Real-World Outcomes of Immunotherapy for Melanoma Brain Metastases in New Zealand.

PURPOSE: Melanoma brain metastases (BMs) are associated with poor survival. Combination immune checkpoint inhibitors (ICIs) with anti-PD1 and anti-CTLA-4 are the international standard-of-care treatment. Most landmark clinical trials excluded real-world patients with symptomatic disease, poor performance status (PS), and steroid use. Despite the high incidence of melanoma in New Zealand (NZ), the only publicly funded systemic treatment is anti-PD1 monotherapy. The real-world outcomes for BMs after ICIs in NZ are unknown. METHODOLOGY: Medical records of patients with melanoma BMs in seven cancer centers across NZ between September 1, 2016, and September 1, 2020, were evaluated. Clinicopathologic characteristics, treatment, intracranial (IC) tumor response rates, IC progression-free survival, and overall survival (OS) are reported. RESULTS: One hundred and forty-four patients received at least one dose of ICI. One hundred and thirty-three (93%) patients received anti-PD1 monotherapy. Almost a quarter of patients had poor baseline PS, 56% were symptomatic, and 33% had corticosteroids. Patients also received local therapies: 61 (42%) patients underwent surgery, 42 (29%) received whole brain radiation, and 47 (33%) received stereotactic radiation. The median OS was 15 months, and a third of patients were alive at 2 years. The toxicity of ICIs was at 28% and 15% for Common Terminology Criteria for Adverse Events grade 1-2 and 3-4 events, respectively. Of the patients who are still alive, 76% of patients remained symptomatic neurologically at last follow-up. CONCLUSION: Most patients in this NZ real-world study were symptomatic and received anti-PD1 monotherapy. Approximately one-third of treated patients are alive at 2 years, but most patients remained symptomatic. This highlights the need for more effective treatment and prospective management of their neurologic rehabilitation needs.

Pembrolizumab-induced Myasthenia Gravis: Literature Review of Ocular Manifestations and a Refractory Case.

Immune checkpoint inhibition is a new and promising therapy approved for the treatment of various malignancies. Pembrolizumab is a potent tumor suppressor that acts by upregulating the immune system to recognize cancer cells which may result in disrupted self-tolerance. We describe a case and perform a literature review of myasthenia gravis with ocular manifestations after treatment with pembrolizumab. Our case had bilateral ptosis refractory to conventional treatment, and she remained functionally blind as a result. The literature review included 28 cases of immune-related myasthenia gravis, and a 30% mortality rate excluding deaths from primary cancer progression was shown. Under half had full symptom resolution (n=13, 46%), and there was no clear correlation between specific management strategies and prognosis. Patients with isolated ocular myasthenia gravis (n=9, 32%) were twice as likely to be symptom-free after treatment compared with generalized myasthenia gravis (75% vs. 39%). Respiratory involvement was associated with twice the mortality rate (60% vs. 33%) and triple the risk of noncomplete symptom resolution (20% vs. 61%). The majority of cases had their pembrolizumab discontinued (n=20, 71%), but 3 were successfully rechallenged by utilizing prophylactic low-dose steroids. Patients with immune-related myasthenia gravis experience increased mortality and morbidity but if steroid-responsive, may benefit from the reintroduction of anti-programmed cell death protein 1 therapy for end-stage malignancy with close monitoring. A high index of clinical suspicion for immune-related adverse effects are critical in an era of rising immunotherapy use.

γδ T Cells in Merkel Cell Carcinomas Have a Proinflammatory Profile Prognostic of Patient Survival.

Merkel cell carcinomas (MCC) are immunogenic skin cancers associated with viral infection or UV mutagenesis. To study T-cell infiltrates in MCC, we analyzed 58 MCC lesions from 39 patients using multiplex-IHC/immunofluorescence (m-IHC/IF). CD4+ or CD8+ T cells comprised the majority of infiltrating T lymphocytes in most tumors. However, almost half of the tumors harbored prominent CD4/CD8 double-negative (DN) T-cell infiltrates (>20% DN T cells), and in 12% of cases, DN T cells represented the majority of T cells. Flow cytometric analysis of single-cell suspensions from fresh tumors identified DN T cells as predominantly Vδ2- γδ T cells. In the context of γδ T-cell inflammation, these cells expressed PD-1 and LAG3, which is consistent with a suppressed or exhausted phenotype, and CD103, which indicates tissue residency. Furthermore, single-cell RNA sequencing (scRNA-seq) identified a transcriptional profile of γδ T cells suggestive of proinflammatory potential. T-cell receptor (TCR) analysis confirmed clonal expansion of Vδ1 and Vδ3 clonotypes, and functional studies using cloned γδ TCRs demonstrated restriction of these for CD1c and MR1 antigen-presenting molecules. On the basis of a 13-gene γδ T-cell signature derived from scRNA-seq analysis, gene-set enrichment on bulk RNA-seq data showed a positive correlation between enrichment scores and DN T-cell infiltrates. An improved disease-specific survival was evident for patients with high enrichment scores, and complete responses to anti-PD-1/PD-L1 treatment were observed in three of four cases with high enrichment scores. Thus, γδ T-cell infiltration may serve as a prognostic biomarker and should be explored for therapeutic interventions.See related Spotlight on p. 600.

18F-FDG PET/CT based spleen to liver ratio associates with clinical outcome to ipilimumab in patients with metastatic melanoma.

BACKGROUND: Immune checkpoint blockade such as ipilimumab and anti-PD1 monoclonal antibodies have significantly improved survival in advanced melanoma. Biomarkers are urgently needed as a majority of patients do not respond, despite treatment-related toxicities. We analysed pre-treatment 18F-fluorodeoxyglucose positron emission tomography/computerised tomography (FDG PET/CT) parameters to assess its correlation with patient outcome. METHODS: This retrospective study evaluated pre-treatment FDG PET/CT scans in a discovery cohort of patients with advanced melanoma treated with ipilimumab or anti-PD1. Pre-treatment scans were assessed for maximum tumoral standardised uptake value (SUVmax), metabolic tumour volume (MTV) and spleen to liver ratio (SLR). Progression-free survival (PFS) and overall survival (OS) were characterised and modelled using univariable and multivariable analyses. Correlation of SLR and OS was validated in an independent cohort. Blood parameters and stored sera of patients from the discovery cohort was analysed to investigate biological correlates with SLR. RESULTS: Of the 90 evaluable patients in the discovery cohort: 50 received ipilimumab monotherapy, 20 received anti-PD1 monotherapy, and 20 patients received ipilimumab followed by anti-PD1 upon disease progression. High SLR > 1.1 was associated with poor PFS (median 1 vs 3 months; HR 3.14, p = 0.008) for patients treated with ipilimumab. High SLR was associated with poor OS after ipilimumab (median 1 vs 21 months; HR 5.83, p = 0.0001); as well as poor OS after first line immunotherapy of either ipilimumab or anti-PD1 (median 1 vs 14 months; HR 3.92, p = 0.003). The association of high SLR and poor OS after ipilimumab was validated in an independent cohort of 110 patients (median 2.3 months versus 11.9 months, HR 3.74). SLR was associated with poor OS in a multi-variable model independent of stage, LDH, absolute lymphocyte count and MTV. CONCLUSIONS: Pre-treatment Spleen to liver ratio (SLR) > 1.1 was associated with poor outcome after ipilimumab in advanced melanoma. This parameter warrants prospective evaluation.

Balancing the Hype with Reality: What Do Patients with Advanced Melanoma Consider When Making the Decision to Have Immunotherapy?

BACKGROUND: Immunotherapy has resulted in unprecedented improvements in survival and maintained quality of life for many patients with advanced melanoma. However, durable responses are observed in only a minority of patients, and severe treatment side effects are experienced by 5%-30%. There are no reliable tests that can differentiate between patients who are likely to respond to immunotherapy and those who will not. Hence, new challenges have arisen as clinicians try to facilitate patients in their decision-making regarding immunotherapy. Furthermore, little is known about the real-world patients' experience and understanding of immunotherapy outside the clinical trial setting. Here, we explore the perspectives of patients undergoing immunotherapy for melanoma and focus on factors that influenced their treatment decision-making. MATERIALS AND METHODS: Twenty-three in-depth semistructured interviews were conducted with patients receiving pembrolizumab for stage IV melanoma at an Australian public cancer hospital. Patients were recruited at a range of time points after commencing therapy, and their experience of treatment was explored. Interviews were audio recorded, transcribed verbatim, coded, and analyzed thematically. RESULTS: Immunotherapy is viewed as a symbol of hope, with high-profile anecdotes reinforcing this perception. Only a minority of patients expressed a good understanding of the likely efficacy and potential treatment side effects. Patients are reliant on their clinicians' recommendation regarding immunotherapy treatment decisions. CONCLUSION: Novel treatments such as immunotherapy provide significant hope for patients. This may influence their preference for immunotherapy over and above the usual considerations of the trade-off between efficacy and toxicity. Careful counsel and individualized patient resources may further facilitate treatment decision-making. IMPLICATIONS FOR PRACTICE: This study highlighted some of the misconceptions held by patients that need to be addressed when discussing the possibility of receiving treatment with immunotherapy for advanced melanoma. Patients placed a lot of importance on high-profile anecdotes rather than truly understanding likely outcomes of treatment based on personal circumstances. The majority of patients had a poor understanding of the potential side effects and long-term implications of treatment with immunotherapy. Careful counsel is required in order to facilitate informed decision-making about treatment and to ensure possible side effects are known and appreciated. Further research is needed to develop tools to aid decision-making in everyday clinical practice.

Outcomes of Australian patients receiving non-funded anti-PD-1 immune checkpoint inhibitors for non-melanoma cancers.

AIM: To characterize the outcomes of patients with nonmelanoma solid tumors receiving anti-PD-1 immunotherapy not funded by the Australian Pharmaceutical Benefits Scheme. METHODS: Medical records of patients with metastatic nonmelanoma tumor diagnoses treated with anti-PD-1 (self-funded pembrolizumab or nivolumab through an access program) from January 1, 2014, to December 31, 2016, at Peter MacCallum Cancer Centre, were retrospectively reviewed. Events after December 31, 2016, were censored. RESULTS: Of 47 patients identified, 27 (57%) had lung cancer. Twenty-six had compassionate access to nivolumab (24 lung, one renal, one gastroesophageal with possible new lung primary). Median overall survival was 5.7 months. Eleven (23%) achieved a partial response; none had complete response. Twenty (43%) had disease progression on first imaging; 16 (48%) of these continued treatment beyond radiological progression, with three achieving subsequent partial responses. Ten (21%) were not re-staged mostly due to rapid deterioration or death. At 6 and 12 months, nine (20%) and two (4%) remained on treatment, respectively. Five (12%) discontinued treatment due to immune-related toxicities. Of 34 patients who died, 71% received treatment within the last month of life; 38% died in an acute hospital. None of 25 patients with poor Eastern Cooperative Oncology Group performance scores of 2-4 responded. CONCLUSION: The response rates and overall survival of patients with NSCLC, renal carcinoma and triple negative breast cancer of good performance status receiving anti-PD-1 therapy outside of a clinical trial are consistent with clinical trial data. However, patients with poor ECOG performance status are unlikely to respond. Careful patient selection and counseling about the potential outcomes of self-funding treatment in this setting is needed.

Clinical and palliative care outcomes for patients of poor performance status treated with antiprogrammed death-1 monoclonal antibodies for advanced melanoma.

BACKGROUND: Antiprogrammed death-1 antibodies (anti-PD1) have response rates of 40% in metastatic melanoma. Patients with poor performance status (PS) were excluded from clinical trials, yet use of anti-PD1 is widespread in clinical practice. Literature regarding clinical and palliative care outcomes in patients with poor PS treated with anti-PD1 is lacking. METHODS: Retrospective review of outcomes for all patients with advanced melanoma treated with anti-PD1 between 2012 and June 2015 at Peter MacCallum Cancer Centre, a tertiary specialist cancer center in Australia. RESULTS: Between 2012 and 2015, 91 patients received anti-PD1: median age 63, 65% males, 77% elevated LDH>1xULN (37/48 patients). Fifty-eight patients had baseline ECOG PS of 0-1 (64%), 24 patients ECOG PS 2-3 (26%) and ECOG PS was not recorded in nine patients (10%). Median overall survival (OS) for the ECOG PS 0-1 group was 19.5 months and 1.8 months for ECOG PS 2-3 (HR 5.5; 95% CI, 9.1-50.3; P = 0.0001). Tumor response was 23/58 (39%) in ECOG PS 0-1, 2/16 (12%) in ECOG PS 2 and 0/8 in ECOG PS 3. Toxicity did not differ between different groups. ECOG PS 2-3 patients were more likely to be treated and hospitalized within the last month of life compared to ECOG PS 0-1 patients, RR 1.75 (95% CI, 1.04-2.56, P = 0.019) and RR 1.73 (95% CI, 1.10-2.16, P = 0.009), respectively. ECOG PS 2-3 patients were more likely to die in an acute hospital RR 2.68 (95% CI, 1.17-6.51, P = 0.016). CONCLUSIONS: Patients with poor baseline PS have a significantly lower OS and reduced response to anti-PD1. Further quality of life and palliative care research is needed.

Efficacy of anti-PD-1 therapy in patients with melanoma brain metastases.

BACKGROUND: There is limited data on the efficacy of anti-programmed death 1 (PD-1) antibodies in patients (pts) with melanoma brain metastasis (BM), particularly those which are symptomatic. METHOD: We retrospectively assessed pts with melanoma BM treated with PD-1 antibodies, nivolumab and pembrolizumab. Clinicopathologic and treatment parameters were collected and outcomes determined for intracranial (IC) response rate (RR) using a modified RECIST criteria, with up to five IC target lesions used to determine IC response, disease control rate (DCR) and progression-free survival (PFS). RESULTS: A total of 66 pts were identified with a median follow up of 7.0 months (range 0.8-24.5 months). A total of 68% were male and 45% BRAF V600 mutation positive. At PD-1 antibody commencement, 50% had an elevated LDH; 64% had local therapy to BM prior to commencing anti-PD1, of which 5% had surgical resection, 14% stereotactic radiosurgery (SRS), 18% whole-brain radiotherapy (WBRT), 27% had surgery and radiotherapy. Twenty-one per cent started anti-PD-1 as first line systemic therapy. No pt had prior anti-PD-1 treatment. The IC overall RR was 21 and DCR 56%. Responses occurred in 21% of pts with symptomatic BM. The median OS was 9.9 months (95% CI 6.93-17.74). Pts with symptomatic BM had shorter PFS than those without symptoms (2.7 vs 7.4 months, P=0.035) and numerically shorter OS (5.7 vs 13.0 months, P=0.068). Pts requiring corticosteroids also had a numerically shorter PFS (3.2 vs 7.4 months, P=0.081) and OS (4.8 vs 13.1 months, P=0.039). CONCLUSIONS: IC responses to anti-PD-1 antibodies occur in pts with BM, including those with symptomatic BM requiring corticosteroids. Prospective trials evaluating anti-PD-1 therapy in pts with BM are underway.

The Advantages and Challenges of Using FDG PET/CT for Response Assessment in Melanoma in the Era of Targeted Agents and Immunotherapy.

The treatment of melanoma has been revolutionised in recent years by advances in the understanding of the genomic landscape of this disease, which has led to the development of new targeted therapeutic agents, and the ability to therapeutically manipulate the immune system through inhibition of cancer cell-T-cell interactions that prevent an adaptive immune response. While these therapeutic interventions have dramatically improved the prospects of survival for patients with advanced melanoma, they bring significant complexity to the interpretation of therapeutic response because their mechanisms and temporal profile of response vary considerably. In this review, we discuss the mode of action of these emerging therapies and their toxicities to provide a framework for the use of FDG PET/CT in therapeutic response assessment. We propose that the greatest utility of PET in assessment of response to agents that abrogate signalling related to BRAF mutation is for early assessment of resistance, while in anti-CTLA4 therapy, immunological flare can compromise early assessment of response but can identify potentially life-threatening autoimmune reactions. For anti-PD1/PDL1 therapy, the role of FDG PET/CT is more akin to its use in other solid malignancies undergoing treatment with conventional chemotherapy. However, further research is required to optimise the timing of scans and response criteria in this disease.

CD271 Expression on Patient Melanoma Cells Is Unstable and Unlinked to Tumorigenicity.

The stability of markers that identify cancer cells that propagate disease is important to the outcomes of targeted therapy strategies. In human melanoma, conflicting data exist as to whether hierarchical expression of CD271/p75/NGFR (nerve growth factor receptor) marks cells with enriched tumorigenicity, which would compel their specific targeting in therapy. To test whether these discrepancies relate to differences among groups in assay approaches, we undertook side-by-side testing of published methods of patient-derived melanoma xenografting (PDX), including comparisons of tissue digestion procedures or coinjected Matrigel formulations. We found that CD271(-) and CD271(+) melanoma cells from each of seven patients were similarly tumorigenic, regardless of assay variations. Surprisingly variable CD271 expression patterns were observed in the analyses of sibling PDX tumors (n = 68) grown in the same experiments from either CD271(-) or CD271(+) cells obtained from patients. This indicates unstable intratumoral lineage relationships between CD271(-) and CD271(+) melanoma cells that are inconsistent with classical, epigenetically based theories of disease progression, such as the cancer stem cell and plasticity models. SNP genotyping of pairs of sibling PDX tumors grown from phenotypically identical CD271(-) or CD271(+) cells showed large pairwise differences in copy number (28%-48%). Differences were also apparent in the copy number profiles of CD271(-) and CD271(+) cells purified directly from each of the four melanomas (1.4%-23%). Thus, CD271 expression in patient melanomas is unstable, not consistently linked to increased tumorigenicity and associated with genetic heterogeneity, undermining its use as a marker in clinical studies. Cancer Res; 76(13); 3965-77. ©2016 AACR.

Differential kinetics of response and toxicity using stereotactic radiation and interventional radiological coiling for pulmonary arterio-venous shunting from metastatic leiomyosarcoma.

Case report demonstrating the differential kinetics of response and toxicity using stereotactic radiation and interventional radiological coiling for pulmonary arterio-venous shunting from leiomyosarcoma pulmonary metastases.

Evidence supporting the 19 ß-strand model for Tom40 from cysteine scanning and protease site accessibility studies.

Most proteins found in mitochondria are translated in the cytosol and enter the organelle via the TOM complex (translocase of the outer mitochondrial membrane). Tom40 is the pore forming component of the complex. Although the three-dimensional structure of Tom40 has not been determined, the structure of porin, a related protein, has been shown to be a ß-barrel containing 19 membrane spanning ß-strands and an N-terminal α-helical region. The evolutionary relationship between the two proteins has allowed modeling of Tom40 into a similar structure by several laboratories. However, it has been suggested that the 19-strand porin structure does not represent the native form of the protein. If true, modeling of Tom40 based on the porin structure would also be invalid. We have used substituted cysteine accessibility mapping to identify several potential ß-strands in the Tom40 protein in isolated mitochondria. These data, together with protease accessibility studies, support the 19 ß-strand model for Tom40 with the C-terminal end of the protein localized to the intermembrane space.

Generic affiliations of Canthium species placed under Pyrostria group B sensu Bridson (Vanguerieae, Rubiaceae) inferred from morphology and molecular data.

BACKGROUND: Pyrostria sensu lato (s.l.) is regarded as one of the polyphyletic group within Vanguerieae formerly comprising of Pyrostria sensu stricto (s.s.), Pyrostria group A and Pyrostria group B delineated by the number of locules and geographical occurrence. Recent molecular phylogenetic studies within the genus have narrowed its circumscription that resulted in the merging of Pyrostria group A and Pyrostria s.s. Although some species of Pyrostria group B were already transferred to Pyrostria s.s. and Psydrax based on morphology, other representatives of the group remain unsettled. RESULTS: Bayesian and parsimony analysis of the combined ITS (nrDNA) and trnL-F (cpDNA) datasets showed a well-supported clade of the whole Vanguerieae containing four Philippine endemic representatives of Pyrostria group B. The placement of Canthium oligophlebium, Canthium obovatifolium and Canthium ramosii within Pyrostria s.s. (PP = 0.99; BS = 85%) is robustly supported likewise the affiliation of C. gynochthodes with Psydrax (PP = 0.94; BS = 85%). Morphological features shared by our species with Pyrostria s.s. and Psydrax further supports our molecular data. CONCLUSION: Our study supports the earlier hypothesis that Canthium oligophlebium, C. obovatifolium and C. ramosii should be placed under Pyrostria s.s. except for C. gynochthodes that grouped with Psydrax. Four new combinations are proposed in this study. The generic affiliations of other species of Pyrostria group B should be reinvestigated towards a more natural classfication in Vanguerieae.

Zoledronic acid to prevent bone loss in Chinese men receiving androgen deprivation therapy for prostate cancer.

AIM: To explore the bone mineral density (BMD) preservation effect of zoledronic acid and its renal safety and tolerability in Chinese patients with prostate cancer on androgen deprivation therapy (ADT). METHODS: Overall 26 prostate cancer patients with ADT were given zoledronic acid 4 mg by a 15-min i.v. infusion every 3 months for up to 12 months. Assessment was made at baseline and at 3, 6, 9 and 12 months. Dual-energy X-ray absorptiometry was used to measure the BMD of the lumbar spine and the femoral neck at baseline and 12 months. RESULTS: A total of 23 of 26 recruited patients completed the study. Seven patients had bone metastases. The overall mean increase in BMD (T-score) of the lumbar spine and femoral head from baseline to follow up at 12 months was significant (-2.32 ± 0.98 to -2.03 ± 1.08, P = 0.02 and -1.77 ± 0.72 to -1.63 ± 0.76, P = 0.01, respectively). In subgroup analyses, significant BMD improvement was observed independent of the status of bone metastasis and the means of ADT. Zoledronic acid had no adverse effect on renal function. Adverse events related to zoledronic acid were minimal. CONCLUSION: Zoledronic acid administered every 3 months significantly increased BMD in prostate cancer patients receiving ADT. It had a satisfactory adverse event profile and imposed minimal risk on patients' renal function.

Development and pilot-testing of a Decision Aid for use among Chinese women facing breast cancer surgery.

BACKGROUND: Women choosing breast cancer surgery encounter treatment decision-making (TDM) difficulties, which can cause psychological distress. Decision Aids (DAs) may facilitate TDM, but there are no DAs designed for Chinese populations. We developed a DA for Chinese women newly diagnosed with breast cancer, for use during the initial surgical consultation. AIMS: Conduct a pilot study to assess the DA acceptability and utility among Chinese women diagnosed with breast cancer. METHODS: Women preferred the DA in booklet format. A booklet was developed and revised and evaluated in two consecutive pilot studies (P1 and P2). On concluding their initial diagnostic consultation, 95 and 38 Chinese women newly diagnosed with breast cancer received the draft and revised draft DA booklet, respectively. Four-day post-consultation, women had questionnaires read out to them and to which they responded assessing attitudes towards the DA and their understanding of treatment options. RESULTS: The original DA was read/partially read by 66/22% (n = 84) of women, whilst the revised version was read/partially read by 74/16% (n = 35), including subliterate women (χ(2) = 0.76, P = 0.679). Knowledge scores varied with the extent the booklet was read (P1: F = 12.68, d.f. 2, P < 0.001; P2: F = 3.744, d.f. 2, P = 0.034). The revised, shorter version was graphically rich and resulted in improved perceived utility, [except for the 'treatment options' (χ(2) = 5.50, P = 0.019) and 'TDM guidance' (χ(2) = 8.19, P = 0.004) sections] without increasing anxiety (F = 0.689, P = 0.408; F = 3.45, P = 0.073). CONCLUSION: The DA was perceived as acceptable and useful for most women. The DA effectiveness is currently being evaluated using a randomized controlled trial.

Effect of body mass index on serum prostate-specific antigen levels among patients presenting with lower urinary tract symptoms.

PURPOSE: Studies among asymptomatic male subjects have suggested that a higher body mass index (BMI) is associated with lower serum prostate-specific antigen (PSA) levels. We aimed to investigate whether a similar effect also occurs in patients presenting with lower urinary tract symptoms (LUTS) to a urological unit and its potential implications. METHODS: A retrospective review was carried out at our centre between 2005 and 2009. The serum PSA and BMI of the patients were retrieved from a prospectively collected database. The BMI was divided into normal (< 23 kg/m2), overweight (23-27 kg/m2), and obese (>27 kg/m2) categories according to WHO recommendation for analysis of the association with PSA level. RESULTS: A total of 1,612 patients with a mean age of 64.6 were included. The mean PSA levels for the normal, overweight, and obese patients were 4.84, 4.54, and 3.95 ng/ml, respectively, with a significant negative correlation (Spearman's coefficient=-0.05, p=0.03). A significant negative association between PSA and BMI among the normal, overweight, and obese groups was also demonstrated by analysis of variance (p=0.01). After adjusting for age differences, there was a significant difference between PSA level for obese patients with a BMI>27 (3.95 ng/ml) and non-obese patients with a BMI<27 (4.67 ng/ml) with analysis of covariance (p=0.02). CONCLUSION: In symptomatic male patients, a higher BMI was significantly associated with lower PSA levels. BMI should be considered in the interpretation of serum PSA levels in overweight and obese patients presenting with LUTS.