MAPK/ERK Signaling in Osteosarcomas, Ewing Sarcomas and Chondrosarcomas: Therapeutic Implications and Future Directions

The introduction of cytotoxic chemotherapeutic drugs in the 1970's improved the survival rate of patients with bone sarcomas and allowed limb salvage surgeries. However, since the turn of the century, survival data has plateaued for a subset of metastatic, nonresponding osteo, and/or Ewing sarcomas. In addition, most high-grade chondrosarcoma does not respond to current chemotherapy. With an increased understanding of molecular pathways governing oncogenesis, modern targeted therapy regimens may enhance the efficacy of current therapeutic modalities. Mitogen-Activated Protein Kinases (MAPK)/Extracellular-Signal-Regulated Kinases (ERK) are key regulators of oncogenic phenotypes such as proliferation, invasion, angiogenesis, and inflammatory responses; which are the hallmarks of cancer. Consequently, MAPK/ERK inhibitors have emerged as promising therapeutic targets for certain types of cancers, but there have been sparse reports in bone sarcomas. Scattered papers suggest that MAPK targeting inhibits proliferation, local invasiveness, metastasis, and drug resistance in bone sarcomas. A recent clinical trial showed some clinical benefits in patients with unresectable or metastatic osteosarcomas following MAPK/ERK targeting therapy. Despite in vitro proof of therapeutic concept, there are no sufficient in vivo or clinical data available for Ewing sarcomas or chondrosarcomas. Further experimental and clinical trials are awaited in order to bring MAPK targeting into a clinical arena

Synchronous primary colorectal and liver metastasis: impact of operative approach on clinical outcomes and hospital charges

AbstractObjectivesThe management of patients with colorectal cancer (CRC) and synchronous colorectal liver metastasis (CLM) remains controversial. The present study was conducted in order to assess the clinical and economic impacts of managing synchronous CLM with a staged versus a simultaneous surgery approach.MethodsA total of 224 patients treated for synchronous CLM during 1990–2012 were identified in the Johns Hopkins Hospital liver database. Data on clinicopathological features, perioperative outcomes and total hospital charges (inflation-adjusted) were collected and analysed.ResultsOverall, 113 (50.4%) patients underwent staged surgery and 111 (49.6%) were submitted to a simultaneous CRC and liver operation. At surgery, liver-directed therapy included hepatectomy (75.0%) or combined resection and ablation (25.0%). Perioperative morbidity (30.0%) and mortality (1.3%) did not differ between groups (both P > 0.05). Median total length of hospitalization was longer in the staged (13 days) than the simultaneous (7 days) surgery group (P < 0.001). Median total hospital charges were higher among patients undergoing staged surgery (US$61 938) than among those undergoing a simultaneous operation (US$34 114) (P < 0.01). Median (simultaneous, 32.4 months versus staged, 39.6 months; P = 0.65) and 5-year (simultaneous, 27% versus staged, 29%; P = 0.60) overall survival were similar between groups.ConclusionsPatients with synchronous CLM managed with either simultaneous or staged surgery have comparable perioperative and longterm outcomes. However, patients treated with simultaneous surgery spent an average of 6 days fewer in hospital, resulting in a reduction of median hospital charges of US$27 824 (55.1%). When appropriate and technically feasible, the simultaneous surgery approach to synchronous CLM should be preferred

Modern Interpretation of Giant Cell Tumor of Bone: Predominantly Osteoclastogenic Stromal Tumor

Owing to striking features of numerous multinucleated cells and bone destruction, giant cell tumor (GCT) of bone, often called as osteoclastoma, has drawn major attractions from orthopaedic surgeons, pathologists, and radiologists. The name GCT or osteoclastoma gives a false impression of a tumor comprising of proliferating osteoclasts or osteoclast precursors. The underlying mechanisms for excessive osteoclastogenesis are intriguing and GCT has served as an exciting disease model representing a paradigm of osteoclastogenesis for bone biologists. The modern interpretation of GCT is predominantly osteoclastogenic stromal cell tumors of mesenchymal origin. A diverse array of inflammatory cytokines and chemokines disrupts osteoblastic differentiation and promotes the formation of excessive multi-nucleated osteoclastic cells. Pro-osteoclastogenic cytokines such as receptor activator of nuclear factor kappa-B ligand (RANKL), interleukin (IL)-6, and tumor necrosis factor (TNF) as well as monocyte-recruiting chemokines such as stromal cell-derived factor-1 (SDF-1) and monocyte chemoattractant protein (MCP)-1 participate in unfavorable osteoclastogenesis and bone destruction. This model represents a self-sufficient osteoclastogenic paracrine loop in a localized area. Consistent with this paradigm, a recombinant RANK-Fc protein and bisphosphonates are currently being tried for GCT treatment in addition to surgical excision and conventional topical adjuvant therapies

Prognostic value of CD8CD45RO Tumor Infiltrating Lymphocytes in Patients with Extrahepatic Cholangiocarcinoma

Cholangiocarcinoma is a malignancy arising from the biliary tract epithelial cells with poor prognosis. Tumor infiltrating lymphocytes (TIL)s and programmed cell death receptor ligand 1 (PD-L1) have a prognostic impact in various solid tumors. We aimed to investigate TILs and PD-L1 expression and their clinical relevance in cholangiocarcinoma. Tumor samples from 44 patients with resected and histologically verified extrahepatic cholangiocarcinoma were evaluated for CD8, CD45RO and PD-L1 expression, and their correlations with clinicopathological data and survival data were analyzed. Total 44 extrahepatic cholangiocarcinoma tissues were evaluated. CD8+ tumor infiltrating lymphocytes (TIL)s were observed in 30 (68%) tumors. Among them, 14 had CD8+CD45RO+ TILs. PD-L1 was expressed on cancer cells in 10 (22.7%) tumors in 34 evaluable extrahepatic cholangiocarciniomas. The presence of CD8+ TILs or CD8+CD45RO+ TILs was not associated with clinical staging or tumor differentiation. Extrahepatic cholangiocarcinoma with CD8+CD45RO+ TILs had longer overall survival (OS) on univariate (P = 0.013) and multivariate (P = 0.012) analysis. Neither CD8+TIL nor PD-L1 expression on cancer cells correlated significantly with OS. These results add to the understanding of the clinical features associated with CD8 TILs and PD-L1 expression in extrahepatic cholangiocarcinoma, and they support the potential rationale of using PD-1 blockade immunotherapy in cholangiocarcinoma

Prognostic value of CD8CD45RO Tumor Infiltrating Lymphocytes in Patients with Extrahepatic Cholangiocarcinoma

Cholangiocarcinoma is a malignancy arising from the biliary tract epithelial cells with poor prognosis. Tumor infiltrating lymphocytes (TIL)s and programmed cell death receptor ligand 1 (PD-L1) have a prognostic impact in various solid tumors. We aimed to investigate TILs and PD-L1 expression and their clinical relevance in cholangiocarcinoma. Tumor samples from 44 patients with resected and histologically verified extrahepatic cholangiocarcinoma were evaluated for CD8, CD45RO and PD-L1 expression, and their correlations with clinicopathological data and survival data were analyzed. Total 44 extrahepatic cholangiocarcinoma tissues were evaluated. CD8+ tumor infiltrating lymphocytes (TIL)s were observed in 30 (68%) tumors. Among them, 14 had CD8+CD45RO+ TILs. PD-L1 was expressed on cancer cells in 10 (22.7%) tumors in 34 evaluable extrahepatic cholangiocarciniomas. The presence of CD8+ TILs or CD8+CD45RO+ TILs was not associated with clinical staging or tumor differentiation. Extrahepatic cholangiocarcinoma with CD8+CD45RO+ TILs had longer overall survival (OS) on univariate (P = 0.013) and multivariate (P = 0.012) analysis. Neither CD8+TIL nor PD-L1 expression on cancer cells correlated significantly with OS. These results add to the understanding of the clinical features associated with CD8 TILs and PD-L1 expression in extrahepatic cholangiocarcinoma, and they support the potential rationale of using PD-1 blockade immunotherapy in cholangiocarcinoma

Prognostic value of CD8CD45RO tumor infiltrating lymphocytes in patients with extrahepatic cholangiocarcinoma

Cholangiocarcinoma is a malignancy arising from the biliary tract epithelial cells with poor prognosis. Tumor infiltrating lymphocytes (TIL)s and programmed cell death receptor ligand 1 (PD-L1) have a prognostic impact in various solid tumors. We aimed to investigate TILs and PD-L1 expression and their clinical relevance in cholangiocarcinoma. Tumor samples from 44 patients with resected and histologically verified extrahepatic cholangiocarcinoma were evaluated for CD8, CD45RO and PD-L1 expression, and their correlations with clinicopathological data and survival data were analyzed. Total 44 extrahepatic cholangiocarcinoma tissues were evaluated. CD8+ tumor infiltrating lymphocytes (TIL)s were observed in 30 (68%) tumors. Among them, 14 had CD8+CD45RO+ TILs. PD-L1 was expressed on cancer cells in 10 (22.7%) tumors in 34 evaluable extrahepatic cholangiocarciniomas. The presence of CD8+ TILs or CD8+CD45RO+ TILs was not associated with clinical staging or tumor differentiation. Extrahepatic cholangiocarcinoma with CD8+CD45RO+ TILs had longer overall survival (OS) on univariate (P = 0.013) and multivariate (P = 0.012) analysis. Neither CD8+TIL nor PD-L1 expression on cancer cells correlated significantly with OS. These results add to the understanding of the clinical features associated with CD8 TILs and PD-L1 expression in extrahepatic cholangiocarcinoma, and they support the potential rationale of using PD-1 blockade immunotherapy in cholangiocarcinoma

Quality of life after treatment of neuroendocrine liver metastasis

Background: A large subset of patients with neuroendocrine liver metastasis (NELM) is symptomatic at the time of presentation. In addition to improving survival, treatment of NELM seeks to provide palliation of symptoms. However, data on health-related quality of life (QoL) are uncommon. We sought to define patient-reported QoL after treatment of NELM. Methods: Patients who underwent treatment of NELM at Johns Hopkins Hospital between 1998 and 2013 and who were alive as of March 2014 were identified (n \ubc 125). These patients were invited to complete a QoL survey designed using validated assessment tools, to assess their physical, mental, and general health before treatment, after the most recent treatment and at the time of the study. Clinicopathologic data were collected and correlated with QoL data. Results: The response rate was 68.0% (n \ubc 85). Median patient age was 55 y and most were male (59.2%). Most patients had a pancreatic (24.7%) or a small bowel (37.7%) primary tumor; the overwhelming majority had multiple NELM (83.5%). Patient-reported symptoms before any treatment included diarrhea (41.1%), flushing (34.1%), fatigue (36.5%), and osteoarticular pain (18.8%). Initial treatment of NELM consisted of surgery in 55 patients (64.7%) and nonsurgical treatment in 30 patients (35.3%). Many patients reported an overall improvement in physical health and mental health. Specifically, the proportion of patients reporting diarrhea (before any treatment, 41.1% versus currently, 25.9%; P \ubc 0.019) and flushing (before any treatment, 34.1% versus currently, 10.5%; P &lt; 0.001) tended to decrease over time and a lower proportion of patients reported to be currently sad about being ill (before any treatment, 31.8% versus currently, 23.2%; P \ubc 0.009). Patients with a very poor QoL at the time of the diagnosis were more likely to experience an improvement in QoL after treatment. Interestingly, there was no difference in the improvement in overall QoL whether the initial treatment for NELM was surgical or nonsurgical; however, a lower proportion of patients were dissatisfied with surgery versus nonsurgical therapy (5.4% versus 9.4%; P \ubc 0.001). Conclusions: Less than one-fourth of patients experienced a significant improvement in QoL after treatment of NELM. The patients who benefit the most of treatment were those who were more symptomatic before any treatment