Salivary toxicity from PSMA-targeted radiopharmaceuticals: What we have learned and where we are going.

Clinical trials of prostate-specific membrane antigen (PSMA) targeted radiopharmaceuticals have shown encouraging results. Some agents, like lutetium-177 [177Lu]Lu-PSMA-617 ([177Lu]Lu-PSMA-617), are already approved for late line treatment of metastatic castration-resistant prostate cancer (mCRPC). Projections are for continued growth of this treatment modality; [177Lu]Lu-PSMA-617 is being studied both in earlier stages of disease and in combination with other anti-cancer therapies. Further, the drug development pipeline is deep with variations of PSMA-targeting radionuclides, including higher energy alpha particles conjugated to PSMA-honing vectors. It is safe to assume that an increasing number of patients will be exposed to PSMA-targeted radiopharmaceuticals during the course of their cancer treatment. In this setting, it is important to better understand and mitigate the most commonly encountered toxicities. One particularly vexing side effect is xerostomia. In this review, we discuss the scope of the problem, inventories to better characterize and monitor this troublesome side effect, and approaches to preserve salivary function and effectively palliate symptoms. This article aims to serve as a useful reference for prescribers of PSMA-targeted radiopharmaceuticals, while also commenting on areas of missing data and opportunities for future research.

Theranostics and artificial intelligence: new frontiers in personalized medicine.

The field of theranostics is rapidly advancing, driven by the goals of enhancing patient care. Recent breakthroughs in artificial intelligence (AI) and its innovative theranostic applications have marked a critical step forward in nuclear medicine, leading to a significant paradigm shift in precision oncology. For instance, AI-assisted tumor characterization, including automated image interpretation, tumor segmentation, feature identification, and prediction of high-risk lesions, improves diagnostic processes, offering a precise and detailed evaluation. With a comprehensive assessment tailored to an individual's unique clinical profile, AI algorithms promise to enhance patient risk classification, thereby benefiting the alignment of patient needs with the most appropriate treatment plans. By uncovering potential factors unseeable to the human eye, such as intrinsic variations in tumor radiosensitivity or molecular profile, AI software has the potential to revolutionize the prediction of response heterogeneity. For accurate and efficient dosimetry calculations, AI technology offers significant advantages by providing customized phantoms and streamlining complex mathematical algorithms, making personalized dosimetry feasible and accessible in busy clinical settings. AI tools have the potential to be leveraged to predict and mitigate treatment-related adverse events, allowing early interventions. Additionally, generative AI can be utilized to find new targets for developing novel radiopharmaceuticals and facilitate drug discovery. However, while there is immense potential and notable interest in the role of AI in theranostics, these technologies do not lack limitations and challenges. There remains still much to be explored and understood. In this study, we investigate the current applications of AI in theranostics and seek to broaden the horizons for future research and innovation.

Metabolic PET/CT analysis of aggressive Non-Hodgkin lymphoma prior to Axicabtagene Ciloleucel CAR-T infusion: predictors of progressive disease, survival, and toxicity.

PET/CT is used to evaluate relapsed/refractory non-Hodgkin lymphoma (NHL) prior to chimeric antigen receptor T-cell (CAR-T) infusion at two time points: pre-leukapheresis (pre-leuk) and pre-lymphodepletion chemotherapy (pre-LD). We hypothesized that changes in PET/CT between these time points predict outcomes after CAR-T. Metabolic tumor volume (MTV), total lesion glycolysis (TLG), and other metrics were calculated from pre-leuk and pre-LD PET/CT scans in patients with NHL who received axicabtagene ciloleucel, and assessed for association with outcomes. Sixty-nine patients were analyzed. While single time point PET/CT characteristics were not associated with risk of PD or death, increases from pre-leuk to pre-LD in parenchymal MTV, nodal MTV, TLG of the largest lesion, and total number of lesions were associated with increased risk of death (p < 0.05 for all). LASSO analysis identified increasing extranodal MTV and increasing TLG of the largest lesion as strong predictors of death (AUC 0.74). Greater pre-LD total MTV was associated with higher risk of grade 3+ immune effector cell-associated neurotoxicity syndrome (ICANS) (p = 0.042). Increasing metabolic disease burden during CAR-T manufacturing is associated with increased risk of progression and death. A two variable risk score stratifies prognosis prior to CAR-T infusion and may inform risk-adapted strategies.

Potential applications of PET/MRI in non-oncologic conditions within the abdomen and pelvis.

PET/MRI is a relatively new imaging modality with several advantages over PET/CT that promise to improve imaging of the abdomen and pelvis for specific diagnostic tasks by combining the superior soft tissue characterization of MRI with the functional information acquired from PET. PET/MRI has an established role in staging and response assessment of multiple abdominopelvic malignancies, but the modality is not yet established for non-oncologic conditions of the abdomen and pelvis. In this review, potential applications of PET/MRI for non-oncologic conditions of abdomen and pelvis are outlined, and the available literature is reviewed to highlight promising areas for further research and translation into clinical practice.

Technologist-Based Implementation of Total Metabolic Tumor Volume into Clinical Practice.

Metabolic tumor volume (MTV) is defined as the total metabolically active tumor volume seen on 18F-FDG PET/CT examinations. Calculating MTV is often time-consuming, requiring a high degree of manual input. In this study, the MTV calculations of a board-certified nuclear radiologist were compared with those of 2 nuclear medicine technologists. As part of the technologists' educational program, after their classroom time they were trained by the radiologist for 30 min. The technologists calculated MTV within 7.5% of the radiologist's calculations in a set of patients who had diffuse large B-cell lymphoma and were undergoing initial staging 18F-FDG PET/CT. These findings suggest that nuclear medicine technologists may help accelerate implementation of MTV into clinical practice with favorable accuracy, possibly as an initial step followed by validation by the interpreting physician. The aim of this study was to explore whether efficiency is improved by integrating nuclear medicine technologists into a semiautomated workflow to calculate total MTV.

Can the use of deception be justified in medical education research? A point/counterpoint and case study.

Deception is a common feature of behavioral research design, although not commonly employed in the medical literature. It can promote scientific validity but is ethically controversial because it compromises subject autonomy and incurs additional costs.  In this Point/Counterpoint monograph, we review the nature of deception in research and present arguments for and against its ethical use as a research methodology in behavioral studies.  We describe the necessary guidelines, safeguards, and oversight, when deceptive methodology is considered, and report our experiences and lessons learned from conducting a multi-institutional audit study that relied upon deception of academic radiology faculty.

Factors Influential in the Selection of Radiology Residents in the Post-Step 1 World: A Discrete Choice Experiment.

OBJECTIVES: Reporting of United States Medical Licensing Examination Step 1 results will transition from a numerical score to a pass or fail result. We sought an objective analysis to determine changes in the relative importance of resident application attributes when numerical Step 1 results are replaced. METHODS: A discrete choice experiment was designed to model radiology resident selection and determine the relative weights of various application factors when paired with a numerical or pass or fail Step 1 result. Faculty involved in resident selection at 14 US radiology programs chose between hypothetical pairs of applicant profiles between August and November 2020. A conditional logistic regression model assessed the relative weights of the attributes, and odds ratios (ORs) were calculated. RESULTS: There were 212 participants. When a numerical Step 1 score was provided, the most influential attributes were medical school (OR: 2.35, 95% confidence interval [CI]: 2.07-2.67), Black or Hispanic race or ethnicity (OR: 2.04, 95% CI: 1.79-2.38), and Step 1 score (OR: 1.8, 95% CI: 1.69-1.95). When Step 1 was reported as pass, the applicant's medical school grew in influence (OR: 2.78, 95% CI: 2.42-3.18), and there was a significant increase in influence of Step 2 scores (OR: 1.31, 95% CI: 1.23-1.40 versus OR 1.57, 95% CI: 1.46-1.69). There was little change in the relative influence of race or ethnicity, gender, class rank, or clerkship honors. DISCUSSION: When Step 1 reporting transitions to pass or fail, medical school prestige gains outsized influence and Step 2 scores partly fill the gap left by Step 1 examination as a single metric of decisive importance in application decisions.

Amyloid arthropathy in smoldering myeloma: Do not take it lightly.

We report a case of smoldering multiple myeloma patient who developed signs and symptoms consistent with polyarthritis. A PET-CT demonstrated marked FDG activity in multiple joints, concerning for inflammatory arthritis. Arthrocentesis from the glenohumeral joint was consistent with inflammatory synovial fluid with no evidence for infection or crystals. Congo-red stain of the synovial fluid was positive, and mass-spectrometry based amyloid typing was consistent with wild-type transthyretin type. The patient responded instantly to glucocorticoids. This case reports highlights the feasibility of non-tissue diagnosis of amyloidosis using body fluids and underscores the importance of accurate typing to avoid erroneous treatment.

Frequency and Characteristics of Nodal and Deltoid FDG and 11C-Choline Uptake on PET Performed After COVID-19 Vaccination.

BACKGROUND. COVID-19 vaccination may trigger reactive lymphadenopathy, confounding imaging interpretation. There has been limited systematic analysis of PET findings after COVID-19 vaccination. OBJECTIVE. The purpose of this study was to evaluate the frequency and characteristics of abnormal FDG and 11C-choline uptake on PET performed after COVID-19 vaccination. METHODS. This retrospective study included 67 patients (43 men and 24 women; mean [± SD] age, 75.6 ± 9.2 years) who underwent PET examination between December 14, 2020, and March 10, 2021, after COVID-19 vaccination and who had undergone prevaccination PET examination without visible axillary node uptake. A total of 52 patients received the BNT162b2 mRNA COVID-19 vaccine (Pfizer-BioNTech; hereafter referred to as the Pfizer-BioNTech vaccine), and 15 received the SARS-CoV-2 mRNA-1273 vaccine (Moderna; hereafter referred to as the Moderna vaccine). Sixty-six of the patients underwent PET/CT, and one underwent PET/MRI. Fifty-four PET examinations used FDG, and 13 used 11C-choline. PET was performed a median of 13 and 10 days after vaccination for patients who had received one (n = 44) and two (n = 23) vaccine doses, respectively. Two nuclear medicine physicians independently reviewed images and were blinded to injection laterality and the number of days since vaccination. Lymph node or deltoid SUVmax greater than the blood pool SUVmax was considered positive. Interreader agreement was assessed, and the measurements made by the more experienced physician were used for subsequent analysis. RESULTS. Positive axillary lymph node uptake was observed in 10.4% (7/67) of patients (7.4% [4/54] of FDG examinations and 23.1% [3/13] of 11C-choline examinations); of the patients with positive axillary lymph nodes, four had received the Pfizer vaccine, and three had received the Moderna vaccine. Injection laterality was documented for five of seven patients with positive axillary lymph nodes and was ipsilateral to the positive node in all five patients. PET was performed within 24 days of vaccination for all patients with a positive node. One patient showed extraaxillary lymph node uptake (ipsilateral supraclavicular uptake on FDG PET). Ipsilateral deltoid uptake was present in 14.5% (8/55) of patients with documented injection laterality, including 42.9% (3/7) of patients with positive axillary lymph nodes. Interreader agreement for SUV measurements (expressed as intraclass correlation coefficients) ranged from 0.600 to 0.988. CONCLUSION. Increased axillary lymph node or ipsilateral deltoid uptake is occasionally observed on FDG or 11C-choline PET performed after COVID-19 vaccination with the Pfizer-BioNTech or Moderna vaccine. CLINICAL IMPACT. Interpreting physicians should recognize characteristics of abnormal uptake on PET after COVID-19 vaccination to guide optimal follow-up management and reduce unnecessary biopsies.

Radium-223 in the Third-Line Setting in Metastatic Castration-Resistant Prostate Cancer: Impact of Concomitant Use of Enzalutamide on Overall Survival (OS) and Predictors of Improved OS.

INTRODUCTION: Radium-223 (Ra-223) has been recommended for bone-dominant metastatic castration-resistant prostate cancer (mCRPC). Second-generation hormone therapy in combination with Ra-223 in mCRPC has been utilized, yet its benefit has not been well elucidated. We investigated the potential survival benefit of concomitant enzalutamide with Ra-223 in the third-line setting and predictors of improved overall survival (OS). PATIENTS AND METHODS: We retrospectively identified 51 patients with bone-dominant mCRPC that were treated with Ra-223 in the postchemotherapy and post-hormone therapy setting, either alone (group A; n = 32) or with concomitant enzalutamide (group B; n = 19). The primary endpoint was to study the OS difference between groups A and B. The secondary endpoint was to identify predictors of improved OS with Ra-223 in the third-line setting. RESULTS: Mean age was 70.9 years, median baseline prostatic-specific antigen (PSA) was 23.1 ng/mL, alkaline phosphatase was 91 IU/L, and hemoglobin was 12.5 g/dL. There was no difference in median OS between groups A and B, at 20.4 versus 17.5 months, respectively (P = .5186). In univariate and multivariate analyses, only pre-Ra-223 PSA < 30 ng/mL and Eastern Cooperative Oncology Group performance status < 2 were associated with improved OS. CONCLUSION: In our study cohort, concomitant use of enzalutamide with Ra-223 in the mCRPC setting was not associated with improved OS. Only pretreatment PSA < 30 ng/mL and pretreatment Eastern Cooperative Oncology Group performance status < 2 were associated with improved OS. Further prospective studies are warranted.

You're Biased! Deal With It.

Widespread implementation of the Implicit Association Test has revealed that most doctors, and many radiologists, hold implicit racial bias. Because implicit bias is thought to drive discrimination, it has emerged as a primary explanation for radiology's ongoing racial disparity. In this critical review of the literature, which includes empirical studies of radiology resident selection, the authors argue that implicit bias is a universal human instinctual characteristic, but one that humans have the capacity to override through more deliberative thought processes. Overstating the validity of the Implicit Association Test, and the role of implicit bias in causing radiology's racial disparities, is unwarranted, unhelpful, and potentially distracting from addressing actual causes and real solutions.

Awareness of implicit bias mitigates discrimination in radiology resident selection.

OBJECTIVES: Implicit bias is common and is thought to drive discriminatory behaviour. Having previously demonstrated discrimination against specific applicant demographics by academic radiology departments in a simulated resident selection process, the authors sought to better understand the relationship between implicit bias and discrimination, as well as the potential and mechanisms for their mitigation. METHODS: A total of 51 faculty reviewers at three academic radiology departments, who had participated in a 2017 audit study in which they were shown to treat applicants differently based on race or ethnicity and physical appearance, were invited to complete testing for implicit racial and weight bias using the Implicit Association Test in 2019. Respondents were also surveyed regarding awareness of their own personal racial and weight biases, as well as any prior participation in formal diversity training. Comparisons were made between implicit bias scores and applicant ratings, as well as between diversity training and self-awareness of bias. RESULTS: A total of 31 out of 51 faculty reviewers (61%) completed and submitted results of race and weight Implicit Association Tests. A total of 74% (23/31) reported implicit anti-obese bias, concordant with discrimination demonstrated in the resident selection simulation, in which obese applicants were rated 0.40 standard deviations (SDs) lower than non-obese applicants (P < .001). A total of 71% (22/31) reported implicit anti-Black bias, discordant with application ratings, which were 0.47 SDs higher for Black than for White applicants (P < .001). A total of 84% (26/31) of participants reported feeling self-aware of potential racial bias at the time of application review, significantly higher than the 23% (7/31) reporting self-awareness of potential anti-obese bias (P < .001). Participation in formal diversity training was not associated with implicit anti-Black or anti-fat bias, nor with self-reported awareness of potential racial or weight-based bias (all P > .2). CONCLUSIONS: These findings suggest that implicit bias, as measured by the Implicit Association Test, does not inevitably lead to discrimination, and that personal awareness of implicit biases may allow their mitigation.

Moving Radiology Workflow to the Electronic Health Record: Quantitative and Qualitative Experience From a Large Academic Medical Center.

RATIONALE AND OBJECTIVES: To objectively and subjectively evaluate a large, academic radiology department's transition to electronic health record (EHR) centered workflow. MATERIALS AND METHODS: Multiple metrics were compared from before and after the move to EHR-driven workflow. Examination ordering and reading priority data were obtained for 30 days both before and after the transition. Sixteen radiologists were observed opening a computed tomography (CT) examination, and time to open, mouse clicks, and keystrokes were recorded. Information available to the radiologist during interpretation was also compared. Additionally, a 12 question survey was sent out to the residents and faculty both before and after the transition. RESULTS: Implementation of an eight-level reading priority system increased worklist granularity and improved identification of more urgent studies to read. Radiologists opened CT studies in picture archiving and communications system-driven workflow in 52.4 ± 16.9 seconds using 9.5 ± 3.9 clicks and 6.3 ± 2.9 keystrokes, compared to 17.3 ± 9.5 seconds, 4.8 ± 1.5 clicks, and 0.1 ± 0.3 keystrokes in EHR-driven workflow (p < 0.001 for each measure). More information was available to the radiologist during examination interpretation, and 54.7% of radiologists rated the ease of use of the new system as good or very good (compared to 4.2% for the old system, p < 0.001). CONCLUSION: Transitioning to an EHR-driven workflow at a large academic medical center improved efficiency, was favorable to radiologists, and enhanced examination prioritization.

Long-Term Outcomes of 125 Patients With Metastatic Pheochromocytoma or Paraganglioma Treated With 131-I MIBG.

CONTEXT: Prognosis of metastatic pheochromocytoma/paraganglioma following 131-Iodine metaiodobenzylguanidine (MIBG) is incompletely characterized due to small samples and shorter follow-up in these rare, often indolent tumors. OBJECTIVE: To describe long-term survival, frequency, and prognostic impact of imaging, biochemical, and symptomatic response to 131-I MIBG. DESIGN: Retrospective chart and imaging review at a tertiary referral center. PATIENTS: Six hundred sixty-eight person-years of follow-up in 125 patients with metastatic pheochromocytoma/paraganglioma with progression through prior multimodal treatment. INTERVENTION: Median 18 800 MBq 131-I MIBG. MAIN OUTCOME MEASURES: Overall survival, Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST) imaging response, symptomatic response per chart review, and biochemical response (20% change over 2 consecutive assays of catecholamines, vanillylmandelic acid, metanephrines, or chromogranin A). RESULTS: Median survival standard deviation [SD] from diagnosis was 11.5 years [2.4]; following metastasis, 6.5 years [0.8]; post treatment, 4.3 years [0.7]. Among 88 participants with follow-up imaging, 1% experienced complete response, 33% partial response, 53% stability, and 13% progression. Fifty-one percent showed subsequent progression, median progression-free survival [SD] of 2.0 years [0.6]. Stability/response vs progression at first imaging follow-up (3-6 months) predicted improved survival, 6.3 vs 2.4 years (P = 0.021). Fifty-nine percent of 54 patients demonstrated biochemical response. Fifty percent of these relapsed, with median time to laboratory progression [SD] of 2.8 years [0.7]. Biochemical response did not predict extended survival. Seventy-five percent of 83 patients reported improvement in pretreatment symptoms, consisting primarily of pain (42%), fatigue (27%), and hypertension (14%). Sixty-one percent of these patients experienced subsequent symptomatic progression at median [SD] 1.8 years [0.4]. Symptomatic response did not predict extended survival. CONCLUSIONS: Imaging, symptomatic, and laboratory response to multimodal treatment including high-dose 131-I MIBG were achieved on long-term follow-up in metastatic pheochromocytoma or paraganglioma. Imaging response at 3 to 6 months was prognostic.

Bias in Radiology Resident Selection: Do We Discriminate Against the Obese and Unattractive?

PURPOSE: To evaluate for appearance-based discrimination in the selection of radiology residents. METHOD: A deception study simulating the resident selection process examined the impact of attractiveness and obesity on resident selection. Seventy-four core faculty from 5 academic radiology departments reviewed mock residency applications in September and October 2017. Each application included demographic information and a photograph, representing a prespecified distribution of facial attractiveness and obesity, combined with randomized academic and supporting variables. Reviewers independently scored applications for interview desirability. Reviewer scores and application variables were compared using linear mixed fixed- and random-effects models. RESULTS: Reviewers evaluated 5,447 applications (mean: 74 applications per reviewer). United States Medical Licensing Examination Step 1 scores were the strongest predictor of reviewer rating (B = 0.35 [standard error (SE) = 0.029]). Applicant facial attractiveness strongly predicted rating (attractive vs unattractive, B = 0.30 [SE = 0.056]; neutral vs unattractive, B = 0.13 [SE = 0.028]). Less influential but still significant predictors included race/ethnicity (B = 0.25 [SE = 0.059]), preclinical class rank (B = 0.25 [SE = 0.040]), clinical clerkship grades (B = 0.23 [SE = 0.034]), Alpha Omega Alpha membership (B = 0.21 [SE = 0.032]), and obesity (vs not obese) (B = -0.14 [SE = 0.024]). CONCLUSIONS: Findings provide preliminary evidence of discrimination against facially unattractive and obese applicants in radiology resident selection. Obesity and attractiveness were as influential in applicant selection for interview as traditional medical school performance metrics. Selection committees should invoke strategies to detect and manage appearance-based bias.

Predictors of Survival in 211 Patients with Stage IV Pulmonary and Gastroenteropancreatic MIBG-Positive Neuroendocrine Tumors Treated with 131I-MIBG.

This retrospective analysis identifies predictors of survival in a cohort of patients with meta-iodobenzylguanidine (MIBG)-positive stage IV pulmonary and gastroenteropancreatic neuroendocrine tumor (P/GEP-NET) treated with 131I-MIBG therapy, to inform treatment selection and posttreatment monitoring. Methods: Survival, symptoms, imaging, and biochemical response were extracted via chart review from 211 P/GEP-NET patients treated with 131I-MIBG between 1991 and 2014. For patients with CT follow-up (n = 125), imaging response was assessed by RECIST 1.1 if images were available (n = 76) or by chart review of the radiology report if images could not be reviewed (n = 49). Kaplan-Meier analysis and Cox multivariate regression estimated survival and progression-free survival benefits predicted by initial imaging, biochemical response, and symptomatic response. Results: All patients had stage IV disease at the time of treatment. Median survival was 29 mo from the time of treatment. Symptomatic response was seen in 71% of patients, with the median duration of symptomatic relief being 12 mo. Symptomatic response at the first follow-up predicted a survival benefit of 30 mo (P < 0.001). Biochemical response at the first clinical follow-up was seen in 34% of patients, with stability of laboratory values in 48%; response/stability versus progression extended survival by 40 mo (P < 0.03). Imaging response (20% of patients) or stability (60%) at the initial 3-mo follow-up imaging extended survival by 32 mo (P < 0.001). Additionally, multiple 131I-MIBG treatments were associated with 24 mo of additional survival (P < 0.05). Conclusion: Therapeutic 131I-MIBG for metastatic P/GEP-NETs appears to be an effective means of symptom palliation. Imaging, biochemical, and symptomatic follow-up help prognosticate expected survival after 131I-MIBG therapy. Multiple rounds of 131I-MIBG are associated with prolonged survival.

Comparison of Bayesian penalized likelihood reconstruction versus OS-EM for characterization of small pulmonary nodules in oncologic PET/CT.

OBJECTIVE: To determine whether the recently introduced Bayesian penalized likelihood PET reconstruction (Q.Clear) increases the visual conspicuity and SUVmax of small pulmonary nodules near the PET resolution limit, relative to ordered subset expectation maximization (OS-EM). METHODS: In this institutional review board-approved and HIPAA-compliant study, 29 FDG PET/CT scans performed on a five-ring GE Discovery IQ were retrospectively selected for pulmonary nodules described in the radiologist's report as "too small to characterize", or small lung nodules in patients at high risk for lung cancer. Thirty-two pulmonary nodules were assessed, with mean CT diameter of 8 mm (range 2-18). PET images were reconstructed with OS-EM and Q.Clear with noise penalty strength ß values of 150, 250, and 350. Lesion visual conspicuity was scored by three readers on a 3-point scale, and lesion SUVmax and background liver and blood pool SUVmean and SUVstdev were recorded. Comparison was made by linear mixed model with modified Bonferroni post hoc testing; significance cutoff was p < 0.05. RESULTS: Q.Clear improved lesion visual conspicuity compared to OS-EM at ß = 150 (p < 0.01), but not 250 or 350. Lesion SUVmax was increased compared to OS-EM at ß = 150 and 250 (p < 0.01), but not 350. CONCLUSION: In a cohort of small pulmonary nodules with size near an 8 mm PET full-width half maximum, Q.Clear significantly increased lesion visual conspicuity and SUVmax compared to our standard non- time-of-flight OS-EM reconstruction, but only with low noise penalization. Q.Clear with ß = 150 may be advantageous when evaluation of small pulmonary nodules is of primary concern.

Effects of protein intake and gender on body composition changes: a randomized clinical weight loss trial.

UNLABELLED: Limited data on sex differences in body composition changes in response to higher protein diets (PRO) compared to higher carbohydrate diets (CARB) suggest that a PRO diet helps preserve lean mass (LM) in women more so than in men. OBJECTIVE: To compare male and female body composition responses to weight loss diets differing in macronutrient content. DESIGN: Twelve month randomized clinical trial with 4mo of weight loss and 8mo weight maintenance. SUBJECTS: Overweight (N = 130; 58 male (M), 72 female (F); BMI = 32.5 ± 0.5 kg/m2) middle-aged subjects were randomized to energy-restricted (deficit ~500 kcal/d) diets providing protein at 1.6 g.kg-1.d-1 (PRO) or 0.8 g.kg-1.d-1 (CARB). LM and fat mass (FM) were measured using dual X-ray absorptiometry. Body composition outcomes were tested in a repeated measures ANOVA controlling for sex, diet, time and their two- and three-way interactions at 0, 4, 8 and 12mo. RESULTS: When expressed as percent change from baseline, males and females lost similar amounts of weight at 12mo (M:-11.2 ± 7.1 %, F:-9.9 ± 6.0 %), as did diet groups (PRO:-10.7 ± 6.8 %, CARB:-10.1 ± 6.2 %), with no interaction of gender and diet. A similar pattern emerged for fat mass and lean mass, however percent body fat was significantly influenced by both gender (M:-18.0 ± 12.8 %, F:-7.3 ± 8.1 %, p < 0.05) and diet (PRO:-14.3 ± 11.8 %, CARB:-9.3 ± 11.1 %, p < 0.05), with no gender-diet interaction. Compared to women, men carried an extra 7.0 ± 0.9 % of their total body fat in the trunk (P < 0.01) at baseline, and reduced trunk fat during weight loss more than women (M:-3.0 ± 0.5 %, F:-1.8 ± 0.3 %, p < 0.05). Conversely, women carried 7.2 ± 0.9 % more total body fat in the legs, but loss of total body fat in legs was similar in men and women. CONCLUSION: PRO was more effective in reducing percent body fat vs. CARB over 12mo weight loss and maintenance. Men lost percent total body fat and trunk fat more effectively than women. No interactive effects of protein intake and gender are evident.