Development Of Bone Metastases Research Articles

Role of Bone Metastases in Patients Receiving Immunotherapy for Pre-Treated Urothelial Carcinoma: The Multicentre, Retrospective Meet-URO-1 Bone Study.

Considerable numbers of patients with metastatic urothelial carcinoma (mUC) develop bone metastases (BoM). Their impact on the efficacy of immune-checkpoint inhibitors (ICIs) is not yet investigated. Between July 2014 and August 2020 data on pts treated with single-agent ICIs after failure of at least 1 previous line of chemotherapy for advanced disease, were retrospectively collected across 14 Italian centers. Overall survival (OS) and progression-free survival (PFS) were analyzed using the Kaplan-Meier method. Cox regression analysis was performed evaluating potential prognostic factors for OS and PFS. Each factor was evaluated in univariable (UVA) and multivariable analysis (MVA). A total of 208 evaluable patients treated with ICIs were identified, including 122 (59%) without BoM (BoM-) and 86 (41%) with bone metastases (BoM+). After a median follow-up of 22.3 months, BoM+ patients showed shorter OS (median 3.9 vs 7.8 months, HR 1.59 [95%CI, 1.15-2.20], P=.005) and shorter PFS (median 2.0 vs 2.6 months, HR 1.76 [95%CI, 1.31-2.37], P < .001). Probability of being alive was 62% vs 40% after 6 months, 38% vs 23% after 1 year and 24% vs 13% after 2 years, in BoM- and BoM+ respectively. Within each Bellmunt score, OS and PFS of BoM+ patients were shorter. Both presence of BoM and higher Bellmunt risk score were significantly associated with shorter OS and PFS in UVA and MVA. Patients treated with single-agent ICIs for BoM+ mUC have a dismal prognosis compared to BoM-. Further research is needed to understand the mechanism behind these outcomes.

Risk Factors, Prognostic Factors, and Nomograms for Bone Metastasis in Patients with Newly Diagnosed Clear Cell Renal Cell Carcinoma: A Large Population-Based Study.

BackgroundThis study aimed to investigate risk factors and prognostic factors in patients with clear cell renal cell carcinoma (ccRCC) with bone metastasis (BM) and establish nomograms to provide a quantitative prediction of the risk of BM and survival probability.MethodsThe clinicopathological characteristics of patients with ccRCC between January 2010 and December 2015 were obtained from the Surveillance, Epidemiology and End Results (SEER) database. Independent factors for BM in ccRCC patients were identified using univariate and multivariate logistic regression analyses. Prognostic factors for predicting cancer-specific death were evaluated using univariate and multivariate analyses based on a competing risk regression model. We then constructed a diagnostic nomogram and a prognostic nomogram. The two nomograms were evaluated using calibration curves, receiver operating characteristic curves, and decision curve analysis.ResultsOur study included 34,659 patients diagnosed with ccRCC in the SEER database, with 1,415 patients who presented with bone metastasis. Risk factors for BM in patients with ccRCC included age, stage T, stage N, brain metastasis, liver metastasis, lung metastasis, tumor size, and laterality. Independent prognostic factors for patients with ccRCC patients with BM were Fuhrman grade, tumor size, T stage, N stage, brain metastases, lung metastasis, and surgery. For the diagnostic nomogram, the area under the curve values in the training and testing cohorts were 0.863 (95% CI, 0.851–0.875) and 0.859 (95% CI, 0.839–0.878), respectively. In the prognostic cohort, the area under the curve values for 1-, 2-, and 3-year cancer-specific survival rates in the training cohort were 0.747, 0.774, and 0.780, respectively, and 0.671, 0.706, and 0.696, respectively, in the testing cohort. Through calibration curves and decision curve analyses, the nomograms displayed excellent performance.ConclusionsSeveral factors related to the development and prognosis of BM in patients with ccRCC were identified. The nomograms constructed in this study are expected to become effective and precise tools for clinicians to improve cancer management.

Roles of the RANKL-RANK Axis in Immunity-Implications for Pathogenesis and Treatment of Bone Metastasis.

A substantial amount patients with cancer will develop bone metastases, with 70% of metastatic prostate and breast cancer patients harboring bone metastasis. Despite advancements in systemic therapies for advanced cancer, survival remains poor for those with bone metastases. The interaction between bone cells and the immune system contributes to a better understanding of the role that the immune system plays in the bone metastasis of cancer. The immune and bone systems share various molecules, including transcription factors, signaling molecules, and membrane receptors, which can stimulate the differentiation and activation of bone‐resorbing osteoclasts. The process of cancer metastasis to bone, which deregulates bone turnover and results in bone loss and skeletal-related events (SREs), is also controlled by primary cancer-related factors that modulate the intratumoral microenvironment as well as cellular immune process. The nuclear factor kappa B ligand (RANKL) and the receptor activator of nuclear factor kappa B (RANK) are key regulators of osteoclast development, bone metabolism, lymph node development, and T-cell/dendritic cell communication. RANKL is an osteoclastogenic cytokine that links the bone and the immune system. In this review, we highlight the role of RANKL and RANK in the immune microenvironment and bone metastases and review data on the role of the regulatory mechanism of immunity in bone metastases, which could be verified through clinical efficacy of RANKL inhibitors for cancer patients with bone metastases. With the discovery of the specific role of RANK signaling in osteoclastogenesis, the humanized monoclonal antibody against RANKL, such as denosumab, was available to prevent bone loss, SREs, and bone metastases, providing a unique opportunity to target RANKL/RANK as a future strategy to prevent bone metastases.

Vitamin D Metabolites in Nonmetastatic High-Risk Prostate Cancer Patients with and without Zoledronic Acid Treatment after Prostatectomy.

Simple SummaryRecent research on prostate cancer and vitamin D is controversial. We measured three vitamin D3 metabolites in 32 selected prostate cancer patients after surgery at four time points over four years. Within a large European study, half of the patients were prophylactically treated with zoledronic acid (ZA); the others received a placebo. After the study start, all the patients daily took calcium and vitamin D3. The development of metastasis was not affected by ZA treatment. While two vitamin D metabolites had higher values after the study’s start, with constant follow-up values, the 1,25(OH)2-vitamin D3 concentrations remained unchanged. The latter form was the only metabolite that was higher in the patients with metastasis as compared to those without bone metastasis. This result is surprising. However, it is too premature to discuss possible prognostic value yet. Our results should be confirmed in larger cohorts.There are limited and discrepant data on prostate cancer (PCa) and vitamin D. We investigated changes in three vitamin D3 metabolites in PCa patients after prostatectomy with zoledronic acid (ZA) treatment regarding their metastasis statuses over four years. In 32 patients from the ZEUS trial, 25(OH)D3, 24,25(OH)2D3, and 1,25(OH)2D3 were measured with liquid chromatography coupled with tandem mass spectrometry at four time points. All the patients received daily calcium and vitamin D3. Bone metastases were detected in 7 of the 17 ZA-treated patients and in 5 of the 15 controls (without ZA), without differences between the groups (p = 0.725). While 25(OH)D3 and 24,25(OH)2D3 increased significantly after the study’s start, with following constant values, the 1,25(OH)2D3 concentrations remained unchanged. ZA treatment did not change the levels of the three metabolites. 25(OH)D3 and 24,25(OH)2D3 were not associated with the development of bone metastases. In contrast, 1,25(OH)2D3 was also higher in patients with bone metastasis before the study’s start. Thus, in high-risk PCa patients after prostatectomy, 25(OH)D3, 24,25(OH)2D3, and 1,25(OH)2D3 were not affected by supportive ZA treatment or by the development of metastasis over four years, with the exception of 1,25(OH)2D3, which was constantly higher in metastatic patients. There might be potential prognostic value if the results can be confirmed.

Vulvar cancer during pregnancy and/or breastfeeding: a report of five cases from a single center study at the University Hospital of Düsseldorf

BackgroundThe incidence of vulvar cancer (VC) in pregnancy is unknown due to its rarity; between 1955 and 2014 only 36 case reports were reported worldwide. Underreporting may also be a contributing factor to the unknown incidence of VC in pregnancy. The aim of this study was to analyze the diagnosis, treatment and outcome of vulvar cancer cases diagnosed during pregnancy and/or breastfeeding.Case presentationPatient 1 was diagnosed at 18 weeks’ gestation (WG) with Grade 2 VC (pT1a, pN0, 0/4 sentinel lymph nodes biopsy (SLNB) involved) and was treated by having the tumor resected (R0). She is currently recurrence-free at 4 years post-diagnosis.Patient 2 was diagnosed at 7 WG with Grade 2 VC (pT1b, pN1a, 1/17 SLNB, R0) and was treated during the first trimester and during the second trimester with SLNB. She is currently recurrence-free at 5 years post-diagnosis.Patient 3 was diagnosed at 30 WG with Grade 2 VC (pT1b, pN0, 0/5 SLNB, R0). She subsequently experienced a number of local recurrences postpartum that were managed by resection and is currently recurrence-free at 3 years post-diagnosis.Patient 4 was diagnosed a VL later, at 14 months during breastfeeding, that was diagnosed as Grade 3 VC (pT1b, pN1a, 1/14 SLNB, R0). The patient is currently recurrence-free at 9 years post-diagnosis.Patient 5 was not diagnosed during pregnancy, but was diagnosed with G3 VC (pT2, pN2c, 2/17 SLNB, R0) 8 months postpartum. The patient due to the extent of tumor involvement and lymph node metastasis, underwent chemoradiation therapy post-surgery. Despite adjuvant therapy, the patient progressed and developed bone metastases. Analysis of the tumour tissue revealed increased expression of PD-L1 (programmed cell death protein 1) indicating that the patient may have benefited from treatment with nivolumab to block the PD-L1 interaction; unfortunately the patient passed away at 24 months post-diagnosis before immunotherapy treatment could commence.ConclusionSurgical resection and simultaneous SLNB in VC cases are considered safe during pregnancy, with comparable outcomes to non-pregnant women. Prompt diagnostic workup and treatment should never be delayed during pregnancy as delayed diagnosis could lead to tumour progression with fatal consequences.

833 Potential Palliative Role for Neoadjuvant Arterial Embolization in Patients with Spine Metastases

INTRODUCTION: Approximately two-thirds of all cancer patients will develop bone metastasis, and the spine is the most common site.1 Spine metastases may lead to significant pain, instability, and/or neurological morbidity. A high rate of local control can be achieved with local therapies such as radiation and surgery, but persistent pain is described among some patients. Prior clinical research demonstrated that arterial embolization without surgery may improve pain associated with spine metastases.2 This study aimed to determine the effects of embolization on pain in patients undergoing surgical decompression and stabilization. METHODS: A retrospective single-center review between 2012 and 2020 identified 117 patients receiving adjuvant SRS or SBRT following surgical intervention for spine metastases. The study group included various primary tumor types and patients treated with laminectomy and/or varying degrees of vertebrectomy. Data analyzed included demographic information, embolization and surgical details, KPS, defensive veterans pain rating scale (DVPRS), dose of radiotherapy, and daily doses of analgesic medications. RESULTS: Of 117 patients, 47 (40.2%) underwent preoperative embolization. Forty-nine (70%) and 24 (51.1%) patients underwent laminectomy/partial vertebrectomy in the non-embolization and embolization cohorts, respectively. Demographics were similar between groups at baseline. DVPRS scores did not differ by primary tumor histopathology (p = 0.63). DVPRS daily average and maximum rest scores decreased from 5.6 to 3.7, p &lt; 0.001, and 5.7 to 3.8, p &lt; 0.001, respectively following embolization. Throughout postoperative days 1-14, pain scores and daily doses of analgesic medications were largely similar between cohorts. CONCLUSIONS: Preoperative arterial embolization decreases pain scores immediately after the procedure, consistent with prior literature. This palliative effect largely disappears in the postoperative period, likely due to surgical pain. Future prospective studies identifying long-term palliative effects of embolization for spine metastasis are needed.

Intervention with the Bone-Associated Tumor Vicious Cycle through Dual-Protein Therapeutics for Treatment of Skeletal-Related Events and Bone Metastases.

Bone metastasis is a common metastasis site such as lung cancer, prostate cancer, and other malignant tumors. The occurrence of bone metastases of lung cancer is often accompanied by bone loss, fracture, and other skeletal-related events (SREs) caused by tumor proliferation and osteoclast activation. Furthermore, along with the differentiation and maturation of osteoclasts in the bone microenvironment, it will further promote the occurrence and development of bone metastasis. Protein drugs are one of the most promising therapeutic pharmaceuticals, but in vivo delivery of protein therapeutics still confronts great challenges. In order to more effectively conquer bone metastases and alleviate SREs, herein, we constructed biomineralized metal-organic framework (MOF) nanoparticles carrying protein toxins with both bone-seeking and CD44-receptor-targeting abilities. More importantly, through combination with Receptor Activator of Nuclear Factor-κ B Ligand (RANKL) antibody, in vivo results demonstrated that these two protein agents not only enhanced the detraction effects of protein toxin agents as ribosome-inactivating protein (RIP) on bone metastatic tumor cells but also exhibited synergistic intervention of the crosstalk between bone cells and tumor cells and reduced SREs such as bone loss. Collectively, we expect that this strategy can provide an effective and safe option in regulating bone-tumor microenvironments to overcome bone metastasis and SREs.

GDF15 promotes prostate cancer bone metastasis and colonization through osteoblastic CCL2 and RANKL activation

Bone metastases occur in patients with advanced-stage prostate cancer (PCa). The cell-cell interaction between PCa and the bone microenvironment forms a vicious cycle that modulates the bone microenvironment, increases bone deformities, and drives tumor growth in the bone. However, the molecular mechanisms of PCa-mediated modulation of the bone microenvironment are complex and remain poorly defined. Here, we evaluated growth differentiation factor-15 (GDF15) function using in vivo preclinical PCa-bone metastasis mouse models and an in vitro bone cell coculture system. Our results suggest that PCa-secreted GDF15 promotes bone metastases and induces bone microarchitectural alterations in a preclinical xenograft model. Mechanistic studies revealed that GDF15 increases osteoblast function and facilitates the growth of PCa in bone by activating osteoclastogenesis through osteoblastic production of CCL2 and RANKL and recruitment of osteomacs. Altogether, our findings demonstrate the critical role of GDF15 in the modulation of the bone microenvironment and subsequent development of PCa bone metastasis.

Bone health and therapeutic agents in advanced prostate cancer.

Prostate cancer is the most frequent genitourinary tumor worldwide. Maintaining an optimum bone health throughout the natural course of prostate cancer is an important aspect in the management of this disease, particularly in this at risk population of older and frail patients who experience bone loss related to androgen-deprivation therapy (ADT) and/or patients who develop bone metastases. The number of treatment options for advanced prostate cancer that combine ADT with docetaxel, new hormonal agents and/or radiotherapy has increased substantially in recent years. Bisphosphonates and other bone targeted agents such as denosumab have shown an improvement in bone mineral density and are suited for patients with treatment-related osteoporosis and/or bone metastases with an increased risk of skeletal-related events (SREs). In this context, the aim of this review is to analyse key aspects of bone health and therapies that can prevent the occurrence of SREs throughout the clinical course of prostate cancer, and how to combine them with new available treatments in this setting.

Pathological Fracture as the Initial Presentation of Metastatic Pancreatic Cancer

Pancreatic cancer with bone metastasis is considered a very rare malignancy. Although the incidence rate of people with pancreatic cancer who develop bone metastasis is unknown, it is estimated as between 5% and 20%. We report a 61-year-old lady who had multiple emergency department visits complaining of lower back pain radiating to the lower limbs for five months. Clinical and imaging workup suggested pancreatic adenocarcinoma metastasis to the second lumbar vertebra (L2), lungs, and ovaries.

Incidence of bone metastasis in head and neck malignancy: A retrospective study.

The retrospective analysis was done to describe the characteristics and frequency of bone metastases and prognosis of head and neck cancer patients with bone metastases. We investigated total 16209 patients of which 3620 were head and neck cancer patients entering our oncology outpatient department from January 2010 to December 2019. Of 3620 patients, 29 of them developed solitary or multiple bone metastases during the progression of the disease. The overall incidence of bone metastases was found to be 0.8% (29 cases) in head and neck cancers. Bone metastasis was observed in solitary or multiple bones which includes vertebrae 12 (41.37%), hip 9 (31.03%), femur 3 (10.34%), and involve sternum, ribs, clavicle and orbits in few cases. All the patients had few months of survival after developing bone metastasis. With the recent advancement in technology, the survival rate and quality of life of patient suffering from head and neck carcinoma had increased. Distant metastasis to bones was rarely observed in these cancers. Bone dissemination is associated with poor outcome; thus it must always be taken into consideration when contemplating intervention in these patients. So, for early diagnose of this metastasis in complete responders' appropriate measures should be taken during follow-up.

Deregulated molecules and pathways in the predisposition and dissemination of breast cancer cells to bone

BackgroundBone metastasis is the most common metastatic destination in advanced breast cancer, presenting a poor prognosis and clinical challenges in management. To date, the mechanism of bone metastasis in breast cancer remains largely unclear. MethodsDifferentially expressed genes in primary tumours that developed bone metastases were systematically analysed using both TCGA-BRCA and E-MTAB-4003 databases. Adaptive phenotype in the subsequent bone lesions was analysed in the GSE46161 database. A series of biomarkers including homing, immune escape, angiogenesis, and factors involved in both osteoblastogenesis and osteoclastogenesis were included to dissect the molecular events underlying bone metastasis in breast cancer. ResultsUpregulated expressions of GDF11 expression is positively correlated with colonization, osteoblastogenesis and osteoclastogenesis, whilst CD151 is positively associated with angiogenesis and immune escape. PAFAH1B2 expression is inversely correlated with the angiogenic process. Reduced YTHDF2 may facilitate cancer cell homing, osteoclastogenesis and immune escape in breast cancer. DPP9, FAS, ZNF519, RPP14 and FAU were evaluated for their potential involvement in for the homing to bone, escaping from immune surveillance, angiogenesis, osteoblastic activity and osteoclastic activity in the multi-step process of bone metastasis. ConclusionGDF11, CD151, PAFAH1B2 and YTHDF2 may play a pivotal role in the predisposition of metastasis to the bone from breast cancer, whilst DPP9, FAS, ZNF519, RPP14 and FAU may be actively involved in the adaptative colonisation of metastatic breast cancer cells in bone.

Abstract P033: Bone microenvironment-suppressed T cells increase osteoclast formation and the development of osteolytic bone metastases in mice

Abstract Bone metastases are a highly debilitating complication in more than 70% of patients with advanced breast and prostate cancer, causing fractures, nerve compression, hypercalcemia. Currently approved treatments fail to cure bone metastases or increase patient survival. Immunotherapies activating T cells to fight cancer cells are changing cancer treatment, causing a durable response in some patients. However, it remains unclear whether immunotherapy could benefit patients with bone metastases. The bone microenvironment combines various immunosuppressive factors that could limit its efficacy. Also, T cells could increase bone resorption releases pro-metastatic growth factors from the bone matrix that can increase cancer cell growth. Using syngeneic mouse models, our study revealed that bone metastases from 4T1 breast cancer contain tumor-infiltrating lymphocyte (TILs) and that their development is increased in normal mice compared to immunodeficient and T-cell depleted mice (x3.6 and x1.6, respectively, p&amp;lt;0.05). This effect seemed caused by the TILs in bone, as T-cell depletion did not affect bone metastases from RM-1 prostate cancer cells that lack TILs and increased the volume of 4T1 orthotopic tumors. T cells from bone metastases expressed the pro-osteoclastic genes Rankl and Tnfa, and increased osteoclast formation ex vivo and in vivo, at the tumor-bone interface, contributing to bone metastasis development. This pro-osteoclastic effect is specific to inactivated T cells, since activated T cells, secreting IFNγ and IL-4, actually suppressed osteoclastogenesis, which could benefit patients. We confirmed that T cells in bone metastases were not activated, as &amp;gt;85% of T cells lacked the activation marker CD69. In addition, T cells from 4T1 bone metastases could not be activated in ex vivo cultures confirming the presence of immunosuppressive factors in this microenvironment. 4T1 bone metastases were associated with an increase of polymorphonuclear- and monocytic-MDSCs, metabolically active as they produced elevated levels of ROS and NO, respectively. While effective in other models, the PDE-5 inhibitor sildenafil and the bisphosphonate zoledronic acid did not affect the levels of MDSCs in bone metastases or their production of ROS and NO. Seeking other therapeutic targets, we found that 80% of monocytic-MDSCs are PD-L1+ in bone, which could trigger T-cell suppression since 70% express its receptor, PD-1. Collectively, our findings identified a new mechanism by which suppressed T cells increase osteoclastogenesis and bone metastases, and also provide a rationale for using immune checkpoint inhibitors since T-cell activation would increase their anti-cancer and their anti-osteoclastic properties. Citation Format: Danna L. Arellano, Patricia Juárez, Paloma S. Almeida-Luna, Felipe Olvera, Samanta Jiménez, Pierrick G. J. Fournier. Bone microenvironment-suppressed T cells increase osteoclast formation and the development of osteolytic bone metastases in mice [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P033.

Hematologic Presentation of Metastatic Prostate Carcinoma: A Case Report on a Brca2 Mutated Young Patient

Prostatic adenocarcinoma is one of the most frequent malignancy amongst men, in most patients with advanced disease (65-75%) end up developing bone metastases. One of the factors linked to such condition is the genectic variability of cancer types, the most aggressive of them are derived from a series of mutations in tumor suppressor genes.

Metastatic prostate carcinoma: A case report on a Brca2 mutated young patient

Prostatic adenocarcinoma is one of the most frequent malignancy amongst men, majority patients with advanced disease end up developing bone metastases. One of the factors linked to such condition is the genectic variability of cancer types, the most aggressive of them are derived from a series of mutations in tumor suppressor genes.

Spectrum of biphasic renal cell carcinomas with hyalinized stroma and psammoma bodies associated and not associated with NF2 alteration

A unique subtype of biphasic renal cell carcinoma (RCC) was recently described and termed biphasic hyalinizing psammomatous RCC (BHPRCC). This tumor shows a dual population of larger cells and small cells surrounding basement membrane-like materials and invariably has papillary features, hyalinized stroma, and psammoma calcifications. The biphasic pattern in BHPRCC may resemble that of RCC associated with TFEB gene fusion or t (6;11) RCC. However, all reported BHPRCCs had no TFEB alterations and all were associated with neurofibromin 2 (NF2) mutations. Herein, we present three biphasic RCCs encompassing the reported BHPRCC morphologies. One RCC showed solid, nested, papillary, and tubular growths, with biphasic pattern of larger cells surrounding clusters of smaller cells arranged around basement membrane-like materials, and harbored NF2 mutation consistent with BHPRCC. This patient developed bone metastasis 59 months after surgery. The two other biphasic RCCs showed morphologic overlap to BHPRCC, but in addition had other features not seen in BHPRCC, such as lack of papillary pattern, having large tubules containing mucinous to collagenous spherules (mucicarmine and collagen IV positive) bordered by a single layer of small cells with occasional central targetoidpsammoma bodies, and with widespread nuclear grooves. Interestingly, these two tumors also did not show alterations in NF2 or TFEB including translocation or amplification. In conclusion, we report another example of the novel BHPRCC that had metastasized and two biphasic RCCs not associated with NF2 or TFEB alterations; the latter two shared additional distinct morphological features and may represent a unique biphasic RCC distinct from the novel BHPRCC.

Predicting Bone Metastasis Using Gene Expression-Based Machine Learning Models.

Bone is the most common site of distant metastasis from malignant tumors, with the highest prevalence observed in breast and prostate cancers. Such bone metastases (BM) cause many painful skeletal-related events, such as severe bone pain, pathological fractures, spinal cord compression, and hypercalcemia, with adverse effects on life quality. Many bone-targeting agents developed based on the current understanding of BM onset’s molecular mechanisms dull these adverse effects. However, only a few studies investigated potential predictors of high risk for developing BM, despite such knowledge being critical for early interventions to prevent or delay BM. This work proposes a computational network-based pipeline that incorporates a ML/DL component to predict BM development. Based on the proposed pipeline we constructed several machine learning models. The deep neural network (DNN) model exhibited the highest prediction accuracy (AUC of 92.11%) using the top 34 featured genes ranked by betweenness centrality scores. We further used an entirely separate, “external” TCGA dataset to evaluate the robustness of this DNN model and achieved sensitivity of 85%, specificity of 80%, positive predictive value of 78.10%, negative predictive value of 80%, and AUC of 85.78%. The result shows the models’ way of learning allowed it to zoom in on the featured genes that provide the added benefit of the model displaying generic capabilities, that is, to predict BM for samples from different primary sites. Furthermore, existing experimental evidence provides confidence that about 50% of the 34 hub genes have BM-related functionality, which suggests that these common genetic markers provide vital insight about BM drivers. These findings may prompt the transformation of such a method into an artificial intelligence (AI) diagnostic tool and direct us towards mechanisms that underlie metastasis to bone events.

Changes in the detection of human epidermal growth factor receptor 2 gene (Her-2) status for Her-2 fluorescent in situ hybridization testing

Changes in the detection of human epidermal growth factor receptor 2 gene (Her-2) status for Her-2 fluorescent in situ hybridization testing

Roles of renin-angiotensin system in the regulation of prostate cancer bone metastasis: a critical review

Mestastatic prostate cancer cells (MPCCs) frequently metastasize to bone, which is a “favorite soil” for colonization and proliferation of MPCCs. Prostate cancer bone mestastasis is tightly associated with tumor-induced bone lesions, most commonly caused from (1) the etiological imbalance between osteoblastic bone formation and osteoclastic bone resorption and from (2) the anti-tumor immune response. Therefore, understanding of prostate cancer biology and prostate cancer bone metastasis has led to the establishment of drug development programs for treatment of the patients with bone metastasis. The renin-angiotensin system (RAS) controls systemic body fluid circulation; nonetheless, the existence of a local RAS in tumors has been reported. Importantly, the local RAS has recently emerged as a potential regulator of tumorigenesis and cancer metastasis. This review summarizes and dissects the critical roles of the local RAS in promoting (1) progression of metastatic prostate cancer, and (2) development and progression of PCa bone metastasis, thereby providing multiple solutions for the potential therapeutic intervention.

Bone recurrence in early breast cancer patients: The paradox of aromatase inhibitors induced bone resorption.

Despite the increase in chances of cure for early breast cancer (EBC) patients, approximately 20-45% of them will experience a disease recurrence, particularly bone metastases in 60-80% of cases, which occur more frequently in luminal subtypes. Endocrine therapy (ET) has always been the milestone of adjuvant treatment for hormone receptor-positive EBC patients, leading to indubitable reduction of disease recurrence risk. However, adjuvant aromatase inhibitors (AIs) therapy may promote a progressive decrease in bone mineral density (BMD), which can lead to osteoporosis. The increased bone resorption associated with osteoporosis may provide fertile soil for cancer growth and accelerate the development of bone metastases. In this single-institution cohort study, we performed a retrospective analysis of "luminal-like" EBC patients who experienced bone recurrence after a subsequent disease free interval. The aim of the study was to evaluate the median time to skeletal recurrence (TSkR). 143 patients experienced bone recurrence. Median TSkR was 54 months (95%CI: 45-65). Among patients who received adjuvant AIs median TSkR was 35 months (95%CI: 25-54), while among patients who did not was 61 months (95%CI: 50-80) (HR = 1.45 [95%CI: 0.97-2.17], p =0.0644). After adjusting for TNM stage (AJCC 8th edition), adjuvant AIs treatment was significantly related to a shorter TSkR (HR = 1.60 [95%CI: 1.06-2.42], p =0.0244). Adjuvant Tamoxifen, adjuvant AIs/Tamoxifen and no-treatment did not revealed to be associated to TSkR. In this cohort of EBC patients with bone recurrence, AIs treatment seems to be related to a shorter TSkR. AIs-induced bone resorption might represent the underlying mechanism.