associated with durable survival and disease control, particularly after resection to NED, preoperative immunotherapy, and fewer lines of preoperative systemic therapy.
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http://dx.doi.org/10.1245/s10434-021-10489-xDOI Listing
October 2021

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

ANZ J Surg 2021 08;91 Suppl 2:3-13

Melanoma Institute Australia, The University of Sydney and Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.

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.
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http://dx.doi.org/10.1111/ans.17051DOI Listing
August 2021

Histological regression in melanoma: impact on sentinel lymph node status and survival.

Mod Pathol 2021 Nov 10;34(11):1999-2008. Epub 2021 Jul 10.

Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia.

Regression in melanoma is an immunological phenomenon that results in partial or complete replacement of the tumor with variably vascular fibrous tissue, often accompanied by pigment-laden macrophages and chronic inflammation. In some cases, tumor-infiltrating lymphocytes (TILs) may represent the earliest phase of this process. The prognostic significance of regression has long been a matter of debate, with inconsistent findings reported in the literature to date. This study sought to determine whether regression in primary cutaneous melanomas predicted sentinel lymph node (SLN) status and survival outcomes in a large cohort of patients managed at a single centre. Clinical and pathological parameters for 8,693 consecutive cases were retrieved. Associations between regression and SLN status, overall survival (OS), melanoma-specific survival (MSS) and recurrence-free survival (RFS) were investigated using logistic and Cox regression. Histological evidence of regression was present in 1958 cases (22.5%). Regression was significantly associated with lower Breslow thickness, lower mitotic rate, and absence of ulceration (p < 0.0001). Multivariable analysis showed that regression in combination with TILs independently predicted a negative SLN biopsy (OR 0.33; 95% C.I. 0.20-0.52; p < 0.0001). Patients whose tumors showed both regression and TILs had the highest 10-year OS (65%, 95% C.I. 59-71%), MSS (85%, 95% C.I. 81-89%), and RFS (60%, 95% C.I. 54-66%). On multivariable analyses, the concurrent presence of regression and TILs independently predicted the lowest risk of death from melanoma (HR 0.69; 95% C.I. 0.51-0.94; p = 0.0003) as well as the lowest rate of disease recurrence (HR 0.71; 95% C.I. 0.58-0.85; p < 0.0001). However, in contrast, in the subgroup analysis of Stage III patients, the presence of regression predicted the lowest OS and RFS, with MSS showing a similar trend. Overall, these findings indicate a prognostically favorable role of regression in primary cutaneous melanoma. However, in Stage III melanoma patients, regression may be a marker of more aggressive disease.
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http://dx.doi.org/10.1038/s41379-021-00870-2DOI Listing
November 2021

Clinical and Molecular Heterogeneity in Patients with Innate Resistance to Anti-PD-1 +/- Anti-CTLA-4 Immunotherapy in Metastatic Melanoma Reveals Distinct Therapeutic Targets.

Cancers (Basel) 2021 Jun 25;13(13). Epub 2021 Jun 25.

Melanoma Institute Australia, The University of Sydney, Sydney, NSW 2065, Australia.

While immune checkpoint inhibitors targeting the CTLA-4 and PD-1 receptors have significantly improved outcomes of many patients with metastatic melanoma, there remains a group of patients who demonstrate no benefit. In this study, we sought to characterise patients who do not respond to anti-PD-1-based therapies based on their clinical, genetic and immune profiles. Forty patients with metastatic melanoma who did not respond to anti-PD-1 +/- anti-CTLA-4 treatment were identified. Targeted RNA sequencing ( = 37) was performed on pretreatment formalin-fixed paraffin-embedded (FFPE) melanoma specimens. Patients clustered into two groups based on the expression profiles of 26 differentially expressed genes: an immune gene rich group ( = 17) expressing genes associated with immune and T cell signalling, and a second group ( = 20) expressing genes associated with metabolism, signal transduction and neuronal signalling. Multiplex immunohistochemistry validated significantly higher densities of tumour-infiltrating lymphocytes (TILs) and macrophages in the immune gene-rich group. This TIL-high subset of patients also demonstrated higher expression of alternative immune-regulatory drug targets compared to the TIL-low group. Patients were also subdivided into rapid progressors and other progressors (cut-off 2 mo progression-free survival), with significantly lower TILs ( = 0.04) and CD68+ macrophages ( = 0.0091) in the rapid progressors. Furthermore, a trend towards a higher tumour burden was observed in rapid progressors ( = 0.06). These data highlight the need for a personalised and multilayer (clinical and molecular) approach for identifying the most appropriate treatments for anti-PD-1 resistant patients and provides insight into how individual treatment strategies can be achieved.
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http://dx.doi.org/10.3390/cancers13133186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8267740PMC
June 2021

Characterizing the Clinical Implications of Histologic Regression in Melanoma Requires Clear Diagnostic Criteria That Are Consistently Applied-Reply.

JAMA Dermatol 2021 Aug;157(8):1006-1007

Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia.

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http://dx.doi.org/10.1001/jamadermatol.2021.1497DOI Listing
August 2021

Re-defining the role of surgery in the management of patients with oligometastatic stage IV melanoma in the era of effective systemic therapies.

Eur J Cancer 2021 Aug 12;153:8-15. Epub 2021 Jun 12.

Melanoma Institute Australia, The University of Sydney, North Sydney, New South Wales, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia; Mater Hospital, North Sydney, New South Wales, Australia; Royal North Shore Hospital, St Leonards, New South Wales, Australia.

Although previously the mainstay of treatment, the role of surgery in the management of patients with oligometastatic stage IV melanoma has changed with the advent of effective systemic therapies (most notably immunotherapy). Contemporary treatment options for patients with asymptomatic solitary or oligo-metastases include upfront surgery followed by adjuvant immunotherapy or upfront immunotherapy with salvage surgery as required. For suspected solitary or oligo-metastases, surgery serves both diagnostic and therapeutic purposes. Advances in radiological technology allow metastases to be detected earlier and surgery to be less morbid. Surgical morbidities are generally more tolerable than serious immune-related adverse effects, but surgery may be less effective. Upfront immunotherapy ensures that futile surgery is not offered for rapidly progressive disease. It also provides an opportunity to assess response to treatment, which predicts outcome, and may obviate the need for surgery. However, it is important not to miss a window of opportunity for surgical intervention, whereby if disease progresses on immunotherapy it becomes unresectable. In situations where local therapy is recommended but surgery is not desired, stereotactic radiosurgery may be an effective alternative. The decision-making process regarding upfront surgery versus immunotherapy needs to take place within a specialist melanoma multidisciplinary setting and be customised to individual patient and tumour factors. Ultimately, high-level clinical trial evidence is required to resolve uncertainties in the management of patients with oligometastatic stage IV melanoma but the complexity of the varying presentations may make trial design challenging.
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http://dx.doi.org/10.1016/j.ejca.2021.04.037DOI Listing
August 2021

Melanoma with osseous or chondroid differentiation: a report of eight cases including SATB2 expression and mutation analysis.

Pathology 2021 Jun 2. Epub 2021 Jun 2.

Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia; Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, NSW, Australia; NSW Health Pathology, Sydney, NSW, Australia. Electronic address:

Melanoma can present with osteocartilaginous differentiation, however few reports exist on this rare subtype. We present eight cases of melanoma with osteocartilaginous differentiation to highlight its clinical, pathological and molecular features. The cases showed no association with gender (5 males and 3 females) or age (range 23-84 years). Cases included both primary melanomas and distant metastases (6 and 2, respectively), with the majority arising from cutaneous sites (7/8) and the remaining case from a mucosal site. Tumour-infiltrating lymphocyte (TIL) score ranged from 0 to 3 (median 1), and 2/8 lesions had evidence of inflammatory changes or antecedent trauma. No recurrent mutations were found in the tumours by next generation sequencing, and the mutations observed were typical of melanoma rather than osteosarcomatous lesions. The majority of tumours stained positive for melanoma markers including S100, HMB45, Melan-A, SOX10 and MITF. Staining of the osteoblastic marker SATB2 varied from negative to widespread positive. We demonstrate that melanomas with osteocartilaginous differentiation are heterogeneous in presentation and are not typified by a recurrent mutation in cancer associated genes. Where uncertainty exists in diagnosing an osteocartilaginous lesion, a diagnosis of melanoma can be supported by the presence of genomic mutations typical of melanoma such as BRAF, NRAS and NF1, and IHC staining positive for S100, HMB45, Melan-A, SOX10 and MITF. SATB2 may be positive in these lesions and thus should not be used to rule out melanoma.
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http://dx.doi.org/10.1016/j.pathol.2021.02.012DOI Listing
June 2021

Current Challenges in Access to Melanoma Care: A Multidisciplinary Perspective.

Am Soc Clin Oncol Educ Book 2021 Jun;41:e295-e303

Melanoma Institute Australia, Sydney, Australia.

A diagnosis of melanoma requires multidisciplinary specialized care across all stages of disease. Although many important advances have been made for the treatment of melanoma for local and advanced disease, barriers to optimal care remain for many patients who live in areas without ready access to the expertise of a specialized melanoma center. In this article, we review some of the recent advances in the treatment of melanoma and the persistent challenges around the world that prevent the delivery of the best standard of care to patients living in the community. With the therapeutic landscape continuing to evolve and newer more complex drug therapies soon to be approved, it is important to recognize the many challenges that patients face and attempt to identify tools and policies that will help to improve treatment outcomes for their melanoma.
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http://dx.doi.org/10.1200/EDBK_320301DOI Listing
June 2021

Melanoma In Situ: A Critical Review and Re-Evaluation of Current Excision Margin Recommendations.

Adv Ther 2021 07 28;38(7):3506-3530. Epub 2021 May 28.

Melanoma Institute Australia, The University of Sydney, 40 Rocklands Road, North Sydney, NSW, 2060, Australia.

Most international clinical guidelines recommend 5-10 mm clinical margins for excision of melanoma in situ (MIS). While the evidence supporting this is weak, these guidelines are generally consistent. However, as a result of the high incidence of subclinical extension of MIS, especially of the lentigo maligna (LM) subtype, wider margins will often be needed to achieve complete histologic clearance. In this review, we assessed all available contemporary evidence on clearance margins for MIS. No randomized trials were identified and the 31 non-randomized studies were largely retrospective reviews of single-surgeon or single-institution experiences using Mohs micrographic surgery (MMS) for LM or staged excision (SE) for treatment of MIS on the head/neck and/or LM specifically. The available data challenge the adequacy of current international guidelines as they consistently demonstrate the need for clinical margins > 5 mm and often > 10 mm. For LM, any MIS on the head/neck, and/or ≥ 3 cm in diameter, all may require wider clinical margins because of the higher likelihood of subclinical spread. Histologic clearance should be confirmed prior to undertaking complex reconstruction. However, it is not clear whether wider margins are necessary for all MIS subtypes. Indeed, it seems that this is unlikely to be the case. Until optimal surgical margins can be better defined in a randomized trial setting, ideally controlling for MIS subtype and including correlation with histologic excision margins, techniques such as preliminary border mapping of large, ill-defined lesions and, most importantly, sound clinical judgement will be needed when planning surgical clearance margins for the treatment of MIS.
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http://dx.doi.org/10.1007/s12325-021-01783-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8280024PMC
July 2021

The role of regional chemotherapy for advanced limb melanoma in the era of potentially effective systemic therapies.

Melanoma Res 2021 08;31(4):290-297

Melanoma Institute Australia, The University of Sydney, Sydney, NSW.

To review the current role of regional chemotherapy in the management of advanced limb melanoma. Articles reporting the results of isolated limb infusion (ILI) were identified by performing a comprehensive literature search using the PubMed database. Keywords included isolated limb infusion, in-transit melanoma and melphalan. No publication date restrictions were applied. ILI data were compared with those from current systemic therapy clinical trials and the previously reviewed isolated limb perfusion (ILP) literature. Regional chemotherapy is today required in fewer patients because effective systemic therapies now provide an alternative treatment for those who develop extensive local melanoma recurrence or in-transit metastases (ITMs). However, regional chemotherapy may be a valuable treatment option when the side-effects of systemic therapies are of concern, or after systemic treatment failure. ILP achieves overall response rates (ORRs) of 64-100% and complete response rates (CRRs) of 25-89%. ILI achieves ORRs of 41-91% and CRRs of 6-39%. ILP and ILI can have a low risk of serious morbidity. Early results from treatment with ILP or ILI in conjunction with systemic immune therapies suggest that these modalities can be safely combined, which may be useful in patients with refractory limb disease. Regional chemotherapy remains important in the armamentarium of clinicians managing patients with unresectable limb melanoma and may be preferable in those who are frail, elderly or who are at high risk from complications of systemic therapies. The efficacy of combining regional chemotherapy with systemic immune therapy is currently being assessed.
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http://dx.doi.org/10.1097/CMR.0000000000000740DOI Listing
August 2021

Can patient-led surveillance detect subsequent new primary or recurrent melanomas and reduce the need for routinely scheduled follow-up? A protocol for the MEL-SELF randomised controlled trial.

Trials 2021 May 4;22(1):324. Epub 2021 May 4.

Sydney School of Public Health, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia.

Background: Most subsequent new primary or recurrent melanomas might be self-detected if patients are trained to systematically self-examine their skin and have access to timely medical review (patient-led surveillance). Routinely scheduled clinic visits (clinician-led surveillance) is resource-intensive and has not been shown to improve health outcomes; fewer visits may be possible if patient-led surveillance is shown to be safe and effective. The MEL-SELF trial is a randomised controlled trial comparing patient-led surveillance with clinician-led surveillance in people who have been previously treated for localised melanoma.

Methods: Stage 0/I/II melanoma patients (n = 600) from dermatology, surgical, or general practice clinics in NSW Australia, will be randomised (1:1) to the intervention (patient-led surveillance, n = 300) or control (usual care, n = 300). Patients in the intervention will undergo a second randomisation 1:1 to polarised (n = 150) or non-polarised (n = 150) dermatoscope. Patient-led surveillance comprises an educational booklet, skin self-examination (SSE) instructional videos; 3-monthly email/SMS reminders to perform SSE; patient-performed dermoscopy with teledermatologist feedback; clinical review of positive teledermoscopy through fast-tracked unscheduled clinic visits; and routinely scheduled clinic visits following each clinician's usual practice. Clinician-led surveillance comprises an educational booklet and routinely scheduled clinic visits following each clinician's usual practice. The primary outcome, measured at 12 months, is the proportion of participants diagnosed with a subsequent new primary or recurrent melanoma at an unscheduled clinic visit. Secondary outcomes include time from randomisation to diagnosis (of a subsequent new primary or recurrent melanoma and of a new keratinocyte cancer), clinicopathological characteristics of subsequent new primary or recurrent melanomas (including AJCC stage), psychological outcomes, and healthcare use. A nested qualitative study will include interviews with patients and clinicians, and a costing study we will compare costs from a societal perspective. We will compare the technical performance of two different models of dermatoscope (polarised vs non-polarised).

Discussion: The findings from this study may inform guidance on evidence-based follow-up care, that maximises early detection of subsequent new primary or recurrent melanoma and patient wellbeing, while minimising costs to patients, health systems, and society.

Trial Registration: Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12621000176864 . Registered on 18 February 2021.
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http://dx.doi.org/10.1186/s13063-021-05231-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8096155PMC
May 2021

Active surveillance of patients who have sentinel node positive melanoma: An international, multi-institution evaluation of adoption and early outcomes after the Multicenter Selective Lymphadenectomy Trial II (MSLT-2).

Cancer 2021 Jul 7;127(13):2251-2261. Epub 2021 Apr 7.

Department of Surgery, Sahlgrenska Center for Cancer Research, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Background: For patients with sentinel lymph node (SLN)-positive cutaneous melanoma, the Second Multicenter Selective Lymphadenectomy trial demonstrated equivalent disease-specific survival (DSS) with active surveillance using nodal ultrasound versus completion lymph node dissection (CLND). Adoption and outcomes of active surveillance in clinical practice and in adjuvant therapy recipients are unknown.

Methods: In a retrospective cohort of SLN-positive adults treated at 21 institutions in Australia, Europe, and the United States from June 2017 to November 2019, the authors evaluated the impact of active surveillance and adjuvant therapy on all-site recurrence-free survival (RFS), isolated nodal RFS, distant metastasis-free survival (DMFS), and DSS using Kaplan-Meier curves and Cox proportional hazard models.

Results: Among 6347 SLN biopsies, 1154 (18%) were positive and had initial negative distant staging. In total, 965 patients (84%) received active surveillance, 189 (16%) underwent CLND. Four hundred thirty-nine patients received adjuvant therapy (surveillance, 38%; CLND, 39%), with the majority (83%) receiving anti-PD-1 immunotherapy. After a median follow-up of 11 months, 220 patients developed recurrent disease (surveillance, 19%; CLND, 22%), and 24 died of melanoma (surveillance, 2%; CLND, 4%). Sixty-eight patients had an isolated nodal recurrence (surveillance, 6%; CLND, 4%). In patients who received adjuvant treatment without undergoing prior CLND, all isolated nodal recurrences were resectable. On risk-adjusted multivariable analyses, CLND was associated with improved isolated nodal RFS (hazard ratio [HR], 0.36; 95% CI, 0.15-0.88), but not all-site RFS (HR, 0.68; 95% CI, 0.45-1.02). Adjuvant therapy improved all-site RFS (HR, 0.52; 95% CI, 0.47-0.57). DSS and DMFS did not differ by nodal management or adjuvant treatment.

Conclusions: Active surveillance has been adopted for most SLN-positive patients. At initial assessment, real-world outcomes align with randomized trial findings, including in adjuvant therapy recipients.

Lay Summary: For patients with melanoma of the skin and microscopic spread to lymph nodes, monitoring with ultrasound is an alternative to surgically removing the remaining lymph nodes. The authors studied adoption and real-world outcomes of ultrasound monitoring in over 1000 patients treated at 21 centers worldwide, finding that most patients now have ultrasounds instead of surgery. Although slightly more patients have cancer return in the lymph nodes with this strategy, typically, it can be removed with delayed surgery. Compared with up-front surgery, ultrasound monitoring results in the same overall risk of melanoma coming back at any location or of dying from melanoma.
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http://dx.doi.org/10.1002/cncr.33483DOI Listing
July 2021

The worse survival outcomes reported for melanoma patients having sentinel node biopsy after lymphoscintigraphy the previous day do not appear to be due to overnight migration of Tc99m-nanocolloid tracer.

Eur J Surg Oncol 2021 Sep 17;47(9):2450-2453. Epub 2021 Mar 17.

Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia; Department of Melanoma and Surgical Oncology, Royal Prince Alfred Hospital, Sydney, NSW, Australia.

Introduction: It has been reported that the survival of patients having sentinel node (SN) biopsy for melanoma the day after lymphoscintigraphy using Tc99m-nanocolloid is worse than that of patients having lymphoscintigraphy and SN biopsy on the same day [1,2]. A possible explanation suggested is that overnight migration of the tracer from SNs to 2nd-tier nodes occurs, causing failure to remove true SNs.

Materials And Methods: The possibility of overnight tracer migration leading to errors in SN-identification was investigated in 12 patients scheduled for lymphoscintigraphy the day before surgery by repeating SPECT-CT imaging the next morning, before their SN biopsy. The aim was to check whether onward migration of colloid from previously-identified SNs had occurred.

Results: No significant migration of Tc99m-nanocolloid occurred overnight in any patient. All nodes reported to be SNs on day 1 imaging were also present and regarded as SNs on day 2 images. No new foci were visualised on day 2, but some that had been identified on day 1 were not seen on day 2.

Conclusions: Since migration of nanocolloid overnight did not occur, this cannot explain the reported survival disadvantage for patients undergoing SN biopsy the day after lymphoscintigraphy. A likely alternative possibility is that inadequate doses of radioisotope were used for next-day procedures, causing the mistaken removal of 2nd-tier nodes instead of true SNs more frequently. Further research is required to explain the reported reduction in survival of patients having next-day SN biopsy procedures, since the possibility has important clinical implications.
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http://dx.doi.org/10.1016/j.ejso.2021.03.241DOI Listing
September 2021

Treatment of in-transit melanoma metastases using intralesional PV-10.

Melanoma Res 2021 06;31(3):232-241

Melanoma Institute Australia.

Melanoma in-transit metastases (ITMs) can sometimes be difficult to manage by surgical excision due to their number, size or location. Treatment by intralesional injection of PV-10, a 10% solution of rose bengal, has been reported to be a simple, safe and effective alternative, but more outcome data are required to confirm its value in the management of ITMs. Two hundred and twenty-six melanoma ITMs in 48 patients were treated with intralesional PV-10 supplied under a special-access scheme. By 8 weeks a complete response in all injected ITMs was achieved in 22 patients (46%) and a partial response in 19 patients (40%). Of 19 patients who had uninjected metastases, 3 (16%) had a response in these. The most common adverse event was transient localised pain in injected tumours. New ITMs developed in 25 patients within 8 weeks, and later in another 8 patients. Repeat injection cycles were given to 21 patients: 13 of these received repeat injection into partially responding or nonresponding tumours, 5 had new ITMs, as well as partially-responding lesions injected, and 3 received injection into new ITMs only. Twenty-two patients received subsequent systemic therapy. At 1 year 37 of the 48 patients were alive, 28 with melanoma, and at 2 years 27 were alive, and 19 with melanoma. Injection of PV-10 was simple and safe and resulted in tumour involution in most patients and sometimes in noninjected tumours. However, many patients developed new lesions; these were treated by further PV-10 injections or with alternative therapies.
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http://dx.doi.org/10.1097/CMR.0000000000000729DOI Listing
June 2021

Organ transplantation and outcomes in patients with a past history of melanoma: A systematic review and meta-analysis.

Clin Transplant 2021 06 7;35(6):e14287. Epub 2021 Apr 7.

Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia.

Background: The incidence of melanoma is steadily rising around the world. There is uncertainty about the safety of solid organ transplantation in patients with a prior history of melanoma.

Aim: To review studies reporting patients with a history of melanoma before solid organ transplantation.

Methods: Electronic searches of Medline, Embase, and the Cochrane library up to March 2020. All study designs, in any language and without sample size restriction, were eligible for inclusion. Risk of bias was assessed using established tools, and meta-analysis was performed using a random-effects model.

Results: We identified 41 studies reporting 703 100 transplant recipients and 1692 had pre-transplantation melanomas. Risk of death, expressed as a hazard ratio, in patients with pre-transplantation melanoma relative to those without prior melanoma, was 1.32 (95% CI: 1.09-1.59). After transplantation, 13.1% of patients with pre-transplantation melanoma developed new or recurrent melanoma (IQR: 4.8%-18.2%).

Conclusions: Around 1-in-400 transplant recipients had a prior history of melanoma. This was associated with a greater than 1-in-10 risk of new or recurrent melanoma after transplantation and an increased risk of death. A 5-year waiting time between a melanoma diagnosis and transplantation has been recommended based on historic registry data, but very little additional information is available to justify or revise this.
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http://dx.doi.org/10.1111/ctr.14287DOI Listing
June 2021

Tumour gene expression signature in primary melanoma predicts long-term outcomes.

Nat Commun 2021 02 18;12(1):1137. Epub 2021 Feb 18.

Cambridge Cancer Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.

Adjuvant systemic therapies are now routinely used following resection of stage III melanoma, however accurate prognostic information is needed to better stratify patients. We use differential expression analyses of primary tumours from 204 RNA-sequenced melanomas within a large adjuvant trial, identifying a 121 metastasis-associated gene signature. This signature strongly associated with progression-free (HR = 1.63, p = 5.24 × 10) and overall survival (HR = 1.61, p = 1.67 × 10), was validated in 175 regional lymph nodes metastasis as well as two externally ascertained datasets. The machine learning classification models trained using the signature genes performed significantly better in predicting metastases than models trained with clinical covariates (p = 7.03 × 10), or published prognostic signatures (p < 0.05). The signature score negatively correlated with measures of immune cell infiltration (ρ = -0.75, p < 2.2 × 10), with a higher score representing reduced lymphocyte infiltration and a higher 5-year risk of death in stage II melanoma. Our expression signature identifies melanoma patients at higher risk of metastases and warrants further evaluation in adjuvant clinical trials.
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http://dx.doi.org/10.1038/s41467-021-21207-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893180PMC
February 2021

Development and Validation of Nomograms to Predict Local, Regional, and Distant Recurrence in Patients With Thin (T1) Melanomas.

J Clin Oncol 2021 04 18;39(11):1243-1252. Epub 2021 Feb 18.

Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia.

Purpose: Although the prognosis of patients with thin primary cutaneous melanomas (T1, ≤ 1.0 mm) is generally excellent, some develop recurrence. We sought to develop and validate a model predicting recurrences in patients with thin melanomas.

Methods: A Dutch population-based cohort (n = 25,930, development set) and a cohort from an Australian melanoma treatment center (n = 2,968, validation set) were analyzed (median follow-up 6.7 and 12.0 years, respectively). Multivariable Cox models were generated for local, regional, and distant recurrence-free survival (RFS). Discrimination was assessed using Harrell's C-statistic for each outcome. Each nomogram performance was evaluated using calibration plots defining low-risk and high-risk groups as the lowest and top 5% of the nomogram risk score, respectively. The nomograms' C-statistics were compared with those of a model including the current American Joint Committee on Cancer staging parameters (T-stage and sentinel node status).

Results: Local, regional, and distant recurrences were found in 209 (0.8%), 503 (1.9%), and 203 (0.8%) Dutch patients, respectively, and 23 (0.8%), 61 (2.1%), and 75 (2.5%) Australian patients, respectively. C-statistics of 0.79 (95% CI, 0.75 to 0.82) for local RFS, 0.77 (95% CI, 0.75 to 0.78) for regional RFS, and 0.80 (95% CI, 0.77 to 0.83) for distant RFS were obtained for the development model. External validation showed C-statistics of 0.80 (95% CI, 0.69 to 0.90), 0.76 (95% CI, 0.70 to 0.82), and 0.74 (95% CI, 0.69 to 0.80), respectively. Calibration plots showed a good match between predicted and observed rates. Using the nomogram, the C-statistic was increased by 9%-12% for the development cohort and by 11%-15% for the validation cohort, compared with a model including only T-stage and sentinel node status.

Conclusion: Most patients with thin melanomas have an excellent prognosis, but some develop recurrence. The presented nomograms can accurately identify a subgroup at high risk. An online calculator is available at www.melanomarisk.org.au.
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http://dx.doi.org/10.1200/JCO.20.02446DOI Listing
April 2021

Germline variants are associated with increased primary melanoma tumor thickness at diagnosis.

Hum Mol Genet 2021 01;29(21):3578-3587

Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, 4006, Australia.

Germline genetic variants have been identified, which predispose individuals and families to develop melanoma. Tumor thickness is the strongest predictor of outcome for clinically localized primary melanoma patients. We sought to determine whether there is a heritable genetic contribution to variation in tumor thickness. If confirmed, this will justify the search for specific genetic variants influencing tumor thickness. To address this, we estimated the proportion of variation in tumor thickness attributable to genome-wide genetic variation (variant-based heritability) using unrelated patients with measured primary cutaneous melanoma thickness. As a secondary analysis, we conducted a genome-wide association study (GWAS) of tumor thickness. The analyses utilized 10 604 individuals with primary cutaneous melanoma drawn from nine GWAS datasets from eight cohorts recruited from the general population, primary care and melanoma treatment centers. Following quality control and filtering to unrelated individuals with study phenotypes, 8125 patients were used in the primary analysis to test whether tumor thickness is heritable. An expanded set of 8505 individuals (47.6% female) were analyzed for the secondary GWAS meta-analysis. Analyses were adjusted for participant age, sex, cohort and ancestry. We found that 26.6% (SE 11.9%, P = 0.0128) of variation in tumor thickness is attributable to genome-wide genetic variation. While requiring replication, a chromosome 11 locus was associated (P < 5 × 10-8) with tumor thickness. Our work indicates that sufficiently large datasets will enable the discovery of genetic variants associated with greater tumor thickness, and this will lead to the identification of host biological processes influencing melanoma growth and invasion.
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http://dx.doi.org/10.1093/hmg/ddaa222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7788289PMC
January 2021

Performance of Long-Term CT and PET/CT Surveillance for Detection of Distant Recurrence in Patients with Resected Stage IIIA-D Melanoma.

Ann Surg Oncol 2021 Aug 3;28(8):4561-4569. Epub 2021 Jan 3.

NHMRC Clinical Trials Centre, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia.

Background: Follow-up for patients with resected stage IIIA-D melanoma may include computed tomography (CT) or positron emission tomography (PET)/CT imaging to identify distant metastases. The aim of this study was to evaluate the test performance over follow-up time, of structured 6- and 12-monthly follow-up imaging schedules in these patients.

Methods: We conducted a retrospective analysis of consecutive resected stage IIIA-D melanoma patients from Melanoma Institute Australia (2000-2017). Patients were followed until a confirmed diagnosis of distant metastasis, end of follow-up schedule, or death. Test accuracy was evaluated by cross-classifying the results of the test against a composite reference standard of histopathology, cytology, radiologic imaging, and/or clinical follow-up, and then quantified longitudinally using logistic regression models with random effects.

Results: In total, 1373 imaging tests were performed among 332 patients. Distant metastases were detected in 110 (33%) patients during a median follow-up of 61 months (interquartile range 38-86), and first detected by imaging in 86 (78%) patients. 152 (68%) patients had at least one false-positive result. Sensitivity of the schedule over 5 years was 79% [95% confidence interval (CI) 70-86%] and specificity was 88% (95% CI 86-90%). There was no evidence of a significant difference in test performance over follow-up time or by American Joint Committee on Cancer (AJCC) substage. The positive predictive value ranged between 33 and 48% over follow-up time, reflecting a ratio of 1:2 false-positives per true-positive finding.

Conclusions: Regular 6- or 12-monthly surveillance imaging using CT or PET/CT has reasonable and consistent sensitivity and specificity over 5-year follow-up for resected stage IIIA-D melanoma patients. These data are useful when discussing the risks and benefits of long-term follow-up.
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http://dx.doi.org/10.1245/s10434-020-09270-3DOI Listing
August 2021

Association of Histologic Regression With a Favorable Outcome in Patients With Stage 1 and Stage 2 Cutaneous Melanoma.

JAMA Dermatol 2021 02;157(2):166-173

Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia.

Importance: Although regression is commonly observed in cutaneous melanoma, it is uncertain whether it is associated with patient prognosis.

Objective: To determine whether histologically confirmed regression was associated with better or worse survival in patients with primary cutaneous melanoma.

Design, Setting, And Participants: This cohort study analyzed data from 2 large cohorts of adults (one in the Netherlands and the other in Australia) with histologically proven, stage 1 and 2 primary, invasive cutaneous melanoma with known regression status treated between 2000 and 2014, with median follow-up times of 4.5 and 11.1 years for the Dutch and Australian cohorts, respectively. For the Dutch patients, population-based data from PALGA, the Dutch Pathology Registry, were used, and follow-up data were retrieved from the Netherlands Cancer Registry. For the Australian patients, data from the database of a large, specialized melanoma treatment center were used.

Main Outcomes And Measures: Multivariable Cox proportional hazards analyses were performed per cohort to assess recurrence-free survival (RFS) and overall survival (OS), and subgroup analyses according to Breslow thickness category and melanoma subtype were performed.

Results: A total of 17 271 Dutch patients and 4980 Australian patients were included. In both cohorts, survival outcomes were better for patients with disease regression. For Dutch patients, the hazard ratio (HR) for those with disease regression was 0.55 (95% CI, 0.48-0.63; P < .001) for RFS and 0.87 (95% CI, 0.79-0.96; P = .004) for OS; for the Australian patients, the HR was 0.61 (95% CI, 0.52-0.72; P < .001) for RFS and 0.73 (95% CI, 0.64-0.84; P < .001) for OS. Subgroup analyses showed that the presence of regression improved RFS within thin and intermediate Breslow thickness melanomas in both cohorts. For patients with superficial spreading melanoma (SSM) subtype, regression improved RFS and OS in both cohorts. For Dutch patients with SSM, the HR for those with disease regression was 0.54 (95% CI, 0.46-0.63; P < .001) for RFS and 0.86 (95% CI, 0.76-0.96; P = .009) for OS; for the Australian patients with SSM, the HR was 0.67 (95% CI, 0.52-0.85; P = .001) for RFS and 0.72 (95% CI, 0.59-0.88; P = .001) for OS.

Conclusions And Relevance: In 2 large patient cohorts from 2 different continents, regression was a favorable prognostic factor for patients with stage 1 and 2 melanomas, especially in those with thin and intermediate thickness tumors and those with SSM subtype.
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http://dx.doi.org/10.1001/jamadermatol.2020.5032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7758823PMC
February 2021

Surveillance of Sentinel Node-Positive Melanoma Patients with Reasons for Exclusion from MSLT-II: Multi-Institutional Propensity Score Matched Analysis.

J Am Coll Surg 2021 04 13;232(4):424-431. Epub 2020 Dec 13.

Department of Surgery, Emory University, Atlanta, GA.

Background: In sentinel lymph node (SLN)-positive melanoma, two randomized trials demonstrated equivalent melanoma-specific survival with nodal surveillance vs completion lymph node dissection (CLND). Patients with microsatellites, extranodal extension (ENE) in the SLN, or >3 positive SLNs constitute a high-risk group largely excluded from the randomized trials, for whom appropriate management remains unknown.

Study Design: SLN-positive patients with any of the three high-risk features were identified from an international cohort. CLND patients were matched 1:1 with surveillance patients using propensity scores. Risk of any-site recurrence, SLN-basin-only recurrence, and melanoma-specific mortality were compared.

Results: Among 1,154 SLN-positive patients, 166 had ENE, microsatellites, and/or >3 positive SLN. At 18.5 months median follow-up, 49% had recurrence (vs 26% in patients without high-risk features, p < 0.01). Among high-risk patients, 52 (31%) underwent CLND and 114 (69%) received surveillance. Fifty-one CLND patients were matched to 51 surveillance patients. The matched cohort was balanced on tumor, nodal, and adjuvant treatment factors. There were no significant differences in any-site recurrence (CLND 49%, surveillance 45%, p = 0.99), SLN-basin-only recurrence (CLND 6%, surveillance 14%, p = 0.20), or melanoma-specific mortality (CLND 14%, surveillance 12%, p = 0.86).

Conclusions: SLN-positive patients with microsatellites, ENE, or >3 positive SLN constitute a high-risk group with a 2-fold greater recurrence risk. For those managed with nodal surveillance, SLN-basin recurrences were more frequent, but all-site recurrence and melanoma-specific mortality were comparable to patients treated with CLND. Most recurrences were outside the SLN-basin, supporting use of nodal surveillance for SLN-positive patients with microsatellites, ENE, and/or >3 positive SLN.
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http://dx.doi.org/10.1016/j.jamcollsurg.2020.11.014DOI Listing
April 2021

Safety Findings in Pediatric Patients During Long-Term Treatment With Teduglutide for Short-Bowel Syndrome-Associated Intestinal Failure: Pooled Analysis of 4 Clinical Studies.

JPEN J Parenter Enteral Nutr 2021 Sep 2;45(7):1456-1465. Epub 2021 Mar 2.

Shire Human Genetic Therapies, Inc, a Takeda company, Cambridge, Massachusetts, USA.

Background: This analysis assessed combined safety data from 4 clinical studies of teduglutide in pediatric patients with short-bowel syndrome-associated intestinal failure (SBS-IF).

Methods: Safety data from teduglutide-treated patients in 4 clinical trials were pooled. The completed 12-week and 24-week phase 3 core studies (NCT01952080/EudraCT 2013-004588-30 and NCT02682381/EudraCT 2015-002252-27) enrolled children aged 1-17 years with SBS-IF. Patients could elect to enroll in ongoing open-label extensions (NCT02949362/EudraCT 2016-000863-17 and NCT02954458/EudraCT 2016-000849-30). Interim data from ongoing studies were included.

Results: Safety data are reported for 89 pediatric patients treated with teduglutide for a median (range) of 51.7 (5.0-94.7) weeks. Adverse events (AEs) were reported in all patients; the most common were vomiting (51.7%), pyrexia (43.8%), upper respiratory tract infection (41.6%), and cough (33.7%). Thirty-five patients (39.3%) had AEs considered related to teduglutide treatment; abdominal pain and vomiting were most frequent (5.6% each). Three serious AEs in 3 patients (3.4%) were considered related to teduglutide treatment: ileus, d-lactic acidosis, and gastrointestinal obstruction due to hard stools. All 3 events resolved. One cecal polyp was detected, which was not biopsied or found on repeat colonoscopy. No cases of neoplasia occurred.

Conclusion: Based on integrated data from 4 clinical studies, including long-term follow-up for ≤161 weeks, teduglutide had a safety profile consistent with the individual core pediatric studies and as expected for pediatric patients with SBS-IF who never received teduglutide. The most frequent AEs reflected treatment with teduglutide, complications of the underlying disease, and typical childhood illnesses.
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http://dx.doi.org/10.1002/jpen.2061DOI Listing
September 2021

Molecular analysis of primary melanoma T cells identifies patients at risk for metastatic recurrence.

Nat Cancer 2020 Feb 20;1(2):197-209. Epub 2020 Jan 20.

Brigham and Women's Hospital, Department of Dermatology and Harvard Medical School, Boston, MA, USA.

Primary melanomas >1 mm thickness are potentially curable by resection, but can recur metastatically. We assessed the prognostic value of T cell fraction (TCFr) and repertoire T cell clonality, measured by high-throughput-sequencing of the T cell receptor beta chain (TRB) in T2-T4 primary melanomas (n=199). TCFr accurately predicted progression-free survival (PFS) and was independent of thickness, ulceration, mitotic rate, or age. TCFr was second only to tumor thickness in its predictive value, using a gradient boosted model. For accurate PFS prediction, adding TCFr to tumor thickness was superior to adding any other histopathological variable. Furthermore, a TCFr >20% was protective regardless of tumor ulceration status, mitotic rate or presence of nodal disease. TCFr is a quantitative molecular assessment that predicts metastatic recurrence in primary melanoma patients whose disease has been resected surgically. This study suggests that a successful T cell-mediated antitumor response can be present in primary melanomas.
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http://dx.doi.org/10.1038/s43018-019-0019-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7725220PMC
February 2020
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