The development of a neuroendocrine phenotype as a mechanism of resistance to hormonal treatment is observed in up to 20% of advanced prostate cancer patients. High grade neuroendocrine prostate cancer (NEPC) is associated to poor prognosis and the therapeutic armamentarium is restricted to platinum-based chemotherapy. Prostate-specific membrane antigen (PSMA)-based positron emission tomography (PET)/computed tomography (CT) imaging has recently emerged as a potential new standard for the staging of prostate cancer and PSMA-based radioligand therapy (RLT) as a therapeutic option in advanced metastatic castration resistant prostate cancer (mCRPC). PSMA-based theranostic is not currently applied in the staging and treatment of NEPC since PSMA expression on neuroendocrine differentiated cells was shown to be lost. In this case series, we present 3 consecutive mCRPC patients with histologically proven high grade neuroendocrine differentiation who underwent PSMA-PET/CT and surprisingly showed high tracer uptake. This observation stimulates further research on the use of PSMA-based theranostic in the management of NEPC.
Single-agent tyrosine kinase inhibitors are still prescribed as first-line treatment to a relevant subgroup of patients with metastatic renal cell carcinoma (mRCC). These agents are known to cause disfunction of many endocrine glands (e.g., thyroid). In this two-step trial, we aimed to assess gonadal function among male patients with mRCC treated with sunitinib.We enrolled a first cross-sectional cohort of pre-treated (>6 months) patients and a subsequent cohort of treatment-naïve patients who were prospectively followed-up. All patients were screened for hypogonadism and received a Functional Assessment of Cancer Therapy - General (FACT-G) questionnaire at study entry and after 6 months of therapy. Patients who were candidates for testosterone replacement therapy (TRT) also received a FACT-G questionnaire at baseline and 3 months after supplementation.Among the 30 enrolled patients, the prevalence of hypogonadism was found to be higher in those receiving sunitinib for a longer period (27.3% at baseline, 41.7% in the first 6 months, and 68.4% after 9 months of therapy). The testosterone level of patients correlated with quality of life (R=0.32). A total of six patients received TRT, with a significant improvement in their global quality of life after the first 3 months of treatment.An increasing prevalence of hypogonadism was seen among male patients who received long-term treatment with sunitinib. TRT was associated with relevant improvements in quality of life. These findings corroborate similar published observations and encourage the assessment of gonadal function in male patients with mRCC under treatment with sunitinib.
Supplementary Figure from A Population of TIM4<sup>+</sup>FOLR2<sup>+</sup> Macrophages Localized in Tertiary Lymphoid Structures Correlates to an Active Immune Infiltrate Across Several Cancer Types
Supplementary Data from A Population of TIM4<sup>+</sup>FOLR2<sup>+</sup> Macrophages Localized in Tertiary Lymphoid Structures Correlates to an Active Immune Infiltrate Across Several Cancer Types
<div>Abstract<p>TIM4 has previously been associated with antitumor immunity, yet the pattern of expression and the function of this receptor across human cancer tissues remain poorly explored. Here we combined extensive immunolabeling of human tissues with <i>in silico</i> analysis of pan-cancer transcriptomic data sets to explore the clinical significance of TIM4 expression. Our results unveil that TIM4 is expressed on a fraction of cavity macrophages (<sup>CA</sup>TIM4<sup>+</sup>MΦ) of carcinoma patients. Moreover, we uncover a high expression of TIM4 on macrophages of the T-cell zone of the carcinoma-associated tertiary lymphoid structures (<sup>TLS</sup>TIM4<sup>+</sup>MΦ). <i>In silico</i> analysis of a pan-cancer data set revealed a positive correlation between TIM4 expression and markers of B cells, effector CD8<sup>+</sup> T cells, and a 12-chemokine signature defining tertiary lymphoid structure. In addition, <sup>TLS</sup>TIM4<sup>+</sup>MΦ were enriched in cancers displaying microsatellite instability and high CD8<sup>+</sup> T-cell infiltration, confirming their association with immune-reactive tumors. Both <sup>CA</sup>TIM4<sup>+</sup>MΦ and <sup>TLS</sup>TIM4<sup>+</sup>MΦ express FOLR2, a marker of tissue-resident MΦ. However, <sup>CA</sup>TIM4<sup>+</sup>MΦ had a higher expression of the immunosuppressive molecules TREM2, IL10, and TGFβ as compared with <sup>TLS</sup>TIM4<sup>+</sup>MΦ. By analyzing a scRNA sequence data set of tumor-associated myeloid cells, we identified two TIM4<sup>+</sup>FOLR2<sup>+</sup> clusters coherent with <sup>CA</sup>TIM4<sup>+</sup>MΦ and <sup>TLS</sup>TIM4<sup>+</sup>MΦ. We defined specific gene signatures for each subset and found that the <sup>CA</sup>TIM4<sup>+</sup> MΦ signature was associated with worse patient survival. In contrast, <sup>TLS</sup>TIM4<sup>+</sup>MΦ gene signature positively correlates with a better prognosis. Together, these data illustrate that TIM4 marks two distinct macrophage populations with distinct phenotypes and tissue localization and that may have opposing roles in tumor immunity.</p></div>
Supplementary Table from A Population of TIM4<sup>+</sup>FOLR2<sup>+</sup> Macrophages Localized in Tertiary Lymphoid Structures Correlates to an Active Immune Infiltrate Across Several Cancer Types
Supplementary Data from A Population of TIM4<sup>+</sup>FOLR2<sup>+</sup> Macrophages Localized in Tertiary Lymphoid Structures Correlates to an Active Immune Infiltrate Across Several Cancer Types
Abstract Background Amongst its extragonadal effects, Follicle-Stimulating Hormone (FSH) has an impact on body composition and bone metabolism. Since androgen deprivation therapy (ADT) has a profound impact on circulating FSH concentrations, this hormone could potentially be implicated in the changes of fat body mass (FBM), lean body mass (LBM) and bone fragility induced by ADT. The objective of this study is to correlate FSH serum levels with body composition parameters, bone mineral density (BMD) and bone turnover markers at baseline conditions and after 12 months of ADT. Methods 29 consecutive non-metastatic prostate cancer (PC) patients were enrolled from 2017 to 2019 in a phase IV study. All patients underwent administration of the Luteinizing Hormone-Releasing Hormone antagonist degarelix. FBM, LBM and BMD were evaluated by dual-energy x-ray absorptiometry at baseline and after 12 months of ADT. FSH, alkaline phosphatase (ALP) and C-terminal telopeptide of type I collagen (CTX) were assessed at baseline and after 6 and 12 months. For outcome measurements and statistical analysis, T-test or sign test and Pearson or Spearman tests for continuous variables were used when indicated. Results At baseline conditions, a weak, non-significant, direct relationship was found between FSH serum levels and FBM at arms (r=0.36) and legs (r=0.33). Conversely, a stronger correlation was observed between FSH and total FBM (r=0.52, p=0.006), fat mass at arms (r=0.54, p=0.004) and fat mass at trunk (r=0.45, p=0.018) assessed after 12 months. On the other hand, an inverse relationship between serum FSH and appendicular lean mass index (ALMI)/FBM ratio was observed (r=0.64, p=0.001). This is an ancillary study of a prospective trial and this is the main limitation. Conclusions FSH serum levels after ADT could have an impact on body composition, in particular on fat body mass. Therefore, FSH could be a promising marker to monitor the risk of sarcopenic obesity and cardiovascular complications in PC patients undergoing ADT. Funding this research was partially funded by Ferring Pharmaceuticals. The funder had no role in design and conduct of the study, collection, management, analysis, and interpretation of the data and in preparation, review, or approval of the manuscript. Clinical trial number clinicalTrials.gov NCT03202381 , EudraCT Number 2016-004210-10.
<div>Abstract<p>TIM4 has previously been associated with antitumor immunity, yet the pattern of expression and the function of this receptor across human cancer tissues remain poorly explored. Here we combined extensive immunolabeling of human tissues with <i>in silico</i> analysis of pan-cancer transcriptomic data sets to explore the clinical significance of TIM4 expression. Our results unveil that TIM4 is expressed on a fraction of cavity macrophages (<sup>CA</sup>TIM4<sup>+</sup>MΦ) of carcinoma patients. Moreover, we uncover a high expression of TIM4 on macrophages of the T-cell zone of the carcinoma-associated tertiary lymphoid structures (<sup>TLS</sup>TIM4<sup>+</sup>MΦ). <i>In silico</i> analysis of a pan-cancer data set revealed a positive correlation between TIM4 expression and markers of B cells, effector CD8<sup>+</sup> T cells, and a 12-chemokine signature defining tertiary lymphoid structure. In addition, <sup>TLS</sup>TIM4<sup>+</sup>MΦ were enriched in cancers displaying microsatellite instability and high CD8<sup>+</sup> T-cell infiltration, confirming their association with immune-reactive tumors. Both <sup>CA</sup>TIM4<sup>+</sup>MΦ and <sup>TLS</sup>TIM4<sup>+</sup>MΦ express FOLR2, a marker of tissue-resident MΦ. However, <sup>CA</sup>TIM4<sup>+</sup>MΦ had a higher expression of the immunosuppressive molecules TREM2, IL10, and TGFβ as compared with <sup>TLS</sup>TIM4<sup>+</sup>MΦ. By analyzing a scRNA sequence data set of tumor-associated myeloid cells, we identified two TIM4<sup>+</sup>FOLR2<sup>+</sup> clusters coherent with <sup>CA</sup>TIM4<sup>+</sup>MΦ and <sup>TLS</sup>TIM4<sup>+</sup>MΦ. We defined specific gene signatures for each subset and found that the <sup>CA</sup>TIM4<sup>+</sup> MΦ signature was associated with worse patient survival. In contrast, <sup>TLS</sup>TIM4<sup>+</sup>MΦ gene signature positively correlates with a better prognosis. Together, these data illustrate that TIM4 marks two distinct macrophage populations with distinct phenotypes and tissue localization and that may have opposing roles in tumor immunity.</p></div>
