Shorter Recurrence-free Survival Research Articles

Genetic and clinicopathologic characteristics of lung adenocarcinoma with tumor spread through air spaces

ObjectiveThe World Health Organization Classification of Lung Tumors considers “Spread Through Air Spaces (STAS)” as a form of invasion in lung adenocarcinoma. However, its existence as an independent pathologic entity rather than an artifact caused by spreading through a knife surface is still controversial. Therefore, we performed comprehensive analyses on the genetic and clinicopathologic characteristics of lung adenocarcinoma with STAS. Materials and MethodsA total of 316 surgically resected lung adenocarcinoma cases were analyzed retrospectively. Detailed analyses were performed on clinical-histological-molecular features. Tumor STAS was defined as tumor cells within air spaces in the lung parenchyma beyond the edge of the main tumor. ResultsSTAS was observed in 160 cases (50.6%). STAS was significantly related to lymphovascular invasion, lymph node metastasis, higher stage, and high-grade histologic subtype. STAS was frequently found in tumors with wild-type EGFR or ALK-rearrangement. Logistic regression analysis showed that STAS was significantly associated with absence of lepidic component, presence of micropapillary component, cribriform predominant type, lymphovascular invasion, and wild-type EGFR. Multivariate survival analysis demonstrated that STAS was independently associated with shorter recurrence-free survival. STAS was also associated with recurrences to extrathoracic sites as well as intrathoracic sites. ConclusionSTAS is associated with certain pathological and molecular subtypes. STAS might be a parameter for tumor aggressiveness in that it is strongly associated with poor prognostic factors and recurrence, including to extrathoracic sites.

Prognostic Value of Serum Cholinesterase in Non–muscle-invasive Bladder Cancer

Serum cholinesterase (ChE) has been reported to be a prognostic factor in several cancers, but its relationship with oncologic outcomes of non-muscle-invasive bladder cancer (NMIBC) has not yet been well-studied. We retrospectively assessed 1117 patients with NMIBC undergoing transurethral resection of the bladder. Cox regression analyses were performed to elucidate the association between preoperative ChE and oncologic outcomes such as recurrence-free survival (RFS) and progression-free survival. The median preoperative ChE level was 5.51 kU/L (interquartile range, 4.95-7.01), and the optimal cut-off value of ChE obtained from receiver operator characteristic analysis was 5.55 kU/L. The 5-year RFS in patients with low and normal ChE levels were 41.1% and 70.0%, respectively (P< .001). The 5-year progression-free survival in patients with low and normal ChE levels were 93.2% and 91.4%, respectively (P= .053). On multivariable analysis, ChE was significantly associated with shorter RFS (P< .001). ChE as a continuous variable and low ChE levels improved the C-index for prediction of disease recurrence by 4.0% and 2.7% to 72.4% and 71.1%, respectively. In patients stratified into the European Association of Urology high-risk category, serum ChE was also a strong predictor of disease recurrence (hazard ratio, 4.14; 95% confidence interval, 2.90-5.89). Moreover, in the European Association of Urology high-risk patients treated with bacillus Calmette-Guérin immunotherapy, serum ChE was still strongly correlated with worse RFS (hazard ratio, 5.46; 95% confidence interval, 2.91-10.2). Decreased ChE is associated with shorter RFS in patients with NMIBC undergoing transurethral resection of the bladder. Preoperative ChE could improve patients' risk stratification and selection for adjuvant therapy. The mechanisms underlying this association needs further elucidation to design potential targets for intervention.

Optimal body mass index cut-point for predicting recurrence-free survival in patients with non-muscle-invasive urothelial carcinoma of bladder.

In Japanese patients with non-muscle-invasive urothelial carcinoma of the bladder, the impact of body mass index (BMI) on recurrence following transurethral resection of bladder tumor (TURBT) is unclear. The present study retrospectively examined data collected from 50 patients diagnosed with primary urothelial carcinoma of the bladder (pTa, pTis, and pT1) who had previously undergone TURBT surgery. Two BMI cut-off points for predicting disease recurrence were evaluated: i) A threshold generated through receiver operating characteristic (ROC) curve analysis; ii) the World Health Organization BMI index (24 kg/m2) for overweight status in Japanese populations. Univariate and multivariate analyses were applied to assess individual variables (BMI included) and the effect they had on recurrence-free survival (RFS). Median RFS and BMI values of 19.72 months (range, 3.13-72.13 months) and 23.37 kg/m2 (range, 14.72-36.84 kg/m2), respectively, were recorded. In multivariate analyses, higher continuous BMI was significantly associated with shorter RFS (P=0.019). Based on a ROC-generated BMI cut-off point (23.4 kg/m2), patients were ranked with either a high (≥23.4 kg/m2) or low (<23.4 kg/m2) BMI status. Multivariate analysis indicated that BMI values >23.4 kg/m2 were significantly associated with shorter RFS (P=0.028). Intravesical Bacillus Calmette-Guérin treatment and history of upper-tract urothelial carcinoma were also independently associated (P=0.044 and P=0.010, respectively). However, BMI values >24 kg/m2 (customary cut-off point) had no significant impact on RFS (P=0.066). Thus, a higher BMI status was revealed to be independently predictive of shorter RFS in Japanese patients undergoing TURBT for urothelial carcinoma of the bladder. A greater number of samples are required in order to determine optimal BMI cut-off points in Japanese patients and to investigate whether weight reduction intervention may improve prognosis.

PRDM8 exhibits antitumor activities toward hepatocellular carcinoma by targeting NAP1L1.

Hepatocellular carcinoma (HCC) is a major leading cause of cancer mortality worldwide. PRDI-BF1 and RIZ homology domain containing 8 (PRDM8) is a key regulator in neural development and testis steroidogenesis; however, its role in liver carcinogenesis remains to be investigated. In this study, PRDM8 was found to be down-regulated in HCC, which was linked with shorter recurrence-free survival. Lentiviral-based overexpression and knockdown approaches showed that PRDM8 inhibited HCC cell proliferation, migration, and invasion. PRDM8 caused G1/S cell cycle arrest and induced apoptosis. An in vivo tumor model confirmed the antitumor role of PRDM8 in HCC growth and metastasis. Mechanistic study showed that PRDM8 suppressed the PI3K/AKT/mTOR signaling cascade through the regulation of nucleosome assembly protein 1-like 1 (NAP1L1). Conclusion: PRDM8 as a functional tumor suppressor is frequently down-regulated in HCC. Through regulating NAP1L1, PRDM8 inhibits PI3K/AKT/mTOR signaling in HCC. PRDM8 is a potential target for therapies of HCC. (Hepatology 2018).

The investigation of the survival time after recurrence in patients with pancreatic ductal adenocarcinoma for individualization of adjuvant chemotherapy.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease; however, the frequency of recurrence can be reduced if curative surgery following adjuvant chemotherapy is applied. At present, adjuvant chemotherapy is uniformly performed in all patients, as it is unclear which tumor types are controlled best or worst. We investigated patients with recurrence to establish the optimum treatment strategy. Of 138 patients who underwent curative surgery for PDAC, 85 developed recurrence. Comprehensive clinicopathological factors were investigated for their association with the survival time after recurrence (SAR). The median SAR was 12.6months. Treatments for recurrence included best supportive care, GEM-based therapy and S-1. The performance status [hazard ratio (HR) 0.12, P < 0.001], histological invasion of lymph vessels (HR 0.27, P < 0.001), kind of treatment for recurrence (HR 5.0, P < 0.001) and initial recurrence site (HR 2.9, P < 0.001) were independent significant risk factors for the SAR. The initial recurrence sites were the liver (n = 21, median SAR 8.8months), lung (n = 10, 14.9months), peritoneum (n = 6, 1.7months), lymph nodes (n = 6, 14.7months), local site (n = 17, 13.9months) and multiple sites (n = 25, 10.1months). A shorter recurrence-free survival (< 1year) and higher postoperative CA19-9 level were significantly associated with critical recurrence (peritoneal/liver). Several risk factors for SAR were detected in this study. Further investigations are needed to individualize the adjuvant chemotherapy for each patient with PDAC.

Clinicopathological Features and Prognosis of Primary GISTs with Tumor Rupture in the Real World

BackgroundPatients with ruptured gastrointestinal stromal tumor (GIST) are recommended for imatinib adjuvant therapy; however, their clinicopathological features and prognosis in the era of imatinib are unknown.Patients and MethodsThe study cohort included 665 patients with histologically proven primary GISTs who underwent R0 or R1 surgery between 2003 and 2007; the validation cohort included 182 patients between 2000 and 2014. The definitions of tumor rupture in the study included perforation at tumor site, tumor fracture, piecemeal resection including open biopsy, and macroscopic injuries to the pseudocapsule.ResultsTumor rupture occurred in 21 (3.2%) of 665 and 5 (2.9%) of 182 patients in the study and validation cohort, respectively. Ruptured GISTs were more symptomatic, were larger in size, and had higher mitotic count than nonruptured GISTs but were not associated with tumor location or laparoscopic surgery. GISTs with intraoperative rupture had clinicopathological features and prognostic outcomes similar to those with preoperative rupture. Recurrence rates were higher and median recurrence-free survival (RFS) and overall survival (OS) were shorter with ruptured than nonruptured GIST. Tumor rupture was one of the independent prognostic factors for RFS, but not OS, according to multivariate analysis.ConclusionsRuptured GISTs were symptomatic larger tumors with high mitotic activity, frequent relapse, and shorter RFS. Tumor rupture was an independent prognostic factor for RFS, but not for OS, in the era of imatinib.

Pathological tumor regression grade of metastatic tumors in lymph node predicts prognosis in esophageal cancer patients.

Tumor regression grade of the primary tumor (TRG‐PT) and residual lymph node metastasis have been pathologically determined in esophageal squamous cell carcinoma (ESCC) patients who had received neoadjuvant chemotherapy (nCT) followed by surgery; however, TRG of the metastatic tumor involving lymph nodes (LN) has not yet been determined. The aim of the present study was to clarify the impact of TRG on the prognosis of ESCC patients. ESCC patients (n = 110) who had received nCT followed by surgery were enrolled. Dissected LN were classified into 2 categories: plausible positive metastatic LN (pp‐MLN) where viable and/or degenerated ESCC cells and/or tissue modifications were observed, and non‐metastatic LN (non‐MLN) where neither of them was observed. We defined nCT‐effective rate (CER) as the ratio of the number of pp‐MLN that showed tumor regression to the total number of pp‐MLN, and divided CER into low‐CER (LCER; ≥0% and <50%) and high‐CER (HCER; ≥50% and ≤100%). Relationships between CER and clinicopathological factors including prognosis were then examined. Multivariate analyses of 110 patients indicated that ypT3‐4 (P = .023, HR; 2.551), positive venous infiltration (P = .006, HR; 3.526), and LCER (P = .033, HR; 1.922) were independently associated with shorter recurrence‐free survival (RFS). Multivariate analyses of 43 patients with grade 0 TRG‐PT showed that ypT3‐4 (P = .033, HR; 3.397) and LCER (P = .008, HR; 3.543) were independently associated with shorter RFS. This study showed that CER was one of the prognostic factors for ESCC patients who had received nCT followed by surgery.

Effect of submucosal injection in endoscopic papillectomy of ampullary tumor: Propensity-score matching analysis.

The role of submucosal injection (SI) in endoscopic papillectomy (EP) is controversial. This study investigated the effects of SI before EP of ampullary tumors. All patients who underwent initial curative EP at our institution between March 2006 and March 2014 were retrospectively recruited. The presence of residual tumor after three months, recurrence-free survival and post-procedural adverse events were compared between the SI group and non-injection (NI) group. Propensity-score matching was performed between the two groups to reduce potential selection bias and confounding. A total of 122 patients were included (SI: 26, NI: 96). Following propensity-score matching, 25 paired patients were selected. Residual tumor was not shown in the NI group, whereas seven (28.0%) patients in the SI group had residual tumor (p = 0.010). The recurrence-free survival of the NI group was significantly longer than that of the SI group (p = 0.036). Upon multivariate analysis, pathologic grade (p = 0.026) and SI (p = 0.033) were significantly related to recurrence-free survival. Post-procedural adverse events were not significantly different between the two groups. SI before EP of ampullary tumor was related to more frequent residual tumor and shorter recurrence-free survival and did not reduce post-procedural adverse events.

Survival Outcomes by TP53 Mutation Status in Metastatic Breast Cancer.

We sought to determine the significant genomic alterations in patients with metastatic breast cancer (MBC), and survival outcomes in common genotypes. High-depth next generation sequencing was performed for 202 genes in tumor and normal DNA from 257 patients with MBC, including 165 patients with ER/PR+ HER2- (hormone receptor positive, HR+ positive), 32 patients with HER2+ and 60 patients with triple negative (ER/PR/HER2-) cancer. Kaplan Meier survival analysis was performed in our discovery set, in breast cancer patients analyzed in The Cancer Genome Atlas, and in a separate cohort of 98 patients with MBC who underwent clinical genomic testing. Significantly mutated genes (SMGs) varied by histology and tumor subtype, but TP53 was a SMG in all three subtypes. The most SMGs in HR+ patients included PIK3CA (32%), TP53 (29%), GATA3 (15%), CDH1 (8%), MAP3K1 (8%), PTEN (5%), TGFBR2 (4%), AKT1 (4%), and MAP2K4 (4%). TP53 mutations were associated with shorter recurrence-free survival (P=0.004), progression-free survival (P=0.00057) and overall survival (P=0.003). Further, TP53 status was prognostic among HR+ patients with PIK3CA mutations. TP53 mutations were also associated with poorer overall survival in the 442 HR+ breast cancer patients in the TCGA (P=0.042) and in an independent set of 96 HR+ MBC who underwent clinical sequencing (P=0.0004). SMGs differ by tumor subtype but TP53 is significantly mutated in all three breast cancer subtypes. TP53 mutations are associated with poor prognosis in HR+ breast cancer. TP53 mutations should be considered in the design and interpretation of precision oncology trials.

Carbonic anhydrase 9 expression in well-differentiated pancreatic neuroendocrine neoplasms might be associated with aggressive behavior and poor survival.

Well-differentiated pancreatic neuroendocrine neoplasms/tumors (PanNETs) are rare neoplasms with diverse clinical behavior. Biomarker discovery is important for predicting clinical course and prognosis of PanNET patients. Carbonic anhydrase 9 (CA9) and vimentin are hypoxia and epithelial-mesenchymal transition-related proteins of which expression in many carcinomas has been associated with poor prognosis, but their significance in PanNET has yet to be determined. We assessed CA9 and vimentin expression in 164 PanNETs and compared this with clinicopathologic characteristics. CA9 expression was observed in normal islets, while neuroendocrine microadenomas and small (< 1cm) PanNETs showed loss of CA9 expression. CA9 and vimentin expression was observed in 38 (23%) and 36 (22%) of PanNETs, respectively. CA9 expression was associated with larger size (p = 0.001), higher grade (p < 0.001), higher pT category (p < 0.001), lymph node (p = 0.003) and distant (p = 0.047) metastases, higher AJCC stage (p < 0.001), and lymphovascular (p < 0.001) and perineural (p = 0.002) invasion. PanNET patients with CA9 expression had a shorter recurrence-free survival (5-year survival rate 47%) than those without CA9 expression (76%) by univariate (p = 0.001) but not multivariate analysis. Vimentin expression correlated with CA9 expression (p < 0.001) but not with other clinicopathologic factors. In conclusion, CA9 expression was observed in normal islets, while neuroendocrine microadenomas and small (< 1cm) PanNETs showed CA9 expression loss. CA9 expression gradually reappeared in larger PanNETs, and this was associated with clinical progression and decreased patient survival by univariate but not multivariate analysis.

Ascites tumor microenvironment and chemoresistance in ovarian cancer

Ovarian cancer is inherently silent; most patients are diagnosed in late stage of the disease progression. The progression and resistance to chemotherapy in ovarian cancer patients is closely associated with aberrant accumulation of fluid in the peritoneal cavity, called ascites formation. Malignant ascites constitutes a unique tumor microenvironment providing a physical structure for the accumulation of both pro‐tumorigenic and anti‐tumorigenic factors, each of which cumulatively favor cancer cell proliferation, metastasis and chemoresistance. Almost all patients with recurrent ovarian cancer are presented with ascites and have acquired resistance to chemotherapy. However, underlying mechanism of ascites induced acquired resistance to chemotherapy have not been fully understood yet. We used patient derived ascites to delineate the role of ascites in acquired chemoresistance in ovarian cancer. Of those many soluble factors, we focused on the levels of cholesterol in malignant ascites. We found that cholesterol levels are highly elevated in malignant ascites to that of benign peritoneal fluid from ovarian cyst patients. Treatment of cholesterol significantly induced resistance to cisplatin and paclitaxel via increased expression of drug resistance proteins, ABCG2 and MDR1, together with upregulation of LXRα/β. Moreover, LXRα/β expression was positively correlated with MDR1 but not with ABCG2 expression in ovarian cancer patient‐derived ascites cells. The importance of cholesterol induced LXRα/β in acquired resistance were further confirmed by silencing LXRα/β. In addition, elevated cholesterol in malignant ascites was associated with shorter recurrence free survival in ovarian cancer patients. Collectively, these results suggest that cholesterol in ovarian cancer patient derived ascites causes resistance to cisplatin through upregulation of MDR1 via activation of LXRα/β in ovarian cancer. Targeting the pathological interaction between cancer cell and ascites tumor microenvironment may be an efficient strategy to overcome acquired resistance in ovarian cancer patients.Support or Funding InformationThis research was supported by a grant of the Korea Health Technology R&amp;D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health &amp; Welfare, Republic of Korea (HA17C0037, HI16C2037) and grants from Seoul National University College of Medicine (800‐20150304) and the National R&amp;D Program for Cancer Control, Ministry of Health &amp; Welfare, Republic of Korea (1720110).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Multicystic mesothelioma: Operative and long-term outcomes with cytoreductive surgery and hyperthermic intra peritoneal chemotherapy

BackgroundMulticystic peritoneal mesothelioma (MCPM) is an extremely rare disease with 40–50% rate of recurrence after surgical debulking. Due to the recurrent nature of the disease, the option of cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) was offered for this condition. In the present study we aimed to describe the outcomes of this strategy in a single center cohort. MethodsWe retrospectively reviewed a prospectively collected database of all patients with MCPM that underwent the combined procedure in our center. Clinical presentation, operative procedures and outcomes were reviewed. ResultsBetween August 1997 and October 2017, 19 patients with MCPM underwent 20 cytoreduction and HIPEC procedures in our center. The majority of the patients were females (n = 17, 89%), and mean age was 42, as reported in other series. Disease extent, as measured by mean peritoneal carcinomatosis index (PCI) was 15.5 ± 9.9 and total number of procedures performed 6.7 ± 2.6. Major complications occurred in 3 (15%) patients, with no perioperative mortality. After a median of follow-up of 69 months (range 4–220) all patients were alive and 4 patients had recurrence (21%). Patients with high PCI (defined by median PCI) had shorter recurrence free survival (RFS) than patient with low PCI (mean RFS = 106.4 ± 6.6 for high PCI vs. 125.6 ± 34.1 for low PCI, p = 0.03). ConclusionCytoreduction and HIPEC offer low recurrence rate and prolonged mean RFS for patients with MCPM. The combined procedure can be offered with acceptable morbidity in specialized centers.

C-Myc-dependent repression of two oncogenic miRNA clusters contributes to triptolide-induced cell death in hepatocellular carcinoma cells

BackgroundTriptolide is a structurally unique diterpene triepoxide with potent antitumor activity. However,the effect and mechanism of triptolide on hepatocellular carcinoma (HCC) is not well studied.MethodsCells were treated with triptolide, and the anti-HCC activity of triptolide was evaluated using flow cytometry, western blot, and xenograft studies. MicroRNA microarray and quantitative reverse-transcription polymerase chain reaction was used to identify differential microRNAs induced by triptolide. Chromatin immunoprecipitation assay was employed to study the interaction between c-Myc and genomic regions of miR106b-25. MicroRNAs overexpression and knockdown experiments were performed to determine the role of these microRNAs in triptolide-induced apoptosis.ResultsTriptolide inhibited cell proliferation and induced marked apoptosis in multiple HCC cell lines with different p53 status. Several signaling molecules involved in different pathways were altered after the treatment of triptolide. Xenograft tumor volume was significantly reduced in triptolide-treated group compared with vehicle control group. Two miRNA clusters, miR-17-92 and miR-106b-25, were significantly suppressed by triptolide, which resulted in the upregulation of their common target genes, including BIM, PTEN, and p21. In HCC samples, high levels of these miRNA clusters correlated with shorter recurrence free survival. Triptolide inhibited the expression of theses miRNAs in a c-Myc-dependent manner, which enhanced triptolide-induced cell death. We further showed that triptolide down-regulated the expression of c-Myc through targeting ERCC3, a newly identified triptolide-binding protein.ConclusionsThe triptolide-induced modulation of c-Myc/miRNA clusters/target genes axis enhances its potent antitumor activity, which indicates that triptolide serves as an attractive chemotherapeutic agent against HCC.

Expression of cell cycle regulators and frequency of TP53 mutations in high risk gastrointestinal stromal tumors prior to adjuvant imatinib treatment.

Despite of multitude investigations no reliable prognostic immunohistochemical biomarkers in GIST have been established so far with added value to predict the recurrence risk of high risk GIST besides mitotic count, primary location and size. In this study, we analyzed the prognostic relevance of eight cell cycle and apoptosis modulators and of TP53 mutations for prognosis in GIST with high risk of recurrence prior to adjuvant treatment with imatinib. In total, 400 patients with high risk for GIST recurrence were randomly assigned for adjuvant imatinib either for one or for three years following laparotomy. 320 primary tumor samples with available tumor tissue were immunohistochemically analyzed prior to treatment for the expression of cell cycle regulators and apoptosis modulators cyclin D1, p21, p16, CDK4, E2F1, MDM2, p53 and p-RB1. TP53 mutational analysis was possible in 245 cases. A high expression of CDK4 was observed in 32.8% of all cases and was associated with a favorable recurrence free survival (RFS), whereas high expression of MDM2 (12.2%) or p53 (35.3%) was associated with a shorter RFS. These results were independent from the primary KIT or PDGFRA mutation. In GISTs with higher mitotic counts was a significantly increased expression of cyclin D1, p53 and E2F1. The expression of p16 and E2F1 significantly correlated to a non-gastric localization. Furthermore, we observed a significant higher expression of p21 and E2F1 in KIT mutant GISTs compared to PDGFRA mutant and wt GISTs. The overall frequency of TP53 mutations was low (n = 8; 3.5%) and could not be predicted by the immunohistochemical expression of p53. In summary, mutation analysis in TP53 plays a minor role in the subgroup of high-risk GIST before adjuvant treatment with imatinib. Strong expression of MDM2 and p53 correlated with a shorter recurrence free survival, whereas a strong expression of CDK4 correlated to a better recurrence free survival.

Immunosuppressive tumor microenvironment of usual interstitial pneumonia-associated squamous cell carcinoma of the lung.

Patients with usual interstitial pneumonia (UIP) often develop lung cancer. However, the biological features of lung cancer associated with UIP remain unknown. The aim of this study was to elucidate the clinicopathological characteristics of UIP-associated squamous cell carcinoma (SqCC). A total of 244 patients with p-stage I lung SqCC who underwent complete surgical resection were enrolled in this study. Clinicopathological differences between UIP-associated SqCC and non-UIP SqCC were examined. Moreover, we performed immunohistochemical studies to clarify the biological differences between these two groups. UIP-associated SqCC was detected in 19 patients (6.0%). Patients with UIP-associated SqCC tended to have shorter recurrence-free survival (RFS) (5-year RFS; UIP-associated SqCC 44% vs non-UIP SqCC 62%, p = 0.05). Immunohistochemical analysis revealed that the expression scores of cancer stem cell- and invasion-related molecules in cancer cells were not significantly different between the two groups. However, PD-L1 expression in cancer cells was significantly higher in UIP-associated SqCC (median score; 5.0 vs 0, p < 0.01). In the stroma of UIP-associated SqCC, the number of Foxp3+ tumor-infiltrating lymphocytes was significantly higher than that in non-UIP SqCC (median number 43/HPF vs 24/HPF, p < 0.01). In addition, CD8+/Foxp3+ T-cell ratio in UIP-associated SqCC was significantly lower than that in non-UIP SqCC (median ratio 1.8 vs 3.4, p < 0.01). Our current study clearly revealed that the establishment of an immunosuppressive tumor microenvironment is a characteristic feature of UIP-associated SqCC, which can be correlated with poor prognosis in UIP-associated SqCC.

Decreased Skeletal Muscle Volume Is a Predictive Factor for Poorer Survival in Patients Undergoing Surgical Resection for Pancreatic Ductal Adenocarcinoma

BackgroundThe aim of this study was to investigate the impact of decreased skeletal muscle (SM) volume on survival outcomes in patients undergoing surgical resection for pancreatic ductal adenocarcinoma (PDAC). MethodsBetween March 2000 and February 2015, 323 patients who underwent upfront surgical resection for PDAC were identified from the Mayo Clinic SPORE in Pancreatic Cancer. Body composition data, including SM area, subcutaneous adipose tissue area, and visceral adipose tissue area were calculated using an abdominal computed tomography (CT) image at the third lumbar spinal level. The body composition data were normalized by patients’ height (e.g., SM index, cm2/m2) and analyzed as continuous variables. Clinicopathological findings and body composition data at initial diagnosis were evaluated for association with overall survival and recurrence-free survival. ResultsBecause the median SM index was significantly different between males vs. females (49.9 cm2/m2 [range, 32.0–70.3] vs. 39.4 cm2/m2 [range, 29.2–66.2], P < 0.001), it was standardized for each sex and used for further analyses. Parameters independently associated with a shorter overall survival were a larger tumor size (P = 0.007), a greater tumor extent (P = 0.037), a higher carbohydrate antigen 19–9 level (P < 0.001), and a smaller sex-standardized SM index (P = 0.011). Parameters independently associated with a shorter recurrence-free survival were female sex (P = 0.029), a larger tumor size (P < 0.001), a higher carbohydrate antigen 19–9 level (P = 0.001), and a smaller sex-standardized SM index (P = 0.007). ConclusionsA smaller sex-standardized SM index is a predictive factor for shorter overall and recurrence-free survival in PDAC patients undergoing surgery.

Blockade of the Complement C5a/C5aR1 Axis Impairs Lung Cancer Bone Metastasis by CXCL16-mediated Effects.

C5aR1 (CD88), a receptor for complement anaphylatoxin C5a, is a potent immune mediator. Its impact on malignant growth and dissemination of non-small cell lung cancer cells is poorly understood. To investigate the contribution of the C5a/C5aR1 axis to the malignant phenotype of non-small cell lung cancer cells, particularly in skeletal colonization, a preferential lung metastasis site. Association between C5aR1 expression and clinical outcome was assessed in silico and validated by immunohistochemistry. Functional significance was evaluated by lentiviral gene silencing and ligand l-aptamer inhibition in in vivo models of lung cancer bone metastasis. In vitro functional assays for signaling, migration, invasion, metalloprotease activity, and osteoclastogenesis were also performed. High levels of C5aR1 in human lung tumors were significantly associated with shorter recurrence-free survival, overall survival, and bone metastasis. Silencing of C5aR1 in lung cancer cells led to a substantial reduction in skeletal metastatic burden and osteolysis in in vivo models. Furthermore, metalloproteolytic, migratory, and invasive tumor cell activities were modulated in vitro by C5aR1 stimulation or gene silencing. l-Aptamer blockade or C5aR1 silencing significantly reduced the osseous metastatic activity of lung cancer cells in vivo. This effect was associated with decreased osteoclastogenic activity in vitro and was rescued by the exogenous addition of the chemokine CXCL16. Disruption of C5aR1 signaling in lung cancer cells abrogates their tumor-associated osteoclastogenic activity, impairing osseous colonization. This study unveils the role played by the C5a/C5aR1 axis in lung cancer dissemination and supports its potential use as a novel therapeutic target.

Significance of poor performance status after resection of colorectal liver metastases

BackgroundPerformance status (PS) is known as one of the strongest prognostic factors for survival in metastatic colorectal cancer patients. The aim of the present study was to analyze factors associated with poor PS assessed after resection for colorectal liver metastases and the impact on survival.MethodsAll patients undergoing curative resection for colorectal liver metastases between 2010 and 2015 in a single center were reviewed retrospectively.ResultsA total of 284 patients were included, out of whom 74 patients (26%) presented with a postoperative PS WHO > 2 precluding administration of adjuvant chemotherapy. These patients had a shorter recurrence-free survival (P = 0.002) and shorter overall survival (P < 0.001). Multivariable analysis showed that patients with PS > 2 after surgery had higher preoperative ASA score, had a higher frequency of major complications after surgery, and had more frequently synchronous liver and lung metastases. PS was found to be the strongest independent factor predicting survival (hazard ratio 0.45). When patients with postoperative PS > 2 developed recurrent disease (54 of 74), 43 (80%) received tumor specific treatment.ConclusionsPatients with postoperative PS > 2 who did not receive adjuvant chemotherapy had decreased recurrence-free and overall survival after liver resection for colorectal liver metastases. After recurrence, a large majority of these patients had had improvement in PS allowing for administration of tumor specific treatment.

Prognoses and Clinical Outcomes of Primary and Recurrent Uveal Melanoma.

PurposeUveal melanoma has a very poor prognosis despite successful local primary tumor treatment. In this study, we investigated prognostic factors that more accurately reflected the likelihood of recurrence and survival and delineated a prognostic model that could effectively identify different risk groups based on initial clinical parameters.Materials and MethodsPrognostic factors associated with distant recurrence, recurrence-free survival (RFS), progression-free survival, and overall survival from distant recurrence to death (OS2) were analyzed in 226 patients with stage I-III uveal melanoma who underwent primary local therapy.ResultsForty-nine patients (21.7%) had distant recurrences, which occurred most frequently in the liver (87.7%). In a multivariate analysis, local radiotherapy improved RFS among patients with multiple recurrence risk factors relative to excision (not reached vs. 19.0 months, p=0.004). Patients with BRCA1-associated protein-1 (BAP1)‒negative primary tumors showed a longer RFS duration after primary treatments, while those with BAP1-negative metastatic tissues had a shorter OS2 compared to those with BAP1-positive tumors, both not statistically insignificance (RFS: not reached vs. 82.0 months, p=0.258; OS2: 15.7 vs. 24.4 months, p=0.216). Male sex (hazard ratio [HR], 3.79; p=0.012), a short RFS (HR, 4.89; p=0.014), and a largest metastatic tumor linear diameter ≥ 45 mm (HR, 5.48; p=0.017) were found to correlate with worse post-recurrence survival.ConclusionRisk factors could be used to classify uveal melanoma cases and subsequently direct individual treatment strategies. Furthermore, metastasectomy appears to contribute to improved survival outcomes.

High cripto-1 and low miR-205 expression levels as prognostic markers in early stage non-small cell lung cancer

ObjectivesCripto-1 (CR-1) plays a critical role in the activation of SMAD, SRC, and epithelial-to-mesenchymal transition (EMT) pathways and has been shown to be prognostic in several cancer types. In addition, we showed that CR-1 renders EGFR-mutated NSCLC cells resistant to EGFR-TKI through the activation of SRC and EMT via miR-205 downregulation. This study aimed to investigate the correlation between expression of CR-1 and miR-205 and prognosis of NSCLC patients with or without EGFR mutations. Materials and methodsA total of 265 patients with stage I (AJCC 6th edition) radically resected NSCLC were tested for CR-1 expression and EGFR mutations by immunohistochemistry and miR-205 expression via qPCR assay. ResultsCR-1 expression was evaluated with immunohistochemistry using a tissue microarray on 265 T1-2N0 surgical NSCLC samples. Of the 265 tumors, 250 (94%) expressed various levels of CR-1. A significant inverse correlation was identified between expression of miR-205 and CR-1. NSCLC patients (T1N0, n = 106) with high CR-1 expression had worse prognosis (shorter recurrence-free survival, p = .045) than those with low CR-1 expression. A similar trend was observed in NSCLC patients with normal preoperative carcinoembryonic antigen (CEA) levels (serum CEA levels <5 ng/ml; n = 179; p = .085); however, no significant correlation was found between CR-1 expression and survival rate in the T2N0 or high CEA groups. In addition, NSCLC patients with low miR-205 expression (n = 126) had poorer prognosis in terms of recurrence than those with high miR-205 expression (n = 127; p = .001). ConclusionHigh CR-1 expression is correlated with poor prognosis in NSCLC with low tumor burden and may be used to select high-risk patients for adjuvant chemotherapy in early NSCLC. Moreover, low miR-205 expression likely related to high CR-1 expression could be a prognostic marker for patients with NSCLC.