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Query: UMLS:C0153690 (bone metastases)
 6,382 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bone metastasis is a frequent complication of lung cancer progression, however, studies on bone metastatic tissues are scanty. Here we have collected a small cohort of 11 non-small cell lung cancer cases where primary tumors and corresponding bone metastases were available for pathological analysis. We have tested two molecular markers: EGFR protein expression and K-RAS mutation at codon 12 using immunohistochemistry and RFLPPCR, respectively. We have shown that using improved protocols, EGFR protein (both the extracellular as well as the cytoplasmic domain) is readily detectable in decalcified bone tissue. We found that the EGFR expression status is highly similar in bone metastases compared to the primary tumors, although the expression levels may change. Individual comparison of corresponding primary and metastatic NSCLC tissues indicated that downregulation of EGFR was a rare event (2/11) compared to upregulation (4/11) in bone metastases. On the other hand, our data indicate that the K-RAS mutational status of the primary tumor does not predict the status of the bone metastatic tissue of NSCLC, since we have observed both emergence of mutant clones in metastases from wild-type (wt) primary tumors and loss of mutant clones in metastases from mutant primaries in addition to the maintained mutant status. Our data support that at least two progression models occur in NSCLC, the samegene as well as the clonal selection one. It is noteworthy that in NSCLC cases with wt- or mutant KRAS, downregulation of EGFR expression was a rare event although upregulation in bone metastases was observed more frequently in wt K-RAS cases.
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PMID:Phenotype of bone metastases of non-small cell lung cancer: epidermal growth factor receptor expression and K-RAS mutational status. 1760 70

Targeted therapies have improved patient survival in metastatic lung adenocarcinoma. Molecular diagnosis is a key element to identify oncogenic drivers predicting the efficacy of these agents. In stage IV patients, histopathological diagnosis is often performed on bone metastases biopsy, but routine procedure of decalcification may alter DNA quality for subsequent molecular tests. We set up a procedure to perform molecular analyses on bone metastasis and describe the results of mutational profiling. POUMOS-TEC is a prospective study conducted in stage IV lung adenocarcinomas. Bone metastasis specimens from surgery and CT-scan guided biopsies were sent fresh for immediate formalin-fixation. Decalcification was performed, only when necessary, using EDTA. Controls were processed with acid decalcification. DNA extraction was performed after laser microdissection. Mutational profiling of oncogenic drivers was conducted as recommended by the French National Cancer Institute. Diagnosis efficiency of the computed tomography (CT)-scan guided biopsy process was assessed. Among 177 collected bone metastases specimens, 49 came from lung adenocarcinomas. Specimens processed with no decalcification or EDTA (n=45) provided high-quality DNA. Molecular profiling was performed in 44/45 (98%) of cases. The results of the whole panel of oncogenic drivers (EGFR, KRAS, BRAF, PIK3CA, HER2 and ALK) were obtained in 41/45 (91%) of cases. A mutation was observed in 50% of cases including 32% of KRAS and 14% of epidermal growth factor receptor (EGFR) mutations. CT-scan biopsy efficiency rate was 96%. We demonstrated the feasibility to routinely conduct mutational profiling on bone metastases biopsies. We observed a higher rate of EGFR mutations (+42%) in comparison with the average rate of all stage IV lung adenocarcinomas. This procedure is a new step toward the goal of personalized medicine to treat lung cancers and other osteophilic tumors.
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PMID:Mutational profiling of bone metastases from lung adenocarcinoma: results of a prospective study (POUMOS-TEC). 2532 76

Bone is a common site for metastatic colonization in patients with breast cancer, hence the importance of identifying new treatments for this disease. Preclinical studies of bone metastases have commonly employed MDA-MB-231 cells that possess an activated KRAS allele. While activating RAS mutations are relatively rare in human breast cancer, increased RAS-RAF-MEK pathway activity is common in high-grade breast cancers. To study the consequences of MEK inhibition on bone metastases stemming from the intra-cardiac injection of luciferase-expressing MDA-MB-231 cells in mice, we used the MEK inhibitor AZD6244 (Selumetinib). We found that AZD6244 treatment caused decreased tumor bioluminescence that was associated with cavitation of the bone metastases, owing to apoptosis of cells specifically within the central region of the bone lesions. Hypothesizing that the latter effect was due to the increased sensitivity of poorly perfused regions to pro-apoptotic stimuli, we found that the combination of serum deprivation and AZD6244 led to dramatic induction pf MDA-MB-231 apoptosis in vitro. Our results suggest that MEK inhibition may be a strategy for triggering cell death within the hypoperfused, oxygen and nutrient poor regions of tumors with activated RAS alleles.
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PMID:Selumetinib produces a central core of apoptosis in breast cancer bone metastases in mice. 2562 Dec 97

Sinonasal mucosal melanoma (SMM) is an aggressive and rare type of melanoma. Although the classic RAS-RAF-MEK pathway is thought to be the main pathway involved in melanoma pathogenesis, genetic alterations in the phosphatidylinositol 3-kinase-AKT pathway, including PTEN-regulated signaling, are also thought to contribute. So far, data regarding altered PTEN expression and epigenetic mechanism of PTEN silencing in development of SMM is extremely limited. Herein we report on a case of SMM with liver and bone metastases with an epigenetic alteration of PTEN. Results of mutation analysis for BRAF, NRAS, HRAS, KRAS, PIK3CA, c-Kit, and PTEN were negative; however, methylation of PTEN CpG islands was observed. Our case not only supports PTEN as a major tumor suppressor involved in melanoma tumorigenesis, but also a potential epigenetic mechanism of PTEN silencing in development of SMM.
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PMID:PTEN Methylation Dependent Sinonasal Mucosal Melanoma. 2579 73

Somatic mutation status in metastatic colorectal cancer (mCRC) is becoming increasingly clinically relevant as it may be correlated not only with response to biologic therapies, but also with site-specific pattern of metastatic spread and outcome. In this review, we describe our current understanding of associations between mutational activation of the KRAS, BRAF, PIK3CA, and NRAS oncogenes and clinical outcomes and metastatic patterns of mCRC. The presence of a KRAS mutation is associated with a distinct pattern of metastatic spread with decreased liver metastases and increased lung, brain, and bone metastases. In patients who undergo resection of colorectal liver metastases (CLM) with curative intent, KRAS mutation is associated increased risk of recurrence, worse survival, and increased recurrence outside of the liver, particularly in the lung, but also in the brain and bone. BRAF mutation, a poor prognostic factor in mCRC, is associated with decreased liver-limited metastasis and increased peritoneal and distant lymph node metastases. PIK3CA mutation does not clearly affect outcomes in the metastatic setting, but is associated with concurrent KRAS mutations, and has been associated with an increased incidence of lung and brain metastases, metastatic sites preferentially involved in KRAS mutant mCRC. NRAS mutation may confer worse survival and early studies suggest NRAS mutation may promote tumorigenesis in the setting of colorectal inflammation. As metastasectomy with curative intent is increasingly considered in patients with mCRC, understanding patterns of metastasis associated with tumor mutations may help focus medical treatment, surgical management, and surveillance in patients with mCRC.
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PMID:Impact of somatic mutations on patterns of metastasis in colorectal cancer. 2669 97

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice.A 54-year-old man with a former 15-pack-year smoking history presents with cough and dyspnea. Initial work-up with imaging demonstrates a right suprahilar mass measuring 4.7 cm as well as several enlarged hilar and ipsilateral mediastinal lymph nodes. Bronchoscopy with biopsy reveals adenocarcinoma consistent with a lung primary. Staging with positron emission tomography/computed tomography (PET/CT) reidentifies the primary mass and lymph nodes and shows several PET-avid bone metastases. Brain magnetic resonance imaging (MRI) demonstrates a 1.6-cm right parietal mass with mild vasogenic edema and four additional brain metastases measuring 4 to 9 mm in size. Molecular testing is positive for an anaplastic lymphoma kinase (ALK) gene rearrangement using fluorescence in situ hybridization and negative for EGFR, ROS1, RET, BRAF, KRAS, and other oncogenes. The patient denies any neurologic symptoms and has no significant findings on neurologic exam. He is referred to you for management options for newly diagnosed stage IV (T2aN2M1b) lung adenocarcinoma.
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PMID:Management of Brain Metastases in ALK-Positive Non-Small-Cell Lung Cancer. 2802 24

The cribriform-morular variant of papillary thyroid carcinoma (CMV-PTC) is a rare thyroid neoplasm characterized by unique morphologic findings and association with familial adenomatous polyposis. The biologic behavior of this variant has been reported to behave similarly to classic PTC. We report a rare sporadic case of CMV-PTC occurring in a 45-year-old female with multiple lymph nodes and bone metastases, which were detected after total thyroidectomy and radioactive iodine remnant ablation. Molecular analyses of primary thyroid and metastatic tumor tissues revealed a telomerase reverse transcriptase (TERT) promoter mutation, but absence of BRAF, KRAS, NRAS, HRAS, and PIK3CA mutations. Over a 4-year follow-up period, structurally identifiable bone metastases were persistent, but serial post-operative serum thyroglobulin levels remained undetectable in the absence of thyroglobulin antibody. The literature was reviewed. This is the first case of aggressive CMV-PTC showing TERT promoter mutation. TERT promoter mutations may help in predicting aggressive clinical behavior in CMV-PTC. Postoperative serum thyroglobulin measurement may have no impact on clinical decision-making in this type of tumor.
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PMID:TERT Promoter Mutation in an Aggressive Cribriform Morular Variant of Papillary Thyroid Carcinoma. 2768 81

Comprehensive genomic profiling for non-small cell lung cancer (NSCLC) is likely to identify more patients with rare genetic alterations including uncommon epidermal growth factor receptor gene (EGFR) mutations. It remains unclear how such patients should be treated, however. We here report a case of NSCLC positive for two uncommon mutations of EGFR and a KRAS mutation, including its treatment with the second-generation EGFR tyrosine kinase inhibitor (TKI) afatinib. Tumor specimen obtained by a NSCLC patient with no smoking history was analyzed by next-generation sequencing. Comprehensive genomic profiling revealed that the patient harbored the EGFR mutations G719C and S768I as well as the E49K mutation of KRAS. Treatment with afatinib was clinically effective as confirmed by PET-CT scans of bone metastases and by a marked decrease in the serum concentration of carcinoembryonic antigen. Afatinib was the most effective among seven EGFR-TKIs tested in inhibiting the growth of Ba/F3 cells expressing EGFR(S768I), showing an efficacy similar to that apparent with cells expressing the common EGFR mutant L858R, whereas first- and third-generation EGFR-TKIs were markedly less effective against EGFR(S768I) than against EGFR(L858R). These data suggest that EGFR-TKIs differ in their activity toward cells expressing EGFR(S768I) in vitro. Consistently, afatinib was clinically effective for the treatment of NSCLC harboring G719C and S768I mutations of EGFR. Further studies are warranted to determine the most appropriate EGFR-TKI for treatment of NSCLC harboring uncommon EGFR mutations.
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PMID:Case report: Durable response to afatinib in a patient with lung cancer harboring two uncommon mutations of EGFR and a KRAS mutation. 2779 98

Pulmonary sarcomatoid carcinoma (PSC) is a rare subtype of poorly differentiated non-small-cell lung cancer (NSCLC), and no effective treatment is available in clinical practice currently. In the present report, a 61-year-old male patient was hospitalized due to cough, dyspnea, and right chest pain. Computed tomography (CT) showed spot- and piece-shaped shadows. The patient became very weak and had breathing difficulty after preliminary anti-pneumonia treatment with cefoperazone-sulbactam. Physical examination revealed dull sound by percussion and decreased breath sounds in the right lateral lung areas by auscultation. A second CT scan revealed a large amount of pleural effusion, and the patient was diagnosed with bloody pleural effusion through pleural space puncture. Multiple nodular lesions were found in the right pleural cavity under thoracoscopy. PSC was confirmed by biopsy and histopathology in combination with immunohistochemistry (IHC). Single-photon emission CT (SPECT) scan indicated multiple bone metastases. KRAS exon 2 mutation and EML4-ALK fusion were identified in carcinoma tissue by IHC and amplification refractory mutation system (ARMS)-PCR. The patient received one cycle of first-line combination chemotherapy of cisplatin and paclitaxel liposomes. However, the patient did not respond to the platinum-based combination chemotherapy within 3 weeks and was thus administered oral crizotinib instead of chemotherapy. Unfortunately, he still had rapid disease progression and died 2 weeks after the initiation of crizotinib treatment. Collectively, our results suggest that a PSC patient with coexistent KRAS mutation and ALK rearrangement would not benefit from chemotherapy and tyrosine kinase inhibitor (TKI) treatment.
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PMID:Poor prognosis of pulmonary sarcomatoid carcinoma with KRAS mutation and ALK fusion. 3111 83