Five-year analysis of neoadjuvant dabrafenib and trametinib for stage III melanoma.

BACKGROUND: Neoadjuvant dabrafenib plus trametinib has a high pathological response rate and impressive short-term survival in patients with resectable stage III melanoma. We report 5-year outcomes from the phase II NeoCombi trial. PATIENTS AND METHODS: NeoCombi (NCT01972347) was a single-arm, open-label, single-centre, phase II trial. Eligible patients were adults (aged ≥18 years) with histologically confirmed, resectable, RECIST-measurable, American Joint Committee on Cancer seventh edition clinical stage IIIB-C BRAF V600E/K-mutant melanoma and Eastern Cooperative Oncology Group performance status ≤1. Patients received 52 weeks of treatment with dabrafenib 150 mg (orally twice per day) plus trametinib 2 mg (orally once per day), with complete resection of the pre-therapy tumour bed at week 12. RESULTS: Between 20 August 2014 and 19 April 2017, 35 patients were enrolled. At data cut-off (17 August 2021), the median follow-up was 60 months [95% confidence interval (CI) 56-72 months]. Overall, 21 of 35 (60%) patients recurred, including 12 (57%) with first recurrence in locoregional sites (followed by later distant recurrence in 6) and 9 (43%) with first recurrence in distant sites, including 3 in the brain. Most recurrences occurred within 2 years, with no recurrences beyond 3 years. At 5 years, recurrence-free survival (RFS) was 40% (95% CI 27% to 60%), distant metastasis-free survival (DMFS) was 57% (95% CI 42% to 76%), and overall survival was 80% (95% CI 67% to 94%). Five-year survival outcomes were stratified by pathological response: RFS was 53% with pathological complete response (pCR) versus 28% with non-pCR (P = 0.087), DMFS was 59% versus 55% (P = 0.647), and overall survival was 88% versus 71% (P = 0.205), respectively. CONCLUSIONS: Neoadjuvant dabrafenib plus trametinib has high pathological response rates in clinical stage III melanoma, but low rates of RFS, similar to those achieved with adjuvant targeted therapy alone. Patients with a pCR to dabrafenib plus trametinib still had a high risk of recurrence, unlike that seen with immunotherapy where recurrences are rare.

Mohs micrographic surgery for the treatment of invasive melanoma: A systematic review with meta-analyses.

BACKGROUND: The use of Mohs micrographic surgery (MMS) in melanoma treatment has divided opinion and evidence-based guidelines are lacking. OBJECTIVES: This systematic review aimed to analyse clinical outcomes for patients with invasive melanomas treated with Mohs rather than wide local excision (WLE). METHODS: Embase, MEDLINE and Cochrane databases (to 30 August 2023) were searched for studies using Mohs to treat invasive melanoma. Outcomes of interest were local recurrence and death from melanoma. RESULTS: Thirty-five articles involving 41,499 patients with invasive melanoma treated with Mohs were identified. Sixteen studies compared Mohs with WLE and 19 were Mohs-only, non-comparative studies. Patients treated with Mohs differed significantly from those undergoing WLE, in particular Mohs patients were older and had thinner melanomas. Two comparative studies using the same data source reported adjusted hazard ratios for melanoma-specific death and both showed no significant difference between Mohs and WLE-treated patients; 0.87 (95% CI 0.55-1.35) and 1.20 (95% CI 0.71-20.36). There was also no statistically significant difference in local recurrence risk; the unadjusted risk ratio for patients treated with Mohs was 0.46 (95% CI 0.14-1.51 p = 0.20) with moderate heterogeneity (I2 = 62%). No studies reported multivariable analyses for risk of local recurrence. Many studies generated from relatively few and often overlapping data sets have reported the use of Mohs to treat patients with invasive melanoma. Fewer studies were comparative between Mohs and WLE and these reported substantially different baseline risks of recurrence and death from melanoma between the groups. Mohs has generally been used for thinner melanomas in older patients; therefore, comparisons based on univariable analyses are likely to have been misleading. CONCLUSIONS: On the basis of currently available data, it is not possible to reliably assess whether outcomes differ if invasive melanomas with comparable features are treated with Mohs or WLE, and randomized trial evidence will be required for reliable conclusions to be reached.

Survival update of neoadjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma in the OpACIN and OpACIN-neo trials.

BACKGROUND: Neoadjuvant ipilimumab plus nivolumab has yielded high response rates in patients with macroscopic stage III melanoma. These response rates translated to high short-term survival rates. However, data on long-term survival and disease recurrence are lacking. PATIENTS AND METHODS: In OpACIN, 20 patients with macroscopic stage III melanoma were randomized to ipilimumab 3 mg/kg plus nivolumab 1 mg/kg q3w four cycles of adjuvant or split two cycles of neoadjuvant and two adjuvant. In OpACIN-neo, 86 patients with macroscopic stage III melanoma were randomized to arm A (2× ipilimumab 3 mg/kg plus nivolumab 1 mg/kg q3w; n = 30), arm B (2× ipilimumab 1 mg/kg plus nivolumab 3 mg/kg q3w; n = 30), or arm C (2× ipilimumab 3 mg/kg q3w plus 2× nivolumab 3 mg/kg q2w; n = 26) followed by surgery. RESULTS: The median recurrence-free survival (RFS) and overall survival (OS) were not reached in either trial. After a median follow-up of 69 months for OpACIN, 1/7 patients with a pathologic response to neoadjuvant therapy had disease recurrence. The estimated 5-year RFS and OS rates for the neoadjuvant arm were 70% and 90% versus 60% and 70% for the adjuvant arm. After a median follow-up of 47 months for OpACIN-neo, the estimated 3-year RFS and OS rates were 82% and 92%, respectively. The estimated 3-year RFS rate for OpACIN-neo was 95% for patients with a pathologic response versus 37% for patients without a pathologic response (P < 0.001). In multiple regression analyses, pathologic response was the strongest predictor of disease recurrence. Of the 12 patients with distant disease recurrence after neoadjuvant therapy, 5 responded to subsequent anti-PD-1 and 8 to targeted therapy, although 7 patients showed progression after the initial response. CONCLUSIONS: Updated data confirm the high survival rates after neoadjuvant combination checkpoint inhibition in macroscopic stage III melanoma, especially for patients with a pathologic response. Pathologic response is the strongest surrogate marker for long-term outcome.

Pathological response and tumour bed histopathological features correlate with survival following neoadjuvant immunotherapy in stage III melanoma.

BACKGROUND: Guidelines for pathological evaluation of neoadjuvant specimens and pathological response categories have been developed by the International Neoadjuvant Melanoma Consortium (INMC). As part of the Optimal Neo-adjuvant Combination Scheme of Ipilimumab and Nivolumab (OpACIN-neo) clinical trial of neoadjuvant combination anti-programmed cell death protein 1/anti-cytotoxic T-lymphocyte-associated protein 4 immunotherapy for stage III melanoma, we sought to determine interobserver reproducibility of INMC histopathological assessment principles, identify specific tumour bed histopathological features of immunotherapeutic response that correlated with recurrence and relapse-free survival (RFS) and evaluate proposed INMC pathological response categories for predicting recurrence and RFS. PATIENTS AND METHODS: Clinicopathological characteristics of lymph node dissection specimens of 83 patients enrolled in the OpACIN-neo clinical trial were evaluated. Two methods of assessing histological features of immunotherapeutic response were evaluated: the previously described immune-related pathologic response (irPR) score and our novel immunotherapeutic response score (ITRS). For a subset of cases (n = 29), cellular composition of the tumour bed was analysed by flow cytometry. RESULTS: There was strong interobserver reproducibility in assessment of pathological response (κ = 0.879) and percentage residual viable melanoma (intraclass correlation coefficient = 0.965). The immunotherapeutic response subtype with high fibrosis had the strongest association with lack of recurrence (P = 0.008) and prolonged RFS (P = 0.019). Amongst patients with criteria for pathological non-response (pNR, >50% viable tumour), all who recurred had ≥70% viable melanoma. Higher ITRS and irPR scores correlated with lack of recurrence in the entire cohort (P = 0.002 and P ≤ 0.0001). The number of B lymphocytes was significantly increased in patients with a high fibrosis subtype of treatment response (P = 0.046). CONCLUSIONS: There is strong reproducibility for assessment of pathological response using INMC criteria. Immunotherapeutic response of fibrosis subtype correlated with improved RFS, and may represent a biomarker. Potential B-cell contribution to fibrosis development warrants further study. Reclassification of pNR to a threshold of ≥70% viable melanoma and incorporating additional criteria of <10% fibrosis subtype of response may identify those at highest risk of recurrence, but requires validation.

Prevalence of cognitive impairment using the Montreal Cognitive Assessment questionnaire among patients with systemic lupus erythematosus: a cross-sectional study at two tertiary centres in Malaysia.

INTRODUCTION: Cognitive impairment is a common neuropsychiatric manifestation of systemic lupus erythematosus (SLE). However, it is not routinely assessed for despite its high prevalence and significant disease burden. AIMS: This study aimed to determine the prevalence of mild cognitive impairment (MCI) using the Montreal Cognitive Assessment (MoCA) and its associated factors among patients diagnosed with SLE in Malaysia. METHODS: A total of 200 SLE patients were recruited prospectively from the outpatient clinics of two tertiary hospitals in Malaysia. Standardized clinical interview was utilized to obtain information on socio-demographic characteristics. All patients were then assessed using the MoCA questionnaire for presence of cognitive impairment; the Patient Health Questionnaire 9 (PHQ-9) for presence of depressive symptoms; and the Wong-Baker Faces Pain Scale (WBFPS) for severity of pain. The evaluation of disease activity and severity were performed by the treating rheumatologists and nephrologists using the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and Systemic Lupus International Collaborating Clinics Damage Index (SLICC DI). RESULTS: The prevalence of MCI was 35%. The significant associated factors from the bivariate analysis were male gender (p = 0.04), educational level (p = 0.00), WBFPS score (p = 0.035) and anticardiolipin IgM (p = 0.01). Further analysis using logistic regression model found that male gender (OR = 7.43, 95% confidence interval 1.06-52.06, p = 0.04), lower educational level (OR = 4.4, 95% confidence interval 1.47-13.21, p = 0.01) and presence of anticardiolipin IgM (OR = 6.81, 95% confidence interval 1.45-32.01, p = 0.031) were associated with impaired MoCA scores. Also, increasing pain scores increased the risk of patients being affected by cognitive impairment. CONCLUSION: Over one-third of patients with SLE in our cohort were found to have MCI. Risk factors included male gender, lower educational level, higher pain score and presence of anticardiolipin IgM. Physicians are encouraged to perform routine screening to detect cognitive dysfunction in patients with SLE in their clinical practice as part of a more comprehensive management.

Comparison between the radial forearm and superficial circumflex iliac artery perforator free flaps for oral soft tissue reconstruction.

The radial forearm free flap (RFFF) is widely used for oral reconstruction. The superficial circumflex iliac artery perforator (SCIP) flap is an increasingly utilized alternative. The cases of 165 patients who received either an RFFF or SCIP flap for oral reconstruction at Chris O'Brien Lifehouse, Sydney were reviewed. The aim was to report on patient, pathology, treatment, and outcome variables and to compare these between the two flap groups. A RFFF was used in 126 patients and a SCIP flap in 39 patients. SCIP flap patients were younger (P < 0.001) and had shorter operative times (P < 0.001), shorter anaesthetic times (P < 0.001), and more frequent recipient site dehiscence (P = 0.005) when compared to RFFF patients. The SCIP flap was significantly less frequently used for composite resections including bone when compared to the RFFF (P < 0.001). The primary site distribution was more even for RFFF patients (P < 0.001). There were no SCIP flap failures; three RFFF failures occurred. SCIP flaps performed comparably in terms of operative and clinical outcomes. Most SCIP flaps were utilized in younger patients with partial glossectomy defects.

Survival and biomarker analyses from the OpACIN-neo and OpACIN neoadjuvant immunotherapy trials in stage III melanoma.

Neoadjuvant ipilimumab plus nivolumab showed high pathologic response rates (pRRs) in patients with macroscopic stage III melanoma in the phase 1b OpACIN ( NCT02437279 ) and phase 2 OpACIN-neo ( NCT02977052 ) studies1,2. While the results are promising, data on the durability of these pathologic responses and baseline biomarkers for response and survival were lacking. After a median follow-up of 4 years, none of the patients with a pathologic response (n = 7/9 patients) in the OpACIN study had relapsed. In OpACIN-neo (n = 86), the 2-year estimated relapse-free survival was 84% for all patients, 97% for patients achieving a pathologic response and 36% for nonresponders (P < 0.001). High tumor mutational burden (TMB) and high interferon-gamma-related gene expression signature score (IFN-γ score) were associated with pathologic response and low risk of relapse; pRR was 100% in patients with high IFN-γ score/high TMB; patients with high IFN-γ score/low TMB or low IFN-γ score/high TMB had pRRs of 91% and 88%; while patients with low IFN-γ score/low TMB had a pRR of only 39%. These data demonstrate long-term benefit in patients with a pathologic response and show the predictive potential of TMB and IFN-γ score. Our findings provide a strong rationale for a randomized phase 3 study comparing neoadjuvant ipilimumab plus nivolumab versus standard adjuvant therapy with antibodies against the programmed cell death protein-1 (anti-PD-1) in macroscopic stage III melanoma.

In vivo confocal microscopy for the oral cavity: Current state of the field and future potential.

Confocal microscopy (CM) has been shown to correlate with oral mucosal histopathology in vivo. The purposes of this review are to summarize what we know so far about in vivo CM applications for oral mucosal pathologies, to highlight some current developments with CM devices relevant for oral applications, and to formulate where in vivo CM could hold further application for oral mucosal diagnosis and management. Ovid Medline® and/or Google® searches were performed using the terms 'microscopy, confocal', 'mouth neoplasms', 'mouth mucosa', 'leukoplakia, oral', 'oral lichen planus', 'gingiva', 'cheilitis', 'taste', 'inflammatory oral confocal', 'mucosal confocal' and 'confocal squamous cell oral'. In summary, inclusion criteria were in vivo use of any type of CM for the human oral mucosa and studies on normal or pathological oral mucosa. Experimental studies attempting to identify proteins of interest and microorganisms were excluded. In total 25 relevant articles were found, covering 8 main topics, including normal oral mucosal features (n=15), oral dysplasia or neoplasia (n=7), inflamed oral mucosa (n=3), taste impairment (n=3), oral autoimmune conditions (n=2), pigmented oral pathology/melanoma (n=1), delayed type hypersensitivity (n=1), and cheilitis glandularis (n=1). The evidence for using in vivo CM in these conditions is poor, as it is limited to mainly small descriptive studies. Current device developments for oral CM include improved probe design. The authors propose that future applications for in vivo oral CM may include burning mouth syndrome, intra-operative mapping for cancer surgery, and monitoring and targeted biopsies within field cancerization.

A novel method for the detection of variation in solid-phase immobilised antibody concentration and its possible application in quality control in immunoassay.

Variation of solid-phase antibody concentration could give rise to poor intra- and interassay precision. A new method to detect this variation is reported. Pooled sera with thyroxine (T4) values at the low, medium, and high ranges were assayed in duplicate using anti-T4-coated polystyrene beads. The antigen-antibody complexes were dissociated with methanol-water mixture and the antibodies re-used for subsequent T4 assays in which the same beads were used with the same set of standards and pooled sera. A second set of assays using randomised beads after each assay-wash cycle were also carried out. The variations in weights and surface structures of the beads were also studied. The variation of T4 results of group methods using polyethylene glycol in an external quality control program was also compared with that of covalently linked solid-phase particulate antibody methods over 2 periods. The experimental results showed that there was bead-to-bead variation of antibody concentration which could give rise to poor precision. Rigorous control of the immobilised antibody concentration could further improve the assay performance.

In vitro glycation of dried serum.

In vitro glycation of sera dried on water-resistant medium (Parafilm) and on paper were studied by measuring the change of glucose level, fructosamine:total protein ratio, glycated protein concentration and alteration of electrophoretic mobility of sera before and after drying. The results suggested the instability of glucose in dried sera was due to in vitro glycation which was influenced by surface properties of media on which the sera were deposited. A new method for rapid effective in vitro glycation of sera was also proposed.

A novel method of transport for thyroxine (T4), cortisol, thyroid stimulating hormone (TSH), parathormone (PTH), and insulin.

A simple and convenient method of transport of serum in the form of protein disc on water resistant medium is described. The method was used to study the stability of thyroxine (T4), cortisol, thyroid stimulating hormone (TSH), parathormone (PTH) and insulin. The mean recoveries of these hormones were between 98 and 100%. The standard deviations of duplicates of assays for protein disc samples were comparable to that of serum samples except in assays using enzyme immunoassay techniques. The correlation coefficients of the results between the serum and protein disc samples were satisfactory ranging from 0.86-0.99. The proposed method could be used for interlaboratory referral of serum.

Serum apolipoprotein H and its relationship to lipids and other apolipoproteins in normal human men and women.

Apolipoprotein H (apo H), also known as beta-2-glycoprotein I, has recently become of considerable interest in the field of haemostasis. Because of the possible involvement of apo H in lipid pathways, we wished to test the hypothesis that the serum concentration of apo H was related to serum lipids and other apolipoproteins in normal individuals. One hundred and twenty-three healthy young subjects (67 women and 56 men) aged 22.7 +/- 0.70 years (mean +/- SD) were recruited. Serum level of apo H was higher in male subjects that in age-matched female subjects (167.6 +/- 47.5 mg/l versus 148.8 +/- 30.5 mg/l; P < 0.04). Serum levels of apo H were significantly correlated with serum concentration of cholesterol, but only in female subjects (r = 0.28, P < 0.02). No significant correlations were found between serum levels of apo H and triglycerides, high-density lipoprotein cholesterol, apo A1, apo B or lipoprotein (a) in either of the sexes.

Drug interaction between cyclosporine A and quinine in a renal transplant patient with malaria.

We report a previously undocumented drug interaction between cyclosporine A and quinine. A 39 year old Asian with a recent renal transplant was diagnosed to have a mild cerebral falciparum malaria. He was treated with seven days of oral quinine (600 mg, 8 hourly), followed by a stat dose of pyrimethamine (75 mg)--sulfadoxime (1200mg) because of a strong suspicion of chloroquine resistant falciparum malaria. Using a polyclonal radioimmunoassay method, we measured morning trough cyclosporine A level before, during and after the quinine treatment. Results showed a gradual decrease in the cyclosporine A level from a baseline value of 328 ng/ml to 107 ng/ml after seven days of oral quinine with a subsequent rise to pre-treatment level after discontinuation of quinine. There was no significant change in the dose of cyclosporine A administered during the period of quinine treatment (4.05 to 3.83 mg/kg body weight). Biochemical liver function tests, serum creatinine and hematological parameters were also essentially unchanged during this period. In vitro study showed no significant methodological interference in the cyclosporine assay by quinine dihydrochloride. These findings suggest an in vivo drug interaction between cyclosporine A and quinine. The mechanism of this interaction is not clear. Further studies are required to confirm the significance of this observation. Quinine and its stereoisomer, quinidine should be used with caution until further information is available.

Ventilatory function in Malay Muslims during normal activity and the Ramadan fast.

Pulmonary function parameters were examined in a Malay Muslim population during normal activity and Ramadan fasting conditions. The validity of employing various lung function prediction formulae for the subjects was also assessed. Present findings indicate that the water deprivation regime and resultant dehydration during Ramadan did not cause significant changes in ventilatory functions. Although pulmonary prediction formulae based on Caucasian and African populations were inapplicable to the subjects examined, the equations derived from the neighbouring populations in Singapore could be employed.

A case of alkaptonuria with root canal stenosis.

Spinal involvement in alkaptonuria is common. Patients usually present in the third or fourth decade with spondylosis or acute intervertebral disc prolapse. Alkaptonuria with root canal stenosis has however hitherto not been reported. We wish to report one such patient.

The variation of glucose tolerance in a multi racial population.

The pattern of plasma and urine sugar changes after 50g glucose load in 1900 Malaysians (522 males and 1378 females) consisting predominantly of Malays, Chinese and Indians were studied. The data were analysed using Statistical Package for Social Sciences (SPSS). The results show bimodal distribution of 120 min. plasma sugar values in the age groups 21 years and above and trimodal distribution in most groups above 40 years. The mean 120 minutes plasma sugar cut-off values for nondiabetics (ND), impaired glucose tolerance (IGT), and diabetics (DM) of 8.4 and 11.1 mmol/l respectively were close to the values recommended by the National Diabetic Data Group (NDDG). Fifty two percent of all subjects showed peaked plasma sugar values at 60 minutes (14% of them had IGT, 12% DM), 25% peaked at 30 minutes (98% of them were ND). The rest showed peaked values at 90 minutes (17%), 120 minutes (4%) and 150 minutes (2%) and from this group forty two percent were DM and 23% had IGT. Reliance on urine sugar qualitative tests could misclassify 7.3% of subjects (predominantly elderly females) with hyperglycaemia of greater than 11 mmol/l. This study shows that in the 50 g glucose tolerance test, the NDDG criteria for ND, IGT, DM is still applicable to the Malaysian population. The sampling time could be reduced to four points at 0, 60, 90, and 120 minutes. Blood analysis is the preferred method for the diagnosis of hyperglycaemia in elderly females.

C-peptide response in patients on insulin therapy.

This study was undertaken to document clinical features and presentation of Type I diabetes and to study beta cell response in these patients. It provides data on 30 insulin treated patients. Type I diabetes presents most commonly in the 20-40 year age group. A positive family history in first degree relatives was noted in 40%. The commonest complications were retinopathy (63%) and peripheral neuropathy (53%). Proteinuria (10%), ischaemic heart disease (13%) and peripheral vascular disease (13%) were less common. Three kinds of response to C-peptide were noted: 1) no response 2) blunted response (below the normal range) and 3) peak response to glucose within the low normal range. Group 3 probably represents Type II insulin treated diabetes. There was poor correlation between fasting blood glucose and basal or peak C-peptide response, or with duration or complications of diabetes. C-peptide response may be used to differentiate Type I from Type II diabetes.

Effect of altered eating pattern on serum fructosamine: total protein ratio and plasma glucose level.

The effect of alteration of eating pattern during Ramadan on body mass index (BMI), serum fructosamine: total protein ratio (F/TP), and glucose level in 18 healthy male Asiatic Moslems were studied. The results showed a significant decrease (p less than 0.025) in F/TP at the second week of Ramadan in 11 subjects who experienced continuous decrease in BMI throughout Ramadan. The remaining 7 subjects showed no significant changes in BMI and F/TP. No evidence of hypoglycaemia was observed in the subjects during the study. Serum fructosamine: total protein ratio in subjects with altered eating pattern preferably should be interpreted along with the change in body mass index.