The psychosocial impact of prostate cancer screening for BRCA1 and BRCA2 carriers.

OBJECTIVES: To report the long-term outcomes from a longitudinal psychosocial study that forms part of the 'Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted Screening in men at higher genetic risk and controls' (IMPACT) study. The IMPACT study is a multi-national study of targeted prostate cancer (PrCa) screening in individuals with a known germline pathogenic variant (GPV) in either the BReast CAncer gene 1 (BRCA1) or the BReast CAncer gene 2 (BRCA2). SUBJECTS AND METHODS: Participants enrolled in the IMPACT study were invited to complete a psychosocial questionnaire prior to each annual screening visit for a minimum of 5 years. The questionnaire included questions on sociodemographics and the following measures: Hospital Anxiety and Depression Scale, Impact of Event Scale, 36-item Short-Form Health Survey, Memorial Anxiety Scale for PrCa, Cancer Worry Scale, risk perception and knowledge. RESULTS: A total of 760 participants completed questionnaires: 207 participants with GPV in BRCA1, 265 with GPV in BRCA2 and 288 controls (non-carriers from families with a known GPV). We found no evidence of clinically concerning levels of general or cancer-specific distress or poor health-related quality of life in the cohort as a whole. Individuals in the control group had significantly less worry about PrCa compared with the carriers; however, all mean scores were low and within reported general population norms, where available. BRCA2 carriers with previously high prostate-specific antigen (PSA) levels experience a small but significant increase in PrCa anxiety (P = 0.01) and PSA-specific anxiety (P < 0.001). Cancer risk perceptions reflected information provided during genetic counselling and participants had good levels of knowledge, although this declined over time. CONCLUSION: This is the first study to report the longitudinal psychosocial impact of a targeted PrCa screening programme for BRCA1 and BRCA2 carriers. The results reassure that an annual PSA-based screening programme does not have an adverse impact on psychosocial health or health-related quality of life in these higher-risk individuals. These results are important as more PrCa screening is targeted to higher-risk groups.

The impact of inversions across 33,924 families with rare disease from a national genome sequencing project.

Detection of structural variants (SVs) is currently biased toward those that alter copy number. The relative contribution of inversions toward genetic disease is unclear. In this study, we analyzed genome sequencing data for 33,924 families with rare disease from the 100,000 Genomes Project. From a database hosting >500 million SVs, we focused on 351 genes where haploinsufficiency is a confirmed disease mechanism and identified 47 ultra-rare rearrangements that included an inversion (24 bp to 36.4 Mb, 20/47 de novo). Validation utilized a number of orthogonal approaches, including retrospective exome analysis. RNA-seq data supported the respective diagnoses for six participants. Phenotypic blending was apparent in four probands. Diagnostic odysseys were a common theme (>50 years for one individual), and targeted analysis for the specific gene had already been performed for 30% of these individuals but with no findings. We provide formal confirmation of a European founder origin for an intragenic MSH2 inversion. For two individuals with complex SVs involving the MECP2 mutational hotspot, ambiguous SV structures were resolved using long-read sequencing, influencing clinical interpretation. A de novo inversion of HOXD11-13 was uncovered in a family with Kantaputra-type mesomelic dysplasia. Lastly, a complex translocation disrupting APC and involving nine rearranged segments confirmed a clinical diagnosis for three family members and resolved a conundrum for a sibling with a single polyp. Overall, inversions play a small but notable role in rare disease, likely explaining the etiology in around 1/750 families across heterogeneous clinical cohorts.

Medulloblastoma in a child with osteoma cutis - a rare association due to loss of GNAS expression.

OBJECTIVES: Inactivating GNAS mutations result in varied phenotypes depending on parental origin. Maternally inherited mutations typically lead to hormone resistance and Albright's hereditary osteodystrophy (AHO), characterised by short stature, round facies, brachydactyly and subcutaneous ossifications. Paternal inheritance presents with features of AHO or ectopic ossification without hormone resistance. This report describes the case of a child with osteoma cutis and medulloblastoma. The objective of this report is to highlight the emerging association between inactivating germline GNAS mutations and medulloblastoma, aiming to shed light on its implications for tumor biology and promote future development of targeted surveillance strategies to improve outcomes in paediatric patients with these mutations. CASE PRESENTATION: A 12-month-old boy presented with multiple plaque-like skin lesions. Biopsy confirmed osteoma cutis, prompting genetic testing which confirmed a heterozygous inactivating GNAS mutation. At 2.5 years of age, he developed neurological symptoms and was diagnosed with a desmoplastic nodular medulloblastoma, SHH molecular group, confirmed by MRI and histology. Further analysis indicated a biallelic loss of GNAS in the tumor. CONCLUSIONS: This case provides important insights into the role of GNAS as a tumor suppressor and the emerging association between inactivating GNAS variants and the development of medulloblastoma. The case underscores the importance of careful neurological assessment and ongoing vigilance in children with known inactivating GNAS variants or associated phenotypes. Further work to establish genotype-phenotype correlations is needed to inform optimal management of these patients.

Conformational flexibility of apolipoprotein A-I amino- and carboxy-termini is necessary for lipid binding but not cholesterol efflux.

Because of its critical role in HDL formation, significant efforts have been devoted to studying apolipoprotein A-I (APOA1) structural transitions in response to lipid binding. To assess the requirements for the conformational freedom of its termini during HDL particle formation, we generated three dimeric APOA1 molecules with their termini covalently joined in different combinations. The dimeric (d)-APOA1C-N mutant coupled the C-terminus of one APOA1 molecule to the N-terminus of a second with a short alanine linker, whereas the d-APOA1C-C and d-APOA1N-N mutants coupled the C-termini and the N-termini of two APOA1 molecules, respectively, using introduced cysteine residues to form disulfide linkages. We then tested the ability of these constructs to generate reconstituted HDL by detergent-assisted and spontaneous phospholipid microsolubilization methods. Using cholate dialysis, we demonstrate WT and all APOA1 mutants generated reconstituted HDL particles of similar sizes, morphologies, compositions, and abilities to activate lecithin:cholesterol acyltransferase. Unlike WT, however, the mutants were incapable of spontaneously solubilizing short chain phospholipids into discoidal particles. We found lipid-free d-APOA1C-N and d-APOA1N-N retained most of WT APOA1's ability to promote cholesterol efflux via the ATP binding cassette transporter A1, whereas d-APOA1C-C exhibited impaired cholesterol efflux. Our data support the double belt model for a lipid-bound APOA1 structure in nascent HDL particles and refute other postulated arrangements like the "double super helix." Furthermore, we conclude the conformational freedom of both the N- and C-termini of APOA1 is important in spontaneous microsolubilization of bulk phospholipid but is not critical for ABCA1-mediated cholesterol efflux.

HIV viral exposure and mortality in a multicenter ambulatory HIV adult cohort, United States, 1995-2016.

ABSTRACT: The aim of this study was to identify viral exposure (VE) measures and their relationship to mortality risk among persons with HIV.Prospective multicenter observational study to compare VE formulae.Eligible participants initiated first combination antiretroviral therapy (cART) between March 1, 1995 and June 30, 2015. We included 1645 participants followed for ≥6 months after starting first cART, with cART prescribed ≥75% of time, who underwent ≥2 plasma viral load (VL) and ≥1 CD4+ T-lymphocyte cell (CD4) measurement during observation. We evaluated all-cause mortality from 6 months after cART initiation until June 30, 2016. VE was quantified using 2 time-updated variables: viremia copy-years and percent of person-years (%PY) spent >200 or 50 copies/mL. Cox models were fit to estimate associations between VE and mortality.Participants contributed 10,453 person years [py], with median 14 VLs per patient. Median %PY >200 or >50 were 10% (interquartile range: 1%-47%) and 26% (interquartile range: 6%-72%), respectively. There were 115 deaths, for an overall mortality rate of 1.19 per 100 person years. In univariate models, each measure of VE was significantly associated with mortality risk, as were older age, public insurance, injection drug use HIV risk history, and lower pre-cART CD4. Based on model fit, most recent viral load and %PY >200 copies/mL provided the best combination of VE factors to predict mortality, although all VE combinations evaluated performed well.The combination of most recent VL and %PY >200 copies/mL best predicted mortality, although all evaluated VE measures performed well.

Non-AIDS comorbidity burden differs by sex, race, and insurance type in aging adults in HIV care.

OBJECTIVE: To understand the epidemiology of non-AIDS-related chronic comorbidities (NACMs) among aging persons with HIV (PWH). DESIGN: Prospective multicenter observational study to assess, in an age-stratified fashion, number and types of NACMs by demographic and HIV factors. METHODS: Eligible participants were seen during 1 January 1997 to 30 June 2015, followed for more than 5 years, received antiretroviral therapy (ART), and virally suppressed (HIV viral load <200 copies/ml ≥75% of observation time). Age was stratified (18-40, 41-50, 51-60, ≥61 years). NACMs included cardiovascular disease, cancer, hypertension, diabetes, dyslipidemia, arthritis, viral hepatitis, anemia, and psychiatric illness. RESULTS: Of 1540 patients, 1247 (81%) were men, 406 (26%) non-Hispanic blacks (NHB), 183 (12%) Hispanics/Latinos, 575 (37%) with public insurance, 939 (61%) MSM, and 125 (8%) with injection drug use history. By age strata 18-40, 41-50, 51-60, and at least 61 years, there were 180, 502, 560, and 298 patients, respectively. Median HIV Outpatient Study observation was 10.8 years (range: min-max = 5.0-18.5). Mean number of NACMs increased with older age category (1.4, 2.1, 3.0, and 3.9, respectively; P < 0.001), as did prevalence of most NACMs (P < 0.001). Age-related differences in NACM numbers were primarily due to anemia, hepatitis C virus infection, and diabetes. Differences (all P < 0.05) in NACM number existed by sex (women >men, 3.9 vs. 3.4), race/ethnicity (NHB >non-NHB, 3.8 vs. 3.4), and insurance status (public >private, 4.3 vs. 3.1). CONCLUSIONS: Age-related increases existed in prevalence and number of NACMs, with disproportionate burden among women, NHBs, and the publicly insured. These groups should be targeted for screening and prevention strategies aimed at NACM reduction.

Psychosocial impact of undergoing prostate cancer screening for men with BRCA1 or BRCA2 mutations.

OBJECTIVES: To report the baseline results of a longitudinal psychosocial study that forms part of the IMPACT study, a multi-national investigation of targeted prostate cancer (PCa) screening among men with a known pathogenic germline mutation in the BRCA1 or BRCA2 genes. PARTICPANTS AND METHODS: Men enrolled in the IMPACT study were invited to complete a questionnaire at collaborating sites prior to each annual screening visit. The questionnaire included sociodemographic characteristics and the following measures: the Hospital Anxiety and Depression Scale (HADS), Impact of Event Scale (IES), 36-item short-form health survey (SF-36), Memorial Anxiety Scale for Prostate Cancer, Cancer Worry Scale-Revised, risk perception and knowledge. The results of the baseline questionnaire are presented. RESULTS: A total of 432 men completed questionnaires: 98 and 160 had mutations in BRCA1 and BRCA2 genes, respectively, and 174 were controls (familial mutation negative). Participants' perception of PCa risk was influenced by genetic status. Knowledge levels were high and unrelated to genetic status. Mean scores for the HADS and SF-36 were within reported general population norms and mean IES scores were within normal range. IES mean intrusion and avoidance scores were significantly higher in BRCA1/BRCA2 carriers than in controls and were higher in men with increased PCa risk perception. At the multivariate level, risk perception contributed more significantly to variance in IES scores than genetic status. CONCLUSION: This is the first study to report the psychosocial profile of men with BRCA1/BRCA2 mutations undergoing PCa screening. No clinically concerning levels of general or cancer-specific distress or poor quality of life were detected in the cohort as a whole. A small subset of participants reported higher levels of distress, suggesting the need for healthcare professionals offering PCa screening to identify these risk factors and offer additional information and support to men seeking PCa screening.

Iron deficiency anemia in gastric cancer: a Canadian retrospective review.

BACKGROUND: Gastric cancer is highly prevalent amongst men and women. Previous studies have described the high prevalence of iron deficiency anemia (IDA) in gastrointestinal cancer patients, but few have focused on the gastric cancer population. We aimed to determine the point prevalence of patients with gastric cancer who developed IDA and chemotherapy-induced anemia, and to identify types and frequencies of IDA therapies. PATIENTS AND METHODS: A retrospective review was carried out for 126 gastric cancer patients from 2006 to 2016 at St Michael's Hospital, Toronto, Canada. Patient demographics, laboratory (ferritin, iron parameters) and clinical data regarding IDA were reviewed. IDA was defined as transferrin saturation less than 20%, ferritin less than 100 µg/l, and hemoglobin less than 130 g/l in men and less than 120 g/l in women. RESULTS: Of the 126 patients with gastric cancer identified (median age 70, interquartile range: 59-77), 64.3% were men. Only 18.3% of patients had a self-reported history of IDA, 40% had IDA at the time of gastric cancer diagnosis, and 58.7% were anemic. A total of 77 patients received chemotherapy, and of these, 54.2% developed chemotherapy-induced anemia. At the final follow-up, 21.4% of patients were diagnosed with IDA along their treatment course, and 79.4% were anemic. Red blood cell transfusions were most frequently prescribed (48.4%; median: 4 U; interquartile range: 2-6), compared with oral (31.8%) or intravenous iron (16.7%) therapy. CONCLUSION: The point prevalence of IDA was high in our gastric cancer patients despite inconsistent screening for IDA. Our findings indicate the need for a consistent diagnostic and therapeutic approach to IDA in this vulnerable patient population.

Prostate-specific antigen velocity in a prospective prostate cancer screening study of men with genetic predisposition.

This corrects the article DOI: 10.1038/bjc.2017.429.

Prostate-specific antigen velocity in a prospective prostate cancer screening study of men with genetic predisposition.

BACKGROUND: Prostate-specific antigen (PSA) and PSA-velocity (PSAV) have been used to identify men at risk of prostate cancer (PrCa). The IMPACT study is evaluating PSA screening in men with a known genetic predisposition to PrCa due to BRCA1/2 mutations. This analysis evaluates the utility of PSA and PSAV for identifying PrCa and high-grade disease in this cohort. METHODS: PSAV was calculated using logistic regression to determine if PSA or PSAV predicted the result of prostate biopsy (PB) in men with elevated PSA values. Cox regression was used to determine whether PSA or PSAV predicted PSA elevation in men with low PSAs. Interaction terms were included in the models to determine whether BRCA status influenced the predictiveness of PSA or PSAV. RESULTS: 1634 participants had ⩾3 PSA readings of whom 174 underwent PB and 45 PrCas diagnosed. In men with PSA >3.0 ng ml-l, PSAV was not significantly associated with presence of cancer or high-grade disease. PSAV did not add to PSA for predicting time to an elevated PSA. When comparing BRCA1/2 carriers to non-carriers, we found a significant interaction between BRCA status and last PSA before biopsy (P=0.031) and BRCA2 status and PSAV (P=0.024). However, PSAV was not predictive of biopsy outcome in BRCA2 carriers. CONCLUSIONS: PSA is more strongly predictive of PrCa in BRCA carriers than non-carriers. We did not find evidence that PSAV aids decision-making for BRCA carriers over absolute PSA value alone.

Sexually Transmitted Disease Testing of Human Immunodeficiency Virus-Infected Men Who Have Sex With Men: Room for Improvement.

BACKGROUND: In the United States, sexually transmitted infection (STI) testing is recommended at least annually for sexually active men who have sex with men (MSM). We evaluated human immunodeficiency virus (HIV) providers' STI testing practices and frequency of positive test results. METHODS: We analyzed data from HIV Outpatient Study (HOPS) participants who, from 2007 to 2014, completed a confidential survey about risk behaviors. Using medical records data, we assessed the frequency of gonorrhea, chlamydia, and syphilis testing and positive results during the year after the survey for MSM who reported sex without a condom in the prior 6 months. We compared testing frequency and positivity for men having 1, 2 to 3, and 4 or more sexual partners. Correlates of STI testing were assessed using general linear model to derive relative risks (RR) with associated 95% confidence intervals (CI). RESULTS: Among 719 MSM, testing frequency was 74.5%, 74.3%, and 82.9% for gonorrhea, chlamydia, and syphilis, respectively, and was higher in those men who reported more sexual partners (P < 0.001 for all). In multivariable analysis, testing for gonorrhea was significantly more likely among non-Hispanic black versus white men (RR, 1.17; 95% CI, 1.03-1.33), among men seen in private versus public clinics (RR, 1.16; 95% CI, 1.05-1.28), and among men with 2 to 3 and 4 or more sexual partners versus 1 partner (RR, 1.12; 95% CI, 1.02-1.23, and RR, 1.18; 95% CI, 1.08-1.30, respectively). Correlates of chlamydia and syphilis testing were similar. Test positivity was higher among men with more sexual partners: for gonorrhea 0.0%, 3.0%, and 6.7% for men with 1, 2 to 3, and 4 or more partners, respectively (P < 0.001, syphilis 3.7%, 3.8% and 12.5%, P < 0.001). CONCLUSIONS: Among HIV-infected MSM patients in HIV care who reported sex without a condom, subsequent testing was not documented in clinic records during the following year for up to a quarter of patients. Exploring why STI testing did not occur may improve patient care.

Craniosynostosis and Noonan syndrome with KRAS mutations: Expanding the phenotype with a case report and review of the literature.

Noonan syndrome (NS) is a multiple congenital anomaly syndrome caused by germline mutations in genes coding for components of the Ras-mitogen-activated protein kinase (RAS-MAPK) pathway. Features include short stature, characteristic facies, congenital heart anomalies, and developmental delay. While there is considerable clinical heterogeneity in NS, craniosynostosis is not a common feature of the condition. Here, we report on a 2 month-old girl with Noonan syndrome associated with a de novo mutation in KRAS (p.P34Q) and premature closure of the sagittal suture. We provide a review of the literature of germline KRAS mutations and find that approximately 10% of published cases have craniosynostosis. Our findings expand on the NS phenotype and suggest that germline mutations in the KRAS gene are causally involved in craniosynostosis, supporting the role of the RAS-MAPK pathway as a mediator of aberrant bone growth in cranial sutures. The inclusion of craniosynostosis as a possible phenotype in KRAS-associated Noonan Syndrome has implications in the differential diagnosis and surgical management of individuals with craniosynostosis.

Oculo-auriculo-vertebral spectrum: clinical and molecular analysis of 51 patients.

INTRODUCTION: Oculo-auriculo-vertebral spectrum (OAVS OMIM 164210) is a craniofacial developmental disorder affecting the development of the structures derived from the 1st and the 2nd branchial arches during embryogenesis, with consequential maxillary, mandibular, and ear abnormalities. The phenotype in OAVS is variable and associated clinical features can involve the cardiac, renal, skeletal, and central nervous systems. Its aetiology is still poorly understood. METHODS: We have evaluated the clinical phenotypes of 51 previously unpublished patients with OAVS and their parents, and performed comparative genomic hybridization microarray studies to identify potential causative loci. RESULTS: Of all 51 patients, 16 (31%) had a family history of OAVS. Most had no relevant pre-natal history and only 5 (10%) cases had a history of environmental exposures that have previously been described as risk factors for OAVS. In 28 (55%) cases, the malformations were unilateral. When the involvement was bilateral, it was asymmetric. Ear abnormalities were present in 47 (92%) patients (unilateral in 24; and bilateral in 23). Hearing loss was common (85%), mostly conductive, but also sensorineural, or a combination of both. Hemifacial microsomia was present in 46 (90%) patients (17 also presented facial nerve palsy). Ocular anomalies were present in 15 (29%) patients. Vertebral anomalies were confirmed in 10 (20%) cases; 50% of those had additional heart, brain and/or other organ abnormalities. Brain abnormalities were present in 5 (10%) patients; developmental delay was more common among these patients. Limb abnormalities were found in 6 (12%) patients, and urogenital anomalies in 5 (10%). Array-CGH analysis identified 22q11 dosage anomalies in 10 out of 22 index cases screened. DISCUSSION: In this study we carried out in-depth phenotyping of OAVS in a large, multicentre cohort. Clinical characteristics are in line with those reported previously, however, we observed a higher incidence of hemifacial microsomia and lower incidence of ocular anomalies. Furthermore our data suggests that OAVS patients with vertebral anomalies or congenital heart defects have a higher frequency of additional brain, limb or other malformations. We had a higher rate of familial cases in our cohort in comparison with previous reports, possibly because these cases were referred preferentially to our genetic clinic where family members underwent examination. We propose that familial OAVS cases show phenotypic variability, hence, affected relatives might have been misclassified in previous reports. Moreover, in view of its phenotypic variability, OAVS is potentially a spectrum of conditions, which overlap with other conditions, such as mandibulofacial dysostosis. Array CGH in our cohort identified recurrent dosage anomalies on 22q11, which may contribute to, or increase the risk of OAVS. We hypothesize that although the 22q11 locus may harbour gene(s) or regulatory elements that play a role in the regulation of craniofacial symmetry and 1st and 2nd branchial arch development, OAVS is a heterogeneous condition and many cases have a multifactorial aetiology or are caused by mutations in as yet unidentified gene(s).

HIV laboratory monitoring reliably identifies persons engaged in care.

BACKGROUND: Attendance at biannual medical encounters has been proposed as a minimum national standard for adequate engagement in HIV care. Using data from the HIV Outpatient Study, we analyzed how well dates of HIV-related laboratory testing correlated with attendance at biannual medical encounters. METHODS: HIV Outpatient Study is an open prospective cohort study of HIV-infected patients receiving outpatient care in the United States. The data set included dates for laboratory measurements and medical encounters. We included patients with at least 1 HIV laboratory test (CD4 cell count or plasma HIV RNA viral load) during 2010-2011. An HIV laboratory test was defined as associated with a medical encounter if it occurred within 3 weeks of the encounter. We assessed the predictive value of HIV laboratory tests as a proxy for adequate engagement in clinical care, defined as having had ≥2 HIV laboratory tests within 1 year and performed >90 days apart. RESULTS: A total of 10,321 HIV laboratory tests were recorded from 2909 patients. Adequate engagement in clinical care based on medical encounters was 88.2% and 77.3% when based on laboratory tests. Using HIV laboratory tests to assess engagement had a sensitivity of 85.7%, specificity of 86.0%, and positive and negative predictive values of 97.9% and 44.5%, respectively. Of the 22.7% classified as not engaged in care by the proxy measure, over half (55.5%) were actually engaged. CONCLUSIONS: Using laboratory monitoring reliably classified persons as engaged in care. Of the 22.7% of patients classified as not engaged in care, most were actually engaged.

DNA variations in oculocutaneous albinism: an updated mutation list and current outstanding issues in molecular diagnostics.

Oculocutaneous albinism (OCA) is a rare genetic disorder of melanin synthesis that results in hypopigmented hair, skin, and eyes. There are four types of OCA caused by mutations in TYR (OCA-1), OCA2 (OCA-2), TYRP1 (OCA-3), or SLC45A2 (OCA-4). Here we report 22 novel mutations in the OCA genes; 14 from a cohort of 61 patients seen as part of the NIH OCA Natural History Study and eight from a prior study at the University of Minnesota. We also include a comprehensive list of almost 600 previously reported OCA mutations along with ethnicity information, carrier frequencies, and in silico pathogenicity predictions as a supplement. In addition to discussing the clinical and molecular features of OCA, we address the cases of apparent missing heritability. In our cohort, 26% of patients did not have two mutations in a single OCA gene. We demonstrate the utility of multiple detection methods to reveal mutations missed by Sanger sequencing. Finally, we review the TYR p.R402Q temperature-sensitive variant and confirm its association with cases of albinism with only one identifiable TYR mutation.

Minimally invasive pharmacokinetic and pharmacodynamic technologies in hypothesis-testing clinical trials of innovative therapies.

Clinical trials of new cancer drugs should ideally include measurements of parameters such as molecular target expression, pharmacokinetic (PK) behavior, and pharmacodynamic (PD) endpoints that can be linked to measures of clinical effect. Appropriate PK/PD biomarkers facilitate proof-of-concept demonstrations for target modulation; enhance the rational selection of an optimal drug dose and schedule; aid decision-making, such as whether to continue or close a drug development project; and may explain or predict clinical outcomes. In addition, measurement of PK/PD biomarkers can minimize uncertainty associated with predicting drug safety and efficacy, reduce the high levels of drug attrition during development, accelerate drug approval, and decrease the overall costs of drug development. However, there are many challenges in the development and implementation of biomarkers that probably explain their disappointingly low implementation in phase I trials. The Pharmacodynamic/Pharmacokinetic Technologies Advisory committee of Cancer Research UK has found that submissions for phase I trials of new cancer drugs in the United Kingdom often lack detailed information about PK and/or PD endpoints, which leads to suboptimal information being obtained in those trials or to delays in starting the trials while PK/PD methods are developed and validated. Minimally invasive PK/PD technologies have logistic and ethical advantages over more invasive technologies. Here we review these technologies, emphasizing magnetic resonance spectroscopy and positron emission tomography, which provide detailed functional and metabolic information. Assays that measure effects of drugs on important biologic pathways and processes are likely to be more cost-effective than those that measure specific molecular targets. Development, validation, and implementation of minimally invasive PK/PD methods are encouraged.