[Inflammatory and immune biomarkers of radiation response]. / Biomarqueurs inflammatoires et immunologiques de réponse à la radiothérapie.

In radiotherapy, the treatment is adapted to each individual to protect healthy tissues but delivers most of time a standard dose according to the tumor histology and site. The only biomarkers studied to individualize the treatment are the HPV status with radiation dose de-escalation strategies, and tumor hypoxia with dose escalation to hypoxic subvolumes using FMISO- or FAZA-PET imaging. In the last decades, evidence has grown about the contribution of the immune system to radiation tumor response. Many preclinical studies have identified some of the mechanisms involved. In this context, we have realised a systematic review to highlight potential inflammatory and immune biomarkers of radiotherapy response. Some are inside the tumor microenvironment, as lymphocyte infiltration or PD-L1 expression, others are circulating biomarkers, including different types of hematological cells, cytokines and chemokines.

Superiority of capsaicin 8% patch versus oral pregabalin on dynamic mechanical allodynia in patients with peripheral neuropathic pain.

BACKGROUND: Dynamic Mechanical Allodynia (DMA) is a typical symptom of neuropathic pain (NP). In a recent study, the capsaicin 8% patch was noninferior to pregabalin in overall peripheral NP relief. In this study, we report the comparison of the two treatments in relieving DMA. METHODS: In a randomized, open-label, head-to-head, 8-week study, 488 patients with peripheral NP were treated with the capsaicin 8% patch (one application) or an optimized dose of pregabalin. Assessments included the area and intensity of DMA, and the number of patients achieving complete resolution of DMA. RESULTS: At baseline, 253 patients in the capsaicin 8% patch group and 235 patients in the pregabalin group had DMA. From baseline to end of study, the change in DMA intensity was significantly in favour of the capsaicin 8% patch versus pregabalin [-0.63 (95% CI: -1.04, -0.23; p = 0.002)]. Similarly, the capsaicin 8% patch was superior to pregabalin in reducing the area of DMA [-39.5 cm2 (95% CI: -69.1, -10.0; p = 0.009)] from baseline to end of study. Overall, a greater proportion of patients had a complete resolution of allodynia with capsaicin 8% patch treatment compared with pregabalin treatment (24.1% vs. 12.3%; p = 0.001) at end of study. CONCLUSION: Capsaicin 8% treatment was superior to pregabalin in reducing the intensity and area of DMA, and in the number of patients with complete resolution of DMA. SIGNIFICANCE: The superiority of a topical treatment over pregabalin in relieving DMA supports the view that both peripheral and central sensitization can mediate allodynia.

Dorsal longitudinal foreskin cut is associated with reduced risk of HIV, syphilis and genital herpes in men: a cross-sectional study in Papua New Guinea.

INTRODUCTION: Various forms of penile foreskin cutting are practised in Papua New Guinea. In the context of an ecological association observed between HIV infection and the dorsal longitudinal foreskin cut, we undertook an investigation of this relationship at the individual level. METHODS: We conducted a cross-sectional study among men attending voluntary confidential HIV counselling and testing clinics. Following informed consent, participants had a face-to-face interview and an examination to categorize foreskin status. HIV testing was conducted on site and relevant specimens collected for laboratory-based Herpes simplex type-2 (HSV-2), syphilis, Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG), and Trichomonas vaginalis (TV) testing. RESULTS: Overall, 1073 men were enrolled: 646 (60.2%) were uncut; 339 (31.6%) had a full dorsal longitudinal cut; 72 (6.7%) a partial dorsal longitudinal cut; and 14 (1.3%) were circumcised. Overall, the prevalence of HIV was 12.3%; HSV-2, 33.6%; active syphilis, 12.1%; CT, 13.4%; NG, 14.1%; and TV 7.6%. Compared with uncut men, men with a full dorsal longitudinal cut were significantly less likely to have HIV (adjusted odds ratio [adjOR] 0.25, 95%CI: 0.12, 0.51); HSV-2 (adjOR 0.60, 95%CI: 0.41, 0.87); or active syphilis (adjOR 0.55, 95%CI: 0.31, 0.96). This apparent protective effect was restricted to men cut prior to sexual debut. There was no difference between cut and uncut men for CT, NG or TV. CONCLUSION: In this large cross-sectional study, men with a dorsal longitudinal foreskin cut were significantly less likely to have HIV, HSV-2 and syphilis compared with uncut men, despite still having a complete (albeit morphologically altered) foreskin. The protective effect of the dorsal cut suggests that the mechanism by which male circumcision works is not simply due to the removal of the inner foreskin and its more easily accessible HIV target cells. Exposure of the penile glans and inner foreskin appear to be key mechanisms by which male circumcision confers protection.Further research in this unique setting will help improve our understanding of the fundamental immunohistologic mechanisms by which male circumcision provides protection, and may lead to new biomedical prevention strategies at the mucosal level.

Deep sequencing approach for investigating infectious agents causing fever.

Acute undifferentiated fever (AUF) poses a diagnostic challenge due to the variety of possible aetiologies. While the majority of AUFs resolve spontaneously, some cases become prolonged and cause significant morbidity and mortality, necessitating improved diagnostic methods. This study evaluated the utility of deep sequencing in fever investigation. DNA and RNA were isolated from plasma/sera of AUF cases being investigated at Cairns Hospital in northern Australia, including eight control samples from patients with a confirmed diagnosis. Following isolation, DNA and RNA were bulk amplified and RNA was reverse transcribed to cDNA. The resulting DNA and cDNA amplicons were subjected to deep sequencing on an Illumina HiSeq 2000 platform. Bioinformatics analysis was performed using the program Kraken and the CLC assembly-alignment pipeline. The results were compared with the outcomes of clinical tests. We generated between 4 and 20 million reads per sample. The results of Kraken and CLC analyses concurred with diagnoses obtained by other means in 87.5 % (7/8) and 25 % (2/8) of control samples, respectively. Some plausible causes of fever were identified in ten patients who remained undiagnosed following routine hospital investigations, including Escherichia coli bacteraemia and scrub typhus that eluded conventional tests. Achromobacter xylosoxidans, Alteromonas macleodii and Enterobacteria phage were prevalent in all samples. A deep sequencing approach of patient plasma/serum samples led to the identification of aetiological agents putatively implicated in AUFs and enabled the study of microbial diversity in human blood. The application of this approach in hospital practice is currently limited by sequencing input requirements and complicated data analysis.

Capsaicin 8% patch versus oral pregabalin in patients with peripheral neuropathic pain.

BACKGROUND: Clinical trials have not yet compared the efficacy of capsaicin 8% patch with current standard therapy in peripheral neuropathic pain (PNP). OBJECTIVES: Head-to-head efficacy and safety trial comparing the capsaicin patch with pregabalin in PNP. METHODS: Open-label, randomized, multicentre, non-inferiority trial. Patients with PNP, aged 18-80 years, were randomly assigned to either the capsaicin 8% patch (n = 282) or an optimised dose of oral pregabalin (n = 277), and assessed for a ≥30% mean decrease in Numeric Pain Rating Scale (NPRS) score from baseline to Week 8. Secondary endpoints included optimal therapeutic effect (OTE), time-to-onset of pain relief and treatment satisfaction. RESULTS: The capsaicin 8% patch was non-inferior to pregabalin in achievement of a ≥30% mean decrease in NPRS score from baseline to Week 8 (55.7% vs. 54.5%, respectively; Odds ratio: 1.03 [95% CI: 0.72, 1.50]). The proportion of patients achieving OTE at Week 8 was 52.1% for the capsaicin 8% patch versus 44.8% for pregabalin (difference: 7.3%; 95% CI: -0.9%, 15.6%). The median time-to-onset of pain relief was significantly shorter for capsaicin 8% patch versus pregabalin (7.5 vs. 36.0 days; Hazard ratio: 1.68 [95% CI: 1.35, 2.08]; p < 0.0001). Treatment satisfaction was also significantly greater with the capsaicin 8% patch versus pregabalin. TEAEs were mild-to-moderate in severity, and resulted in treatment discontinuation only with pregabalin (n = 24). Systemic adverse drug reactions ranged from 0 to 1.1% with capsaicin 8% patch and 2.5 to 18.4% with pregabalin. CONCLUSIONS: The capsaicin 8% patch provided non-inferior pain relief to an optimized dose of pregabalin in PNP, with a faster onset of action, fewer systemic side effects and greater treatment satisfaction.

Subphenotyping and Classification of Orofacial Clefts: Need for Orofacial Cleft Subphenotyping Calls for Revised Classification.

Nonsyndromic orofacial clefting (OFC) describes a range of phenotypes that represent the most common craniofacial birth defects in humans, with an overall birth prevalence of 1:700 live births. Because of the lifelong negative implications on health and well-being associated with OFC and the numbers of people affected, quality research into its etiology, diagnosis, treatment outcomes, and preventative strategies is essential. A range of different methods is used for recording and classifying OFC subphenotypes, one of which is the International Classification of Diseases (ICD) system. However, there is a general perception that research is being hampered by a lack of sensitivity and specificity in grouping those with OFC into subphenotypes, with potential heterogeneity and confounding in epidemiologic, genetic, and genotype-phenotype correlation studies. This article provides a background to the necessity of OFC research, discusses current controversies within cleft subphenotyping, and provides a brief overview of current OFC classifications as well as their limitations. The LAHSHAL classification is described in the context of a potentially useful tool for OFC that could complement the ICD-10/ICD-11 Beta coding systems to become a simply understood, universally accepted, clinically friendly, and research-sensitive instrument. Empowering registries, clinicians, and researchers to use a common classification system would have significant implications for OFC research across the world at a time when accurate subphenotyping is crucial and health care research is becoming increasingly tailored toward the individual.

HIV prevalence is strongly associated with geographical variations in male circumcision and foreskin cutting in Papua New Guinea: an ecological study.

OBJECTIVE: To examine the correlation between HIV prevalence and male circumcision and other foreskin cutting practices across the four regions of Papua New Guinea (PNG). DESIGN: An ecological substudy using unique data from an interdisciplinary research programme to evaluate the acceptability, sociocultural context and public health impact of male circumcision for HIV prevention in PNG. METHODS: Published data describing (a) self-reported circumcision status by region from the 'Acceptability and Feasibility of Male Circumcision for HIV prevention in PNG' study and (b) HIV prevalence by region from PNG National Department of Health were used to correlate male circumcision and other foreskin cutting practices and HIV prevalence. Maps were constructed to visually represent variations across the four regions of PNG. RESULTS: Regions of PNG with the highest HIV prevalence had the lowest prevalence of male circumcision and other forms of foreskin cutting and vice versa. Male circumcision and dorsal longitudinal cuts were strongly associated with HIV prevalence and able to explain 99% of the observed geographical variability in HIV prevalence in PNG (p<0.01). CONCLUSIONS: The regional prevalence of HIV infection in PNG appears to be closely correlated with the regional distribution of male circumcision and dorsal longitudinal foreskin cuts. Further research is warranted to investigate causality of this correlation as well as the potential of dorsal longitudinal cuts to confer protection against HIV acquisition in heterosexual men.

D1 receptors in the nucleus accumbens-shell, but not the core, are involved in mediating ethanol-seeking behavior of alcohol-preferring (P) rats.

Clinical and preclinical research suggest that activation of the mesolimbic dopamine (DA) system is involved in mediating the rewarding actions of drugs of abuse, as well as promoting drug-seeking behavior. Inhibition of DA D1 receptors in the nucleus accumbens (Acb) can reduce ethanol (EtOH)-seeking behavior of non-selective rats triggered by environmental context. However, to date, there has been no research on the effects of D1 receptor agents on EtOH- seeking behavior of high alcohol-preferring (P) rats following prolonged abstinence. The objective of the present study was to examine the effects of microinjecting the D1 antagonist SCH 23390 or the D1 agonist A-77636 into the Acb shell or Acb core on spontaneous recovery of EtOH-seeking behavior. After 10 weeks of concurrent access to EtOH and water, P rats underwent seven extinction sessions (EtOH and water withheld), followed by 2 weeks in their home cages without access to EtOH or operant sessions. In the 2nd week of the home cage phase, rats were bilaterally implanted with guide cannula aimed at the Acb shell or Acb core; rats were allowed 7d ays to recover before EtOH-seeking was assessed by the Pavlovian Spontaneous Recovery (PSR) model. Administration of SCH23390 (1µg/side) into the Acb shell inhibited responding on the EtOH lever, whereas administration of A-77636 (0.125µg/side) increased responding on the EtOH lever. Microinfusion of D1 receptor agents into the Acb core did not alter responding on the EtOH lever. Responses on the water lever were not altered by any of the treatments. The results suggest that activation of D1 receptors within the Acb shell, but not Acb core, are involved in mediating PSR of EtOH-seeking behavior of P rats.

Anti-CEA antibody fragments labeled with [(18)F]AlF for PET imaging of CEA-expressing tumors.

A facile and rapid method to label peptides with (18)F based on chelation of [(18)F]AlF has been developed recently. Since this method requires heating to 100 °C, it cannot be used to label heat-sensitive proteins. Here, we used a two-step procedure to prepare (18)F-labeled heat-labile proteins using the [(18)F]AlF method based on hot maleimide conjugation. 1,4,7-Triazacyclononae-1,4-diacetate (NODA) containing a methyl phenylacetic acid group (MPA) functionalized with N-(2-aminoethyl)maleimide (EM) was used as a ligand which was labeled with [(18)F]AlF and then conjugated to the humanized anti-CEA antibody derivatives hMN-14-Fab', hMN-14-(scFv)2 (diabody), and a Dock-and-Lock engineered dimeric fragment hMN-14 Fab-AD2 at room temperature. The in vivo tumor targeting characteristics of the (18)F-labeled antibody derivatives were determined by PET imaging of mice with s.c. xenografts. NODA-MPAEM was radiolabeled with [(18)F]AlF at a specific activity of 29-39 MBq/nmol and a labeling efficiency of 94 ± 2%. The labeling efficiencies of the maleimide conjugation ranged from 70% to 77%, resulting in [(18)F]AlF-labeled hMN14-Fab', hMN14-Fab-AD2, or hMN14-diabody with a specific activity of 15-17 MBq/nmol. The radiolabeled conjugates were purified by gel filtration. For biodistribution and microPET imaging, antibody fragments were injected intravenously into BALB/c nude mice with s.c. CEA-expressing LS174T xenografts (right flank) and CEA-negative SK-RC-52 xenografts (left flank). All [(18)F]AlF-labeled conjugates showed specific uptake in the LS174T xenografts with a maximal tumor uptake of 4.73% ID/g at 4 h after injection. Uptake in CEA-negative SK-RC-52 xenografts was significantly lower. Tumors were clearly visualized on microPET images. Using a [(18)F]AlF-labeled maleimide functionalized chelator, antibody fragments could be radiofluorinated within 4 h at high specific activity. Here, we translated this method to preclinical PET imaging studies and showed feasibility of [(18)F]AlF-fluorinated hMN-14-Fab', [(18)F]AlF-hMN-14-Fab-AD2, and [(18)F]AlF-hMN-14-diabody for microPET imaging of CEA-expressing colonic cancer.

Development of an imaging-guided CEA-pretargeted radionuclide treatment of advanced colorectal cancer: first clinical results.

BACKGROUND: Radiolabelled antibody targeting of cancer is limited by slow blood clearance. Pretargeting with a non-radiolabelled bispecific monoclonal antibody (bsMAb) followed by a rapidly clearing radiolabelled hapten peptide improves tumour localisation. The primary goals of this first pretargeting study in patients with the anti-CEACAM5 × anti-hapten (HSG) bsMAb, TF2, and the radiolabelled hapten-peptide, IMP288, were to assess optimal pretargeting conditions and safety in patients with metastatic colorectal cancer (CRC). METHODS: Different dose schedules were studied in four cohorts of five patients: (1) shortening the interval between the bsMAb and peptide administration (5 days vs 1 day), (2) escalating the TF2 dose (from 75 to 150 mg), and (3) reducing the peptide dose (from 100 to 25 µg). After confirmation of tumour targeting by (111)In-IMP288, patients were treated with a bsMAb/(177)Lu-IMP288 cycle. RESULTS: Rapid and selective tumour targeting of the radiolabelled peptide was visualised within 1 h, with high tumour-to-tissue ratios (>20 at 24 h). Improved tumour targeting was achieved with a 1-day interval between the administration of the bsMAb and the peptide and with the 25-µg peptide dose. High (177)Lu-IMP288 doses (2.5-7.4 GBq) were well tolerated, with some manageable TF2 infusion reactions, and transient grades 3-4 thrombocytopaenia in 10% of the patients who received (177)Lu-IMP288. CONCLUSION: This phase I study demonstrates for the first time that pretargeting with bsMAb TF2 and radiolabelled IMP288 in patients with CEA-expressing CRC is feasible and safe. With this pretargeting method, tumours are specifically and rapidly targeted.

Reliability, completeness and accuracy of cleft subphenotyping as recorded on the CLEFTSiS (Cleft Service in Scotland) electronic patient record.

OBJECTIVES: The CLEFTSiS (Cleft Service in Scotland) electronic patient record (EPR) contains pre-surgical photographs among other records and this study proposes to assess the reliability of diagnosis and accuracy of the type and extent of cleft. DESIGN AND SETTING: Retrospective study, University of Dundee. MATERIALS AND METHODS: From all 1092 cases contained by the CLEFTSiS EPR from inception (April 2000) until September 2011; syndromic, atypical and submucous clefts, still births, abortuses, cases with non-cleft velopharyngeal incompetence, Pierre Robin Sequence, or Simonart's bands were excluded to leave 730 case records for analysis. Observer 1 recorded the LAHSAL subphenotype using the pre-surgical photographs for each case. Images that were absent, only partially demonstrated the intended anatomical site or were unclear were excluded. The data for Observer 1 was compared to the EPR subphenotype using the Kappa statistic. Thirty randomly selected cases were recoded one month later to calculate intra-observer reliability and three further observers subphenotyped these cases to determine inter-examiner reliability, both using Kappa statistics. RESULTS: Intra- and inter-observer reliability of the LAHSAL system were excellent (0.809-0.992). The correspondence between Observer 1 and the original CLEFTSiS subphenotype was almost perfect (0.812-0.862) except the soft palate and the left alveolus, where agreement was substantial (0.638-0.776). Only 68 (9.3%) of the records fully demonstrated all six anatomical areas of the LAHSAL coding system with intra-oral images being the most frequently deficient views. CONCLUSIONS: The subphenotype data held on the CLEFTSiS EPR is accurate but incomplete. Only 9.3% of cases contained all relevant pre-surgical photographs. Subphenotyping using the LAHSAL classification has a high degree of intra- and inter-observer reliability.

Seroprevalence of anti-Toxoplasma gondii antibodies in HIV/AIDS patients and healthy blood donors at the Port Moresby General Hospital, Papua New Guinea.

The findings of a seroepidemiological study into the prevalence of Toxoplasma gondii infection amongst normal blood donors and patients infected with HIV (human immunodeficiency virus) are presented. Of the total 301 participants, 181 were HIV antibody positive and 120 blood donors were HIV antibody negative. We used a prevalidated questionnaire, enzyme-linked immunosorbent assay (ELISA) and the Epi Info version 3.2 software plus SPSS version 10 for data analysis. The results showed an overall antibody prevalence rate of 53% in the population and a significantly higher infection rate amongst HIV-positive patients: odds ratio 2.14 (95% CI 1.30-3.53), p = 0.001. The study further showed that exposure to cats and highlands origin were independent risk factors. This study has demonstrated that in light of the current HIV/AIDS (acquired immune deficiency syndrome) epidemic, opportunistic infections such as toxoplasmosis will be a cause of considerable morbidity and mortality. It is therefore important that clinicians and public health practitioners fit these findings into overall management strategies to help control toxoplasmosis.

Seroprevalence of anti-Toxoplasma gondii antibodies in HIV/AIDS patients and healthy blood donors at the Port Moresby General Hospital, Papua New Guinea

The findings of a seroepidemiological study into the prevalence of Toxoplasma gondii infection amongst normal blood donors and patients infected with HIV (human immunodeficiency virus) are presented. Of the total 301 participants, 181 were HIV antibody positive and 120 blood donors were HIV antibody negative. We used a prevalidated questionnaire, enzyme-linked immunosorbent assay (ELISA) and the Epi Info version 3.2 software plus SPSS version 10 for data analysis. The results showed an overall antibody prevalence rate of 53% in the population and a significantly higher infection rate amongst HIV-positive patients: odds ratio 2.14 (95% CI 1.30-3.53), p = 0.001. The study further showed that exposure to cats and highlands origin were independent risk factors. This study has demonstrated that in light of the current HIV/AIDS (acquired immune deficiency syndrome) epidemic, opportunistic infections such as toxoplasmosis will be a cause of considerable morbidity and mortality. It is therefore important that clinicians and public health practitioners fit these findings into overall management strategies to help control toxoplasmosis.

Comparison between an uncalibrated pulse contour method and thermodilution technique for cardiac output estimation in septic patients.

BACKGROUND: The purpose of this study was to evaluate the reliability of a new uncalibrated pulse contour method, the MostCare, in determining cardiac output (CO) in septic patients. METHODS: Thirty patients with septic shock admitted to an intensive care unit, receiving a norepinephrine infusion and requiring haemodynamic monitoring with a pulmonary artery catheter, were prospectively enrolled. Thermodilution measurements of CO (ThD-CO) were considered as the 'gold standard'. MostCare was connected to the monitoring system of the radial arterial pressure waveform to obtain a continuous CO calculation (MostCare-CO). ThD-CO and MostCare-CO measurements were recorded at three different haemodynamic states: baseline (T1), after raising mean arterial pressure (MAP) to 90 mm Hg by increasing the norepinephrine infusion (T2), and after returning the MAP to baseline value by decreasing vasopressor therapy (T3). A Bland-Altman and linear regression analyses were performed. RESULTS: A total of 90 paired ThD-CO and MostCare-CO measures were obtained (range 4.1-13.9 litre min(-1) for ThD-CO and 4.5-13.5 litre min(-1) for MostCare-CO). A good correlation between ThD-CO and MostCare-CO was observed (R = 0.93). The mean bias between the two techniques was -0.26 litre min(-1) (sd 0.98 litre min(-1)) and the 95% limits of agreement were -2.22 to 1.70 litre min(-1). The percentage of error was 25%. Pearson's R was 0.94, 0.92, and 0.93 at T1, T2, and T3, respectively. CONCLUSIONS: MostCare-CO and ThD-CO showed a good agreement at each time of the study. The reliability of the MostCare system was not affected by the vascular tone changes produced by a norepinephrine infusion.

Marizomib, a proteasome inhibitor for all seasons: preclinical profile and a framework for clinical trials.

The proteasome has emerged as an important clinically relevant target for the treatment of hematologic malignancies. Since the Food and Drug Administration approved the first-in-class proteasome inhibitor bortezomib (Velcade) for the treatment of relapsed/refractory multiple myeloma (MM) and mantle cell lymphoma, it has become clear that new inhibitors are needed that have a better therapeutic ratio, can overcome inherent and acquired bortezomib resistance and exhibit broader anti-cancer activities. Marizomib (NPI-0052; salinosporamide A) is a structurally and pharmacologically unique ß-lactone-γ-lactam proteasome inhibitor that may fulfill these unmet needs. The potent and sustained inhibition of all three proteolytic activities of the proteasome by marizomib has inspired extensive preclinical evaluation in a variety of hematologic and solid tumor models, where it is efficacious as a single agent and in combination with biologics, chemotherapeutics and targeted therapeutic agents. Specifically, marizomib has been evaluated in models for multiple myeloma, mantle cell lymphoma, Waldenstrom's macroglobulinemia, chronic and acute lymphocytic leukemia, as well as glioma, colorectal and pancreatic cancer models, and has exhibited synergistic activities in tumor models in combination with bortezomib, the immunomodulatory agent lenalidomide (Revlimid), and various histone deacetylase inhibitors. These and other studies provided the framework for ongoing clinical trials in patients with MM, lymphomas, leukemias and solid tumors, including those who have failed bortezomib treatment, as well as in patients with diagnoses where other proteasome inhibitors have not demonstrated significant efficacy. This review captures the remarkable translational studies and contributions from many collaborators that have advanced marizomib from seabed to bench to bedside.

Male circumcision for HIV prevention in Papua New Guinea: a summary of research evidence and recommendations for public health following a national policy forum.

In 2005, a clinical trial in South Africa found that circumcision of young men could reduce their risk of acquiring HIV (human immunodeficiency virus) infection by over 60%. In the following year, two more trials in Africa confirmed this finding, leading the World Health Organization to recommend male circumcision as a public health strategy for HIV prevention in high-incidence countries. In order to inform public health policy in Papua New Guinea (PNG), two major research projects were initiated with the goals of investigating the status of penile cutting practices and assessing understandings, acceptability, feasibility and cost-effectiveness of male circumcision for HIV prevention. In addition, behavioural surveillance surveys systematically asked questions on penile cutting practices and an ethnographic literature review informed historical perspectives of penile cutting in PNG. Key findings from these research activities were presented at a National Policy Forum on Male Circumcision for HIV Prevention held in Port Moresby in November 2011. The Forum made three key recommendations: (1) the formation of a joint National Department of HealthlNational AIDS Council Secretariat Policy Committee on male circumcision; (2) the establishment of an integrated harm reduction program; and (3) that future policy on wide-scale roll-out of male circumcision for HIV prevention in PNG be informed by a combination of data from (a) male circumcision intervention pilot programs and (b) research on the potential protective effect of other forms of penile cutting.