ABSTRACT
Soft tissue sarcomas (STSs) are heterogeneous cancers associated with poor prognosis due to high rates of local recurrence and metastasis. The programmed death receptor ligand 1 (PD-L1) is expressed in several cancers. PD-L1 interacts with its receptor, PD-1, on the surface of tumor-infiltrating lymphocytes (TILs), thereby attenuating anti-cancer immune response. Immune checkpoint inhibitors targeting this interaction have been established as effective anti-cancer drugs. However, studies on the PD-L1 and PD-1 expression status in STS are commonly limited by small sample size, analysis of single STS subtypes, or lack of combinatorial marker assessment. To overcome these limitations, we evaluated the expression patterns of intratumoral PD-L1, the number of TILs, their PD-1 expression, and associations with clinicopathological parameters in a large and comprehensive cohort of 225 samples comprising six STS subtypes. We found that nearly all STS subtypes showed PD-L1 expression on the tumor cells, albeit with a broad range of positivity across subtypes (50% angiosarcomas to 3% synovial sarcomas). Co-expression and correlation analyses uncovered that PD-L1 expression was associated with more PD-1-positive TILs (P < 0.001), higher tumor grading (P = 0.016), and worse patients' 5-year overall survival (P = 0.028). The results were in line with several publications on single STS subtypes, especially when comparing findings for STS with low and high mutational burden. In sum, the substantial portion of PD-L1 positivity, the co-occurrence of PD-1-positive TILs, and the association of PD-L1 with unfavorable clinical outcome provide rationales for immune checkpoint inhibition in patients with PD-L1-positive STS.
Subject(s)
B7-H1 Antigen/metabolism , Biomarkers, Tumor/metabolism , Programmed Cell Death 1 Receptor/metabolism , Sarcoma/metabolism , Adolescent , Adult , Aged , Cohort Studies , Female , Follow-Up Studies , Gene Expression Regulation, Neoplastic , Humans , Male , Middle Aged , Neoplasm Metastasis , Prognosis , Sarcoma/classification , Sarcoma/pathology , Survival Rate , Young AdultABSTRACT
Soft-tissue sarcomas are rare, heterogeneous, and often aggressive mesenchymal cancers. Many of them are associated with poor outcome, partially because biomarkers that can identify high-risk patients are lacking. Studies on sarcomas are often limited by small sample-sizes rendering the identification of biomarkers difficult when focusing on individual cohorts. However, the increasing number of publicly available 'omics' data opens inroads to overcome this obstacle. Here, we combine transcriptome analyses, immunohistochemistry, and functional assays to show that high adenosine monophosphate deaminase 2 (AMPD2) is a robust prognostic biomarker for worse outcome in undifferentiated pleomorphic sarcoma (UPS). Gene expression and survival data for UPS from two independent studies were subjected to survival association-testing. Genes, whose high expression was significantly correlated with worse outcome in both cohorts, were considered as biomarker candidates. The best candidate, AMPD2, was validated in a tissue microarray. Analysis of DNA copy-number data and matched transcriptomes indicated that high AMPD2 expression is significantly correlated with gains at the AMPD2 locus. Gene set enrichment analyses of AMPD2 co-expressed genes in both transcriptome datasets suggested that AMPD2-high UPS are enriched in tumorigenic signatures. Consistently, knockdown of AMPD2 by RNA interference in an UPS cell line inhibited proliferation in vitro and tumorigenicity in vivo. Collectively, we provide evidence that AMPD2 may serve as a biomarker for outcome prediction in UPS. Our study exemplifies how the integration of 'omics' data, immunohistochemistry, and functional experiments can identify novel biomarkers even in a rare sarcoma, which may serve as a blueprint for biomarker identification for other rare cancers.
Subject(s)
AMP Deaminase/genetics , Biomarkers, Tumor/genetics , Genomics/methods , Histiocytoma, Malignant Fibrous/genetics , AMP Deaminase/metabolism , Adult , Aged , Aged, 80 and over , Animals , Biomarkers, Tumor/metabolism , Cell Line, Tumor , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Histiocytoma, Malignant Fibrous/metabolism , Histiocytoma, Malignant Fibrous/pathology , Humans , Kaplan-Meier Estimate , Mice, Inbred NOD , Mice, Knockout , Mice, SCID , Middle Aged , Prognosis , RNAi Therapeutics/methods , Xenograft Model Antitumor Assays/methods , Young AdultABSTRACT
BACKGROUND: Hepatocellular (HCC) and cholangiocellular carcinomas (CCC) display an exceptionally poor prognosis. Especially for advanced disease no efficient standard therapy is currently available. Recently, somatostatin analogs have been evaluated for the treatment of HCC, however, with contradictory results. Besides, for both malignancies the chemokine receptor CXCR4 has been discussed as a possible new target structure. METHODS: Expression of somatostatin receptor (SSTR) subtypes 1, 2A, 3, 4, and 5, and of CXCR4 was evaluated in a total of 71 HCCs and 27 CCCs by immunohistochemistry using well-characterized novel monoclonal antibodies. RESULTS: In HCC tumor cells, frequency and intensity of expression of SSTRs and CXCR4 were only low. CXCR4 was present in about 40% of the HCCs, although at a low intensity. SSTR5, SSTR2, and SSTR3 were detected in about 15%, 8%, and 5% of the HCC tumors, respectively. SSTR and CXCR4 expression was much higher in CCC than in HCC. CXCR4 and SSTR1 were present in 60% and 67% of the CCC samples, respectively, followed by SSTR2 and SSTR5, which were detected in 30% and 11% of the tumors, respectively. Most notably, CXCR4 was intensely expressed on the tumor capillaries in about 50% of the HCCs and CCCs. CXCR4 expression on tumor vessels was associated with poor patient outcomes. CONCLUSIONS: CCC, but not HCC, may be suitable for SSTR-based treatments. Because of the predominant expression of SSTR1, pan-somatostatin analogs should be preferred. In both HCC and CCC, indirect targeting of tumors via the CXCR4-positive tumor capillaries may represent a promising additional therapeutic strategy.
Subject(s)
Bile Duct Neoplasms/pathology , Biomarkers, Tumor/metabolism , Capillaries/pathology , Carcinoma, Hepatocellular/pathology , Cholangiocarcinoma/pathology , Receptors, CXCR4/metabolism , Receptors, Somatostatin/metabolism , Adult , Aged , Aged, 80 and over , Bile Duct Neoplasms/blood supply , Bile Duct Neoplasms/metabolism , Capillaries/metabolism , Carcinoma, Hepatocellular/blood supply , Carcinoma, Hepatocellular/metabolism , Cholangiocarcinoma/blood supply , Cholangiocarcinoma/metabolism , Female , Follow-Up Studies , Humans , Liver Neoplasms/blood supply , Liver Neoplasms/metabolism , Liver Neoplasms/pathology , Male , Middle Aged , Prognosis , Survival RateABSTRACT
BACKGROUND: Conflicting results on the role of secreted protein acidic and rich in cysteins (SPARC) expression have been reported in resected pancreatic ductal adenocarcinoma (PDAC), and its prognostic and/or predictive role in advanced PDAC (aPDAC) has not been extensively investigated yet. This study was designed to evaluate SPARC expression as a biomarker in aPDAC patients (pts) not receiving nab-paclitaxel. METHODS: Using immunohistochemistry, we examined the stromal as well as the tumoral (i.e., cytoplasmic) SPARC expression in tumour tissue (primary tumours and metastases) of 134 aPDAC pts participating in completed prospective clinical and biomarker trials. The SPARC expression levels were correlated to the pts' clinicopathological parameters and survival times. RESULTS: Sixty-seven per cent of the analysed tumours showed high stromal SPARC expression, which was not associated with overall survival (OS, median 9.1 vs 7.6 months, P=0.316). A positive cytoplasmic SPARC expression was detected in 55% of the tumours and correlated significantly with inferior progression-free survival (PFS, 6.2 vs 8.6 months, P=0.004) and OS (7.8 vs 8.4 months, P=0.032). This association was strongest for pts, where primary tumour tissue was examined (PFS: 6.7 vs 10.8 months, P=0.004; OS: 7.9 vs 11.9 months, P=0.030), whereas no significant correlation was detected for pts, where only metastatic tissue was available (PFS: 5.8 vs 6.6 months, P=0.502; OS: 7.0 vs 7.8 months, P=0.452). In pts receiving gemcitabine-based chemotherapy cytoplasmic SPARC expression was significantly associated with an inferior PFS and OS (PFS: 6.2 vs 9.2 months, P=0.002; OS 7.3 vs 9.9 months, P=0.012), whereas no such association was detected for stromal SPARC expression or for pts receiving fluoropyrimidine-based chemotherapy. CONCLUSION: We identified cytoplasmic SPARC expression in the primary tumour as a biomarker associated with inferior PFS and OS in aPDAC. Cytoplasmic SPARC expression may furthermore act as a negative predictive biomarker in pts treated with gemcitabine-based chemotherapy.
Subject(s)
Osteonectin/metabolism , Paclitaxel/therapeutic use , Pancreatic Neoplasms/metabolism , Algorithms , Antineoplastic Agents, Phytogenic/therapeutic use , Female , Humans , Immunohistochemistry , Male , Middle Aged , Pancreatic Neoplasms/drug therapyABSTRACT
BACKGROUND: Frequent disease relapse and a lack of effective therapies result in a very poor outcome in pancreatic ductal adenocarcinoma (PDAC) patients. Thus, identification of prognostic biomarkers and possible therapeutic targets is essential. Besides their function in cell-cell adhesion, desmogleins may play a role in tumour progression and invasion that has not been investigated in PDAC to date. This study evaluated desmoglein expression as a biomarker in PDAC. METHODS: Using immunohistochemistry, we examined desmoglein 1 (DSG1), desmoglein 2 (DSG2) and desmoglein 3 (DSG3) expression in the tumour tissue of 165 resected PDAC cases. Expression levels were correlated to the patients' clinicopathological parameters and postoperative survival times. We confirmed these results in two independent gene expression data sets. RESULTS: A total of 36% of the tumours showed high DSG3 expression that correlated significantly with shorter patient survival (P=0.011) and poor tumour differentiation (P<0.001), whereas no such association was detected for DSG1 or DSG2. In RNA-Seq data and in microarray expression data, high DSG3 expression correlated significantly with poor survival (P=0.000356 and P=0.00499). CONCLUSIONS: We identify DSG3 as a negative prognostic biomarker in resected PDAC, as high DSG3 expression is associated with poor overall survival and poor tumour-specific survival. These findings suggest DSG3 and its downstream signalling pathways as possible therapeutic targets in DSG3-expressing PDAC.
Subject(s)
Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Carcinoma, Pancreatic Ductal/surgery , Desmoglein 1/genetics , Desmoglein 1/metabolism , Pancreatic Neoplasms/surgery , Adult , Aged , Aged, 80 and over , Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/metabolism , Desmoglein 2/genetics , Desmoglein 2/metabolism , Desmoglein 3/genetics , Desmoglein 3/metabolism , Female , Humans , Male , Middle Aged , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/metabolism , Prognosis , Sequence Analysis, RNA , Survival Analysis , Up-RegulationABSTRACT
PURPOSE: Prognosis after curative resection of colorectal liver metastases is hard to determine based on clinical parameters; biomarkers are therefore needed. The purpose of this study was to determine the value of desmocollins (DSC) as potential biomarkers. Desmocollins are responsible for cell-cell adhesion in epithelial tissue; their loss may lead to reduced cellular adhesion and facilitate cellular migration, enabling tumor cells to form distant metastases. We analyzed DSC expression in colorectal liver metastases with respect to the risk of recurrence following liver resection. METHODS: Tissue microarrays from 257 consecutive patients who underwent R0-resection of colorectal liver metastases were constructed. RESULTS: Low expression of DSC 1, 2, and 3 was observed in 55, 54, and 79 % of liver metastases. There was no correlation between site or stage of the primary tumor, presence of extrahepatic tumor, grading, size or number of metastases, and desmocollin expression. Primary tumor stage I or II (p = 0.005) and no or few lymph node metastases (p < 0.001) were associated with a significantly better disease-free survival on univariate analysis. These parameters reached only marginal significance on multivariate analysis (p = 0.059 and p = 0.052, respectively), as did desmocollin 3 expression (p = 0.050). In the subgroup of patients with stages III-IV primary tumors, however, multivariate analysis showed a significant correlation between DSC 3 expression and disease-free survival after liver resection (p = 0.009). CONCLUSIONS: Reduced expression of DSC3 correlated with an increased risk of developing tumor recurrence after resection of liver metastases. These findings may be helpful in selecting high-risk patients who might benefit from multimodal therapy.
Subject(s)
Colorectal Neoplasms/pathology , Desmocollins/metabolism , Liver Neoplasms/secondary , Liver Neoplasms/surgery , Aged , Disease-Free Survival , Female , Humans , Immunohistochemistry , Liver Neoplasms/drug therapy , Liver Neoplasms/metabolism , Male , Neoplasm Staging , Perioperative Care , PrognosisABSTRACT
PURPOSE: The biology of rare pancreatic tumours, which differs from that of ductal pancreatic cancer, requires increased attention. Although the majority of rare pancreatic tumours are benign, it is difficult to decide whether an invasive component exists without complete removal of the lesion, despite considerable progress in diagnosis. We are investigating a large cohort of patients with histologically confirmed epithelial non-ductal non-neuroendocrine neoplasms of the pancreas. METHODS: Here we analyze long-term survival from patients, who underwent resection of histologically confirmed epithelial non-ductal non-neuroendocrine neoplasms of the pancreas. At our department between Jan 1st, 1999, and Dec 31st, 2019. The median follow-up was 61 (range 0-168) month. All statistical analyses were performed using SPSS 26.0 (IBM, Chicago, IL, USA) software. RESULTS: 46 patients (48%) were followed up for more than 5 years, 18 patients (19%) for more than 10 years. The 5-year and 10-year survival rates for rare non-invasive pancreatic tumours were 72% and 55% respectively. The proportion of rare tumour entities (non-ductal and non-neuroendocrine) increased continuously and statistically significantly (p = 0.004) from 4.2 to 12.3% in our clinic between 1999 and 2019. If there is no invasive growth yet, there is a varying risk of malignant degeneration in the course of the disease. Therefore, the indication for pancreatic resection is still the subject of discussion. CONCLUSION: The long-term prognosis of rare epithelial pancreatic tumours after R0 resection-even if they are already malignant-is much better than that of ductal pancreatic cancer.
Subject(s)
Pancreatic Neoplasms , Humans , Pancreatic Neoplasms/pathology , Pancreatic Neoplasms/surgery , Pancreatic Neoplasms/mortality , Middle Aged , Female , Male , Aged , Adult , Follow-Up Studies , Aged, 80 and over , Survival Rate , Young Adult , Retrospective Studies , Prognosis , PancreatectomyABSTRACT
Inter-alpha-trypsin inhibitor heavy chain 5 (ITIH5) has been identified as a metastasis suppressor gene in pancreatic cancer. Here, we analyzed ITIH5 promoter methylation and protein expression in The Cancer Genome Atlas (TCGA) dataset and three tissue microarray cohorts (n = 618), respectively. Cellular effects, including cell migration, focal adhesion formation and protein tyrosine kinase activity, induced by forced ITIH5 expression in pancreatic cancer cell lines were studied in stable transfectants. ITIH5 promoter hypermethylation was associated with unfavorable prognosis, while immunohistochemistry demonstrated loss of ITIH5 in the metastatic setting and worsened overall survival. Gain-of-function models showed a significant reduction in migration capacity, but no alteration in proliferation. Focal adhesions in cells re-expressing ITIH5 exhibited a smaller and more rounded phenotype, typical for slow-moving cells. An impressive increase of acetylated alpha-tubulin was observed in ITIH5-positive cells, indicating more stable microtubules. In addition, we found significantly decreased activities of kinases related to focal adhesion. Our results indicate that loss of ITIH5 in pancreatic cancer profoundly affects its molecular profile: ITIH5 potentially interferes with a variety of oncogenic signaling pathways, including the PI3K/AKT pathway. This may lead to altered cell migration and focal adhesion formation. These cellular alterations may contribute to the metastasis-inhibiting properties of ITIH5 in pancreatic cancer.
Subject(s)
Cell Adhesion , Cell Movement , Pancreatic Neoplasms , Signal Transduction , Humans , Pancreatic Neoplasms/pathology , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/metabolism , Cell Movement/genetics , Cell Adhesion/genetics , Cell Line, Tumor , Protein-Tyrosine Kinases/metabolism , Protein-Tyrosine Kinases/genetics , Focal Adhesions/metabolism , Focal Adhesions/genetics , DNA Methylation/genetics , Promoter Regions, Genetic/genetics , Gene Expression Regulation, Neoplastic , Proteinase Inhibitory Proteins, SecretoryABSTRACT
BACKGROUND: Resection of colorectal liver or lung metastases is an established therapeutical concept at present. However, an affection of both these organs is frequently still regarded as incurable. METHODS: All cancer patients are documented in our prospective cancer registry since 1995. Data of patients who underwent liver and lung resection for colorectal metastases were extracted and analysed. RESULTS: Sixty-five patients underwent surgery for liver and lung metastases. In 33 cases, the first distant metastasis was diagnosed synchronously to the primary tumour. For the remaining patients, median time interval between primary tumour and first distant metastasis was 18 months (5-69 months). Complete resection was achieved in 51 patients (79 %) and was less likely in patients with synchronous disease (p = 0.017). Negative margins (p = 0.002), the absence of pulmonary involvement in synchronous metastases (p = 0.0003) and single metastases in both organs (p = 0.036) were associated with a better prognosis. Five- and 10-year survival rates for all patients are 57 and 15 % from diagnosis of the primary tumour, 37 and 14 % from resection of the first metastasis and 20 and 15 % from resection of the second metastasis. After complete resection, 5- and 10-year survival rates increased to 61 and 18 %, 43 and 17 % as well as 25 and 19 %, respectively. Long-term survivors (≥10 years) were seen only after complete resection of both metastases. CONCLUSIONS: Patients with resectable liver and lung metastases of the colorectal primary should be considered for surgery after multidisciplinary evaluation regardless of the number or size of the metastases or the disease-free intervals. Clear resection margins are the strongest prognostic parameter.
Subject(s)
Colorectal Neoplasms/pathology , Liver Neoplasms/secondary , Liver Neoplasms/surgery , Lung Neoplasms/secondary , Lung Neoplasms/surgery , Adult , Aged , Biomarkers, Tumor/metabolism , Carcinoembryonic Antigen/metabolism , Female , Humans , Liver Neoplasms/drug therapy , Lung Neoplasms/drug therapy , Male , Middle Aged , Multivariate Analysis , Neoplasm Recurrence, Local/pathology , Postoperative Complications/etiology , Prognosis , Survival Analysis , Time Factors , Young AdultABSTRACT
BACKGROUND: Ten-year survival rates are only rarely reported and frequently include a large proportion of censored data-that is, most of the patients have not survived the 10 years. We therefore selected patients in a prospectively maintained, hospital-based tumor register who had been operated on for colorectal carcinoma (CRC) more than 10 years earlier and who were classified as long-term survivors. METHODS: For 589 consecutive CRC patients who underwent R0 resection in the period 1990-1998, we compared prognosis-relevant characteristics and calculated the survival rate as a function of age, sex, location of the tumor, general state of health, urgency of the operation, and pT and pN class. All patients were observed until their death or until at least 10 years after resection. Patients who died of other causes were censored. Overall survival and relative survival (the latter based on tumor-related death) were assessed. RESULTS: The 10-year survivors were more often female (not significant), younger (p < 0.001), in good general health (p < 0.001), had undergone elective resection (p < 0.001), and had early-stage tumors (p < 0.001). In the univariate analysis emergency operation, impaired general health, invasion beyond the muscularis propria, and lymph-node metastasis were found to reduce relative survival. In the multivariate analysis, location, emergency resection, pT, and pN were found to be statistically independent risk factors. CONCLUSIONS: Long-term freedom from tumor recurrence, like-short-term, is influenced largely by factors that are beneficially influenced by early recognition. The patient's age at resection is immaterial.
Subject(s)
Colectomy , Colorectal Neoplasms/surgery , Rectum/surgery , Survivors , Adult , Aged , Aged, 80 and over , Colorectal Neoplasms/mortality , Female , Follow-Up Studies , Health Status Indicators , Humans , Male , Middle Aged , Multivariate Analysis , Proportional Hazards Models , Prospective Studies , Registries , Risk Factors , Survival Rate , Treatment OutcomeABSTRACT
BACKGROUND: Cholangiocarcinoma is an infrequent malignancy, often unresectable at the time of diagnosis. Liver transplantation may offer a chance for cure, but results in the past have been disappointing, prompting transplant centres to adopt multimodal treatment protocols and extreme patient selection. PURPOSE: This study was designed to evaluate the outcome of patients with irresectable hilar cholangiocarcinoma undergoing liver transplantation in order to determine criteria for patient selection. METHODS: We reviewed our prospective cancer registry for patients with hilar cholangiocarcinoma treated by transplantation since 1997. Data were evaluated regarding tumour location, stage, overall survival, recurrence rates and prognostic factors. RESULTS: Liver transplantation with lymphadenectomy was realised in 16 patients with hilar cholangiocarcinoma. Seven patients received a living donor graft. Lymph node metastases were found in eight patients with a median of 13 harvested nodes and had a statistically significant negative impact on overall survival irrespective of tumour size. Only one patient underwent neoadjuvant brachytherapy and developed fatal septic complications; 3- and 5-year survival rates were 63 and 50 % in lymph node-negative patients without neoadjuvant treatment. CONCLUSIONS: Acceptable survival rates can be achieved by transplantation for hilar cholangiocarcinoma with lymph node metastases as the only exclusion criterion. We recommend staging laparotomy with lymphadenectomy along the common hepatic artery prior to liver transplantation.
Subject(s)
Bile Duct Neoplasms/surgery , Bile Ducts, Extrahepatic/surgery , Cholangiocarcinoma/surgery , Liver Transplantation , Adult , Aged , Bile Duct Neoplasms/mortality , Bile Duct Neoplasms/pathology , Bile Duct Neoplasms/radiotherapy , Brachytherapy , Cholangiocarcinoma/mortality , Cholangiocarcinoma/pathology , Cholangiocarcinoma/radiotherapy , Combined Modality Therapy , Female , Hepatectomy , Humans , Living Donors , Lymph Node Excision , Lymphatic Metastasis/pathology , Male , Middle Aged , Neoadjuvant Therapy , Neoplasm Staging , Prognosis , Recurrence , Retrospective Studies , Survival RateABSTRACT
BACKGROUND: Tumor recurrence is the leading cause of death after liver transplantation in patients with hepatocellular carcinoma. There is an ongoing debate as to whether metabolic indices such as tumor to liver standardized uptake value ratio in 18F-fluorodeoxyglucose positron emission tomography/computed tomography of the primary tumor can identify patients outside the Milan criteria with as low recurrence rates as patients inside Milan and thus should be added to the established prognostic factors. METHODS: This retrospective study analyzes 103 consecutive patients who underwent 18F-fluorodeoxyglucose positron emission tomography/computed tomography before liver transplantation for hepatocellular carcinoma using data of clinical tumor registry. Primary endpoints were overall survival and 10-year cumulative recurrence rates. RESULTS: Tumor to liver standardized uptake value ratio of the primary tumor was statistically significant higher in Milan out tumors, "up-to-seven" out tumors, grade 3 tumors, α- fetoprotein level >400 ng/ml and lesions > 5cm in diameter. Factors with statistically significant influence on the 10- year overall survival in the univariate analysis were Milan, up-to-seven" criteria, number of lesions and pT-category. COX regression analysis did not show independently statistically significant factors for 10-year overall survival. Milan, "up-to-seven" criteria, grade, pV, number of lesions, size of lesion, pT-category, tumor to liver standardized uptake value ratio influenced 10-year cumulative recurrence rates statistically significant. Tumor to liver standardized uptake value ratio, grade and pT-category proved to be independently statistically significant factors for 10-year cumulative recurrence rates. CONCLUSIONS: Our study suggests that tumor to liver standardized uptake value standardized uptake value ratio in 18F-fluorodeoxyglucose positron emission tomography/computed tomography is an independent prognostic factor in transplanted patients with hepatocellular carcinoma. If we focus on preoperative findings, such as tumor size, tumor number and AFP value adding the information given by TLR of 18F-FDG PET/CT allows to estimate the risk of tumor recurrence more accurate than the established classifications Milan and UTS. Therefore, it may add valuable information to other preoperative findings, such as tumor size, tumor number and AFP level.
Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Humans , Carcinoma, Hepatocellular/diagnostic imaging , Carcinoma, Hepatocellular/surgery , Fluorodeoxyglucose F18 , Positron Emission Tomography Computed Tomography/methods , Liver Neoplasms/diagnostic imaging , Liver Neoplasms/surgery , Retrospective Studies , alpha-Fetoproteins/metabolism , Neoplasm Recurrence, Local/diagnostic imaging , Positron-Emission Tomography , RadiopharmaceuticalsABSTRACT
INTRODUCTION: Small intestine neuroendocrine neoplasms (siNENs) will attain more importance due to their increasing incidence. Moreover, siNENs might lead to a desmoplastic reaction (DR) of the mesentery causing severe complications and deteriorating prognosis. The expression of fibrosis-related proteins appears to be the key mechanisms for the development of this desmoplastic reaction. Therefore, this study aimed to investigate the association of the desmoplastic mesentery with specific fibrosis-related protein expression levels. MATERIALS AND METHODS: By immunohistochemistry, the protein expression levels of four fibrosis-related markers (APLP2, BNIP3L, CD59, DKK3) were investigated in primary tumors of 128 siNENs. The expression levels were correlated with the presence of a desmoplastic reaction and clinico-pathological parameters. RESULTS: In the primary tumor, APLP2, BNIP3L, CD59 and DKK3 were highly expressed in 29.7% (n = 38), 64.9% (n = 83), 92.2% (n = 118) and 80.5% (n = 103), respectively. There was no significant correlation of a single marker or the complete marker panel to the manifestation of a desmoplastic mesentery. The desmoplastic mesentery was significantly associated with clinical symptoms, such as flushing and diarrhea. However, neither the fibrosis-related marker panel nor single marker expressions were associated with clinical symptoms. DISCUSSION: The expression rates of four fibrosis-related markers in the primary tumor display a distinct pattern. However, the expression patterns are not associated with desmoplastic altered mesenteric lymph node metastases and the expression patterns did not correlate with prognosis. These findings suggest alternative mechanisms being responsible for the desmoplastic reaction.
Subject(s)
Intestinal Neoplasms , Neuroendocrine Tumors , Humans , Fibrosis , Intestinal Neoplasms/pathology , Neuroendocrine Tumors/pathology , Intestine, Small/pathology , Mesentery/pathologyABSTRACT
(1) Background: The expression of T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), an immune checkpoint receptor on T cells, has been associated with dismal outcomes and advanced tumor stages in various solid tumors. The blockade of TIM-3 is currently under examination in several clinical trials. This study examines TIM-3 expression in high-risk soft tissue sarcomas (HR-STS). (2) Methods: Tumor cell expression of TIM-3 on protein level was analyzed in pre-treatment biopsies of patients with HR-STS. TIM-3 expression was correlated with clinicopathological parameters including tumor-infiltrating lymphocyte (TIL) counts, programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PDL-1) expression in patients with HR-STS. Survival dependent on the expression of TIM-3 was analyzed. (3) Results: TIM-3 expression was observed in 101 (56%) out of 179 pre-treatment biopsies of patients with HR-STS. TIM-3 expression was significantly more often observed in undifferentiated pleomorphic sarcomas (UPS) compared to other histological subtypes (p < 0.001), high TIL counts (p < 0.001), and high PD-1 (p < 0.001) and PD-L1 expression (p < 0.001). TIM-3 expression did not have a prognostic impact on survival in patients with HR-STS. (4) Conclusions: This is the first study to demonstrate a significant tumor cell expression of TIM-3 in specific subsets of patients with HR-STS. TIM-3 qualifies as a potential immunotherapeutic target in HR-STS.
ABSTRACT
BACKGROUND: Although up to 9% of patients with gastric cancer develop liver metastases, liver resection is rarely performed because of co-existing non-curative factors. Furthermore, the benefit of liver resection is still controversially discussed. Our goal was to investigate the outcome of patients who underwent liver resection or radiofrequency ablation (RFA) for hepatic metastasized gastric cancer. METHODS: Retrospectively collected data from a prospectively maintained database were analyzed from 15 patients who underwent liver resection or RFA for liver metastases from gastric cancer. RESULTS: Overall 5-year survival and median survival were 27% and 48 months for resected/RFA patients. The peri-operative complication rate was low. One patient has been tumor-free for 90 months now. CONCLUSIONS: Liver resection in patients with hepatic metastasized gastric cancer is beneficial and safe if an R0 situation can be achieved. RFA might be a useful alternative in those patients where surgery is not feasible.
Subject(s)
Catheter Ablation/methods , Hepatectomy/methods , Liver Neoplasms/secondary , Neoplasm Recurrence, Local/surgery , Stomach Neoplasms/pathology , Adult , Aged , Aged, 80 and over , Combined Modality Therapy , Female , Humans , Kaplan-Meier Estimate , Liver Neoplasms/mortality , Liver Neoplasms/surgery , Male , Middle Aged , Neoplasm Recurrence, Local/secondary , Postoperative Complications , Retrospective Studies , Stomach Neoplasms/surgery , Survival Rate , Treatment OutcomeABSTRACT
BACKGROUND: Genomewide expression profiling has identified a number of genes differentially expressed in colorectal carcinomas (CRCs) compared to normal tissue. Some of these genes were linked to epithelial-mesenchymal transition. We tested whether genes including desmocollins and homeobox genes were distinct on the protein level and correlated the expression with clinicopathological data. METHODS: Tissue microarrays of 402 R0-resected colorectal carcinomas of UICC stage II or III were constructed to evaluate ten biomarkers. Furthermore, mRNA expression of desmocollins was evaluated in eight colon cancer cell lines. Demethylation test was performed by treatment with 5-aza-2´-deoxycytide in five colon cancer cell lines. RESULTS: On protein level, high expression of desmocollin 1 (DSC1) was observed in 41.6%, DSC2 in 58.0%, DSC3 in 61.4%, E-cadherin in 71.4%, CDX2 in 58.0%, PITX1 in 55.0%, CDK4 in 0.2%, TLE1 in 1.3%, Factor H in 42.5%, and MDM2 in 0.2%. Reduced expression of DSC1-3 was statistically linked to higher grading and DSC2, E-cadherin and CDX2 with shorter survival in high-grade carcinomas. Multivariate analysis showed that pathological stage and low PITX1 expression were statistically associated with shorter patients survival. On mRNA level, seven out of eight cell lines exhibited no expression of DSC1, and four out of seven restored DSC1 expression after demethylation test. CONCLUSIONS: Reduced expression of PITX1 was independently correlated to shorter patients survival and could serve as a prognostic marker. Decreased expression of DSC1-3 is significantly correlated with higher tumor grading. Downregulation of DSC1 could be explained by DNA hypermethylation in colon cancer cells.
Subject(s)
Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Desmocollins/genetics , Disease Progression , Genetic Predisposition to Disease , Homeodomain Proteins/genetics , Paired Box Transcription Factors/genetics , Aged , Aged, 80 and over , Azacitidine/pharmacology , CDX2 Transcription Factor , Cell Line, Tumor , Desmocollins/metabolism , Female , Gene Expression Regulation, Neoplastic/drug effects , Homeodomain Proteins/metabolism , Humans , Immunohistochemistry , Male , Multivariate Analysis , Paired Box Transcription Factors/metabolism , Prognosis , Reverse Transcriptase Polymerase Chain Reaction , Survival AnalysisABSTRACT
INTRODUCTION: In the literature, results after surgical treatment of non-colorectal non-neuroendocrine liver metastases (NCNNLM) are reported that are often inferior to those from colorectal liver metastases. The selection of patients with favorable tumor biology is currently still a matter of discussion. MATERIALS/METHODS: The retrospective data analysis was based on data that were collected for the multicenter study "Role of surgical treatment for non-colorectal liver metastases" in county Thuringia. RESULTS: For the study, 637 patients were included from 1995 to 2018. 5 and 10-year survival of R0 resected patients were 33% and 19%, respectively. In the multi-variate analysis of the entire group, sex, timing, disease-free interval, number of metastases, R-classification as well as lymph node status of the primary lesion showed an independent statistical influence on the 5-year survival. In the group of R0 resected patients, disease-free interval, number of metastases and lymph node status of the primary lesion influenced the 5-year survival in the multi-variate analysis. In kidney malignancies, R-classification, timing and number of liver metastases were statistically significant in the multi-variate analysis of the 5-year survival, in mamma carcinomas only the R-classification. CONCLUSION: The Adam score identifies some risk factors which influence prognosis in most but not in all tumor entities. For kidney cancer and breast cancer it can be simplified.
Subject(s)
Liver Neoplasms/mortality , Liver Neoplasms/secondary , Liver Neoplasms/surgery , Adult , Aged , Aged, 80 and over , Female , Germany/epidemiology , Hepatectomy/methods , Hepatectomy/mortality , Hepatectomy/trends , History, 20th Century , History, 21st Century , Humans , Liver Neoplasms/diagnosis , Male , Middle Aged , Prognosis , Retrospective Studies , Survival Analysis , Treatment OutcomeABSTRACT
(1) Background: V domain immunoglobulin suppressor of T cell activation (VISTA) plays a critical role in antitumor immunity and may be a valuable target in cancer immunotherapy. To date, it has never been studied in a large and well-characterised cohort of soft tissue sarcomas (STS). (2) Methods: Using immunohistochemistry, we examined VISTA expression in tumour tissues of 213 high-risk STS. We then analysed whether VISTA was associated with other clinicopathological parameters, including tumour-infiltrating lymphocyte (TIL) counts, programmed death receptor-1 (PD1), programmed death ligand-1 (PDL1), CD3, grading, and long-term survival. (3) Results: We observed VISTA expression in 96 (45%) of 213 specimens with distinct patterns ranging from 26 to 63% for histological subtypes. VISTA was associated with higher grade (G3 vs. G2, p = 0.019), higher TIL counts (p = 0.033), expression of PD1 (p = 0.046), PDL1 (p = 0.031), and CD3+ (p = 0.023). In patients without CD3+ TILs, 10-year survival was higher when VISTA was expressed compared to when there was no VISTA expression (p = 0.013). In a multivariate analysis, VISTA expression was independently associated with prolonged survival (p = 0.043). (4) Conclusions: VISTA is expressed in different STS subtypes and is associated with increased TILs, PD-1, PD-L1, and CD3 expression. Patients with VISTA+ tumours show improved survival. These results may help define future immunotherapeutic approaches in STS.
ABSTRACT
PURPOSE: Prognosis after resection of liver metastases of colorectal cancer is influenced by a variety of clinical factors. For more than 20 years, efforts have been made to restructure and simplify prognostic parameters into clinical scores. We evaluated the influence of various clinical and pathological factors on survival and recurrence and developed a simple model for risk stratification. METHODS: We have analyzed a total of 13 prognostic factors in 382 consecutive and prospectively enrolled R0-resected patients and applied our data set to ten published prognostic scoring systems. Prognostic factors that influenced disease-specific and disease-free survival were included into a model clinical risk score. RESULTS: The 5- and 10-year observed survival rates were 43% and 28%, respectively, for all 382 patients. The disease-specific 5- and 10-year survival rates were 49% and 37%, respectively; the 5- and 10-year recurrence rates were 68% and 70%, respectively. For patients with synchronous liver metastases, survival was not affected by the timing of liver resection. The prognosis after treatment of any recurrence was best after the accomplishment of a repeated R0 situation, independent of the location of the recurrence. In the multivariate analysis, the disease-specific survival and recurrence rates were statistically significantly influenced by more than three lymph node metastases of the primary tumor, more than two lesions within the liver, and the presence of extrahepatic tumor. CONCLUSIONS: From these data, we have developed a simple score for the risk stratification which may be useful for future studies on interdisciplinary management of colorectal liver metastases.
Subject(s)
Colorectal Neoplasms/pathology , Liver Neoplasms/mortality , Liver Neoplasms/secondary , Disease-Free Survival , Humans , Liver Neoplasms/surgery , Multivariate Analysis , Recurrence , Time FactorsABSTRACT
BACKGROUND: The role of surgical treatment of hepato-pancreatic metastases from renal cell carcinoma is still under discussion. MATERIAL AND METHODS: We report about 52 patients of whom 33 underwent surgery for liver metastases and 19 for pancreatic metastases from 1995 to 2018. RESULTS: The 5year survival rate of all patients with partial liver resection was statistically significantly lower (38%, median survival time 34 months) than with pancreas resection (69%, median survival time 69 months, pâ¯= 0.017). Of the patients 21 survived the resection of metastases longer than 5 years and 4 patients longer than 10 years. In R0 resected patients, recurrences were observed in 13 cases after liver resection and in 9 cases after pancreas resection. The cumulative recurrence rate after 5 years was 38% for the liver and 57% for the pancreas. In R0 partial liver resections, an interval <24 months between nephrectomy and liver resection as well as multiple metastases were negative prognostic factors. CONCLUSION: In spite of high recurrence rates, surgical treatment for hepato-pancreatic metastases from renal cell carcinoma yielded very good long-term results, in particular with complete resection of solitary metachronous metastases. Repeated surgery for completely resectable metastases, resulted in long tumor-free intervals and thus contributed to good long-term results.