Fifty Shades of PSMA-Avid Rib Lesions: A Comprehensive Review

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Dear editors:  

 It is a great honor and pleasure for me to be invited as the reviewer for this great work entitled “Fifty Shades of PSMA-Avid Rib Lesions: A Comprehensive Review”. Amirreza Shamshirgaran and co-authors comprehensively reviewed the literature to explore the role of tumor–stroma interactions, metabolic signaling, and immune modulation in cancer progression and therapeutic resistance. The manuscript is generally well-referenced and suitable for the scope of Cancers. However, several areas require further clarification, better integration of recent literature, and more critical balance to avoid overstating conclusions. I have several comments concerning this study:

Major Issues:

1. While the manuscript is comprehensive, its novelty is not always clear. A number of studies could be found, eg., PSMA-avid rib lesions in prostate cancer patients: differentiating false positives from metastatic disease. Eur Radiol. 2025 Sep;35(9):5337-5347. doi: 10.1007/s00330-025-11514-3. A stronger statement is needed in the introduction and conclusion to highlight what distinguishes this review from prior reviews in the same field (e.g., unique angle on metabolic crosstalk or therapeutic translation).
2. Critical appraisal of evidence is required. In several sections, mechanistic studies are described in detail, but there is less discussion on the strength and limitations of the evidence (e.g., reliance on in vitro in vivo data, or the translatability of preclinical findings to clinical practice). Adding critical commentary on conflicting results or gaps in the field would strengthen the review’s authority.
3. While therapeutic implications are mentioned, they remain somewhat general. It would benefit the manuscript to explicitly discuss the following 3W:

Which pathways have the strongest preclinical support for drug targeting?

Where clinical trials have failed or are ongoing?

What are potential biomarkers that could guide therapy?

4. Figures are informative but visually dense. Please consider simplifying or splitting complex schematics to improve readability for a broad readership.

A summary table linking key pathways, their stromal/immune roles, and therapeutic agents under investigation is needed and would greatly enhance the manuscript’s utility and merits.

5. The current conclusion is mainly descriptive. It would be helpful to include a short “Future Perspectives” section that identifies high-priority research directions (e.g., multi-omics approaches, spatial transcriptomics, patient-derived models, or immunometabolic drug targets).

Minor concerns:

1.The abstract could better emphasize the translational implications instead of mainly restating mechanistic details.

2.Some acronyms (e.g., CAF, ECM, EMT) are introduced without definition in the first mention — please ensure consistency.

3.Some key recent reviews and primary studies from 2022–2024 appear to be missing; updating the reference list will ensure comprehensive coverage.

Overall, the manuscript is readable and fits well within the journal’s scope. Whilst a few sentences are too long and could be simplified for clarity. A light English editing pass is recommended.

Author Response

Response to Reviewer 1:

Major concerns

1. While the manuscript is comprehensive, its novelty is not always clear. A number of studies could be found, eg., PSMA-avid rib lesions in prostate cancer patients: differentiating false positives from metastatic disease. Eur Radiol. 2025 Sep;35(9):5337-5347. doi: 10.1007/s00330-025-11514-3. A stronger statement is needed in the introduction and conclusion to highlight what distinguishes this review from prior reviews in the same field (e.g., unique angle on metabolic crosstalk or therapeutic translation).

Reply: We sincerely thank you for the thoughtful feedback and for highlighting the need to better articulate the novelty of our manuscript. Below, we address your comment by outlining the unique contributions of our review and how it differs from prior works in the field. We have revised the Introduction and Conclusion sections to emphasize these distinctions, as suggested.

The introduction has been revised: “This comprehensive review synthesizes the existing literature on the pathophysiology, diagnostic challenges, and imaging interpretation of PSMA-avid rib lesions in PCa, with a focus on distinguishing benign from malignant uptakes to enhance staging accuracy and promote individualized patient care. Unlike prior reviews, this manuscript provides a unique synthesis of evidence across diverse PCa states, including biochemical recurrence, non-metastatic castration-resistant prostate cancer, and oligometastatic disease. We propose a novel diagnostic decision tree that integrates lesion characteristics, clinical context, and tracer-specific patterns to guide precise differentiation of benign versus meta-static rib lesions, addressing a critical gap in standardized interpretive frameworks. By emphasizing therapeutic translation, this review highlights how accurate interpretation can optimize metastasis-directed therapies, prevent overtreatment, and provide a practical approach for clinicians navigating the complexities of PSMA PET/CT imaging.”

The conclusion has been updated: “This review advances the field by offering a comprehensive analysis of PSMA-avid rib lesions. Our proposed diagnostic decision tree represents a novel tool for standardizing interpretation, reducing diagnostic ambiguity, and guiding personalized treatment strategies. By bridging diagnostic and therapeutic perspectives, this work provides a roadmap for improving staging accuracy and optimizing outcomes in prostate cancer patients with suspected rib involvement.”

2. Critical appraisal of evidence is required. In several sections, mechanistic studies are described in detail, but there is less discussion on the strength and limitations of the evidence (e.g., reliance on in vitro in vivo data, or the translatability of preclinical findings to clinical practice). Adding critical commentary on conflicting results or gaps in the field would strengthen the review’s authority.

Reply: We sincerely appreciate your insightful comment. We agree that a more robust discussion of the strengths, limitations, and gaps in the evidence will enhance the review’s authority. In response, we have revised several sections to incorporate critical commentary on the quality of evidence, conflicting results, and existing gaps in the field.

To address your comment, we have made the following revisions:

Section 3: “While mechanistic studies provide valuable insights into the molecular drivers of bone metastasis, much of the evidence is derived from in vitro and in vivo models, which may not fully capture the complexity of human disease. For example, animal models often fail to replicate the heterogeneous tumor microenvironment of prostate cancer, and rib-specific metastatic mechanisms remain underexplored due to limited histopathological data. Furthermore, most preclinical studies focus on axial skeletal metastases, leaving rib-specific mechanisms underexplored. The heterogeneity of PCa and limited clinical validation of these pathways highlight the need for prospective trials to translate these findings into effective therapies for rib metastases. These gaps highlight the need for clinical studies to validate preclinical findings and elucidate rib-specific metastatic pathways.”

Section 6.4: “Conflicting results across studies complicate the interpretation of PSMA-avid rib lesions. For instance, Woo et al. (2025) report a 20% prevalence of equivocal lesions with only 28% confirmed as metastatic, while Fragkiadaki et al. (2024) suggest a higher malignancy rate. These discrepancies may stem from differences in tracer types, patient risk profiles, or imaging protocols. Moreover, many studies rely on retrospective designs or imaging-based follow-up, which may introduce bias compared to biopsy-confirmed diagnoses. The lack of standardized SUV thresholds further contributes to diagnostic variability, representing a critical gap in the field.”

Section 7.3: “While our proposed diagnostic decision tree integrates multiple parameters to enhance diagnostic precision, it is based primarily on retrospective studies with variable follow-up durations. The scarcity of prospective trials focusing specifically on rib metastases, as opposed to axial skeletal lesions, limits the generalizability of our framework. Future studies are needed to validate this approach and address the understudied role of rib-specific metastases in prostate cancer staging and management.”

3. While therapeutic implications are mentioned, they remain somewhat general. It would benefit the manuscript to explicitly discuss the following 3W:

Reply: We greatly appreciate your feedback. We have added the following section to include a detailed and critical discussion of key molecular pathways with robust preclinical evidence for drug targeting and biomarkers in the context of prostate cancer bone metastases, including rib lesions: “3.2. Therapeutic Targeting and Biomarkers for PSMA-Avid Rib Lesions”

Which pathways have the strongest preclinical support for drug targeting?

“Several molecular pathways have shown promise in preclinical studies for drug targeting. The RANKL/RANK pathway, critical for osteoclast-mediated bone resorption, is a prime target, with denosumab reducing tumor burden in mouse models of osteoblastic metastases. However, its efficacy in rib-specific lesions requires further clinical validation, and long-term use carries risks of osteonecrosis. The Wnt pathway, modulated by inhibitors like DKK1 and sclerostin, promotes bone formation and has shown preclinical efficacy in stabilizing osteoblastic rib lesions, though off-target effects limit translatability. PSMA-targeted radioligand therapies, such as ¹⁷⁷Lu-PSMA-617, demonstrate strong pre-clinical efficacy in targeting PSMA-avid rib lesions, but heterogeneous PSMA expression in CRPC may reduce effectiveness. TGF-β signaling, a key mediator of tumor-bone interactions, is another promising target, with inhibitors like galunisertib showing reduced metastasis progression in preclinical models, though clinical trials are needed to confirm rib-specific efficacy.”

Where clinical trials have failed or are ongoing?

“Translation from preclinical models to clinic has been uneven for pathways driving PCa rib metastases. For RANKL/RANK, denosumab reduces SREs in mCRPC bone metastases but failed OS endpoints in prevention trials. Wnt inhibitors like OMP-18R5 failed phase Ib due to bone toxicity, though porcupine inhibitors are ongoing. ¹⁷⁷Lu-PSMA-617 succeeded in VISION and PSMAfore in mCRPC patients. TGF-β inhibitors like galunisertib show promise in combinations, but pan-inhibitors failed due to toxicity; ongoing bispecific traps aim to address this. These efforts underscore the potential for rib lesion control but reveal gaps in site-specific efficacy data.”

What are potential biomarkers that could guide therapy?

“Biomarkers are critical for tailoring therapies to PSMA-avid rib lesions. PSMA expression (e.g., SUVmean >10 on PET/CT) predicts response to ¹⁷⁷Lu-PSMA-617, with high uptake guiding MDTs like SBRT or radioligand therapy, though heterogeneous expression and tracer variability pose challenges. Bone turnover markers reflect osteoblast/osteoclast activity, identifying candidates for denosumab but lack rib specificity. CTC counts (>5 cells/7.5 mL) and ctDNA (e.g., AR-V7) predict ARPI resistance, favoring PSMA-targeted therapies for rib lesions, yet require standardized assays. TGF-β1 (>200 pg/mL) and p-SMAD2/3 signal response to TGF-β inhibitors, but non-specificity and biopsy needs limit use. Rib-specific biomarker data and standardized thresholds remain critical gaps, necessitating prospective validation.”

A summary table linking key pathways, their stromal/immune roles, and therapeutic agents under investigation is needed and would greatly enhance the manuscript’s utility and merits.

We have completely described pathways and therapeutic agents in section 3.2.

4. Figures are informative but visually dense. Please consider simplifying or splitting complex schematics to improve readability for a broad readership.

Reply: We sincerely thank the you for your valuable feedback regarding the visual presentation of figures. We acknowledge the concern that the figures may appear visually dense, however, we respectfully propose retaining the current figures, as their complexity is consistent with standard practices in radiologic and nuclear medicine literature, particularly for reviews addressing diagnostic and therapeutic challenges in prostate cancer imaging. In the context of our review, the density of the figures reflects the multifaceted nature of PSMA PET/CT interpretation, which requires synthesizing data from lesion characteristics, tracer-specific patterns, and patient-specific factors. Below, we provide examples that use a similar figure presentation pattern:

Duan, H., Iagaru, A. The use of advanced imaging in guiding the further investigation and treatment of primary prostate cancer. Cancer Imaging 22, 45 (2022). https://doi.org/10.1186/s40644-022-00481-3

Jochumsen, M.R., Sörensen, J., Tolbod, L.P. et al. Potential synergy between PSMA uptake and tumour blood flow for prediction of human prostate cancer aggressiveness. EJNMMI Res 11, 12 (2021). https://doi.org/10.1186/s13550-021-00757-y

5. The current conclusion is mainly descriptive. It would be helpful to include a short “Future Perspectives” section that identifies high-priority research directions (e.g., multi-omics approaches, spatial transcriptomics, patient-derived models, or immunometabolic drug targets).

Reply: We sincerely thank the you for insightful suggestion. In response, we have added the following statements to conclusion section: “Advancing the management of PSMA-avid rib lesions in PCa requires addressing critical research gaps through innovative approaches. Multi-omics profiling, integrating genomics, proteomics, and metabolomics, could elucidate rib-specific molecular drivers and biomarkers, refining diagnostic algorithms and patient stratification for therapies. Spatial transcriptomics offers potential to map gene expression within the rib lesion microenvironment, revealing metastatic niches and validating PSMA PET/CT findings, though tissue access and technical complexity pose challenges. High-priority research directions include rib-focused clinical trials, prospective validation of biomarkers, and standardized imaging-molecular correlations to enhance precision diagnostics and personalized treatment for PSMA-avid rib lesions.”

Minor concerns:

1.The abstract could better emphasize the translational implications instead of mainly restating mechanistic details.

Reply: Thanks for your insightful feedback. To address your concern, we added these statement to the abstract: “Our diagnostic decision tree guide precise differentiation of benign versus metastatic rib lesions, enhancing staging accuracy and clinical decision-making. Biomarker-guided therapies offer potential for personalized treatment, though rib-specific validation remains a critical need.”

2.Some acronyms (e.g., CAF, ECM, EMT) are introduced without definition in the first mention — please ensure consistency.

Reply: Thanks for your comment. We have double-checked the entire manuscript and fixed the errors.

3.Some key recent reviews and primary studies from 2022–2024 appear to be missing; updating the reference list will ensure comprehensive coverage.

Reply: Thanks for your comment. We have updated our search up to July 2025 and included new articles in our study.

Overall, the manuscript is readable and fits well within the journal’s scope. Whilst a few sentences are too long and could be simplified for clarity. A light English editing pass is recommended.

Reply: Thanks for your valuable feedback. A complete English edit has been done based on your comment.

Reviewer 2 Report

Comments and Suggestions for Authors

Prostate cancer metastasizes more often and primarily to the cancellous bones
Has the correlation between the presence of metastases to the pelvic bones, vertebrae, etc., between rib involvement and regional lymph node involvement been studied?

Author Response

 

 

Comment: Prostate cancer metastasizes more often and primarily to the cancellous bones.
Has the correlation between the presence of metastases to the pelvic bones, vertebrae, etc., between rib involvement and regional lymph node involvement been studied?

Reply: We thank you for their insightful question. We confirm that such correlations have been investigated, primarily through autopsy series and imaging studies which consistently show that rib metastases are rarely isolated and are strongly associated with multifocal disease involving the axial skeleton (vertebrae, pelvis) and regional lymph nodes. To address this comment, we have added a concise paragraph to Section 4: “Autopsy and PSMA PET/CT studies confirm that rib involvement typically signals multifocal disease, with 97.9% of metastatic rib lesions co-occurring with nodal or other bone metastases, guiding systemic therapy over localized approaches. These correlations highlight the importance of comprehensive imaging to assess disease extent and inform treatment planning.”

Reviewer 3 Report

Comments and Suggestions for Authors

Dear Authors,

The paper titled as Fifty Shades of PSMA-Avid Rib Lesions: A Comprehensive Review comprehensively addresses rib lesions that are frequently seen on PSMA PET/CT in prostate cancer patients but present challenges for clinical interpretation. The topic is current and of high clinical importance. I believe that the paper can be published after corrections. Suggested corrections;

Although significant differences were found among the different parameters, the data were sometimes mixed. A more systematic comparison table could be presented.

Please clearly include the clinical validation of the study in the article.

It is important for authors to provide comparative interpretations in review articles. Authors are expected to provide more commentary on this topic.

The study could become more interesting if the effects on treatment decisions were supported by clearer case-based studies.

In the literature section, it can be explained in some detail how and on what basis the studies considered were selected.

It is recommended to make numerical comparisons for some parameters.

Yours Sincerly

 

Author Response

Suggested corrections:

1. Although significant differences were found among the different parameters, the data were sometimes mixed. A more systematic comparison table could be presented.

Reply: We sincerely thank you for the valuable feedback. More systematic comparison of parameters would enhance clarity and improve the manuscript’s utility for readers. To address this, we updated Table 3 that systematically compares key parameters used to differentiate benign from metastatic PSMA-avid rib lesions. This table consolidates data from studies discussed in the manuscript, addressing the mixed presentation.

2. Please clearly include the clinical validation of the study in the article.

Reply: Thanks for your comment. We agree that emphasizing clinical validation enhances the manuscript’s relevance for clinical practice. Validation of the proposed parameters of decision tree in our study were completely presented in section 7.

3. It is important for authors to provide comparative interpretations in review articles. Authors are expected to provide more commentary on this topic.

Reply: We sincerely thank you for your valuable feedback emphasizing the need for more comparative interpretations. We have provided comparative analyses, particularly for clinicians navigating the complexities of PSMA-avid rib lesions in prostate cancer. To address this, we have updated and added new features to Table 3.

4. The study could become more interesting if the effects on treatment decisions were supported by clearer case-based studies.

Reply: We thank you for your insightful suggestion. We agree that case-based examples can enhance clinical relevance, but as a review article, our work synthesizes evidence from multiple studies to propose a novel diagnostic decision tree that integrates diagnostic and clinical factors to guide treatment decisions for PSMA-avid rib lesions in prostate cancer. To address the reviewer’s comment, we have added a concise paragraph to Section 7.3: “The proposed diagnostic decision tree integrates evidence from multiple studies to guide treatment decisions for PSMA-avid rib lesions, synthesizing diagnostic parameters and clinical factors to differentiate benign from metastatic lesions. However, the scarcity of rib-specific data underscores the need for future case-based studies to validate the decision tree’s efficacy in diverse clinical scenarios, such as biochemical recurrence or mCRPC, to refine its impact on treatment outcomes.”

We also presented 6 cases via Figures 2, 3, 4, 5, 6, and 8 to elucidate the utility of different parameters in metastasis diagnosis.

5. In the literature section, it can be explained in some detail how and on what basis the studies considered were selected.

Reply: We sincerely thank you for your valuable feedback. We have updated the study selection methodology: “To ensure a comprehensive and relevant evidence base for this review, studies were systematically selected based on a structured search strategy and predefined inclusion criteria. A literature search was conducted in PubMed, Embase, and Google Scholar, covering publications up to July 2025, using following keywords: ("prostate cancer" OR "prostate carcinoma" OR "prostatic neoplasms") AND (("rib" OR "costal" OR "costovertebral") AND ("metastasis" OR "bone metastasis" OR "skeletal metastasis")) AND ("PSMA PET" OR "PSMA PET/CT" OR "68Ga-PSMA-11" OR "18F-PSMA-1007" OR "18F-DCFPyL" OR "18F-rhPSMA7.3" OR "99mTc-PSMA" OR "Positron Emission Tomography Computed Tomography" OR “Single Photon Emission Computed Tomography”) AND ("diagnosis" OR "detection" OR "sensitivity" OR "specificity" OR "false positive" OR "false negative" OR "accuracy"). Additional studies were identified through reference lists and clinical trial registries. Inclusion criteria comprised: (1) studies reporting on PSMA-avid rib lesions or bone metastases in PCa, with specific mention of ribs where possible; (2) clinical studies with diagnostic or therapeutic outcomes, including sensitivity, specificity, survival, or skeletal-related event (SRE) data; (3) studies published in English with peer-reviewed data; and (4) case reports were included only if they contributed substantial or novel clinical insights into PSMA-avid rib lesions. Exclusion criteria included studies lacking rib-specific or PSMA-related data and non-peer-reviewed sources. Study quality was assessed based on sample size, methodological, and clinical relevance. From an initial pool of 1,234 articles, 82 studies were selected, prioritizing those with rib-specific findings or high-impact outcomes. This approach ensured a robust evidence base focused on PSMA-avid rib lesions, addressing diagnostic, therapeutic, and pathophysiological aspects while acknowledging the scarcity of rib-specific data.”

6. It is recommended to make numerical comparisons for some parameters.

Reply: Thanks for your comment. We have updated Table 3 and some numerical comparison have been added to the table.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

I thank the authors for their detailed responses and revisions. The effort to clarify study design and expand the discussion is appreciated. While the authors have made progress addressing prior comments, I endorse the publication after proofreading.