Prognostic value of tumor-to-parenchymal contrast enhancement ratio on portal venous-phase CT in pancreatic neuroendocrine neoplasms.

OBJECTIVES: We aimed to evaluate the prognostic value of tumor-to-parenchymal contrast enhancement ratio on portal venous-phase CT (CER on PVP) and compare its prognostic performance to prevailing grading and staging systems in pancreatic neuroendocrine neoplasms (PanNENs). METHODS: In this retrospective study, data on 465 patients (development cohort) who underwent upfront curative-intent resection for PanNEN were used to assess the performance of CER on PVP and tumor size measured by CT (CT-Size) in predicting recurrence-free survival (RFS) using Harrell's C-index and to determine their optimal cutoffs to stratify RFS using a multi-way partitioning algorithm. External data on 184 patients (test cohort) were used to validate the performance of CER on PVP in predicting RFS and overall survival (OS) and compare its predictive performance with those of CT-Size, 2019 World Health Organization classification system (WHO), and the 8th American Joint Committee on Cancer staging system (AJCC). RESULTS: In the test cohort, CER on PVP showed C-indexes of 0.83 (95% confidence interval [CI], 0.74-0.91) and 0.84 (95% CI, 0.73-0.95) for predicting RFS and OS, respectively, which were higher than those for the WHO (C-index: 0.73 for RFS [p = .002] and 0.72 for OS [p = .004]) and AJCC (C-index, 0.67 for RFS [p = .002] and 0.58 for OS [p = .002]). CT-Size obtained C-indexes of 0.71 for RFS and 0.61 for OS. CONCLUSIONS: CER on PVP showed superior predictive performance on postoperative survival in PanNEN than current grading and staging systems, indicating its potential as a noninvasive preoperative prognostic tool. KEY POINTS: • In pancreatic neuroendocrine neoplasms, the tumor-to-parenchymal enhancement ratio on portal venous-phase CT (CER on PVP) showed acceptable predictive performance of postoperative outcomes. • CER on PVP showed superior predictive performance of postoperative survival over the current WHO classification and AJCC staging system.

Blood Vessel Invasion Predicts Postoperative Survival Outcomes and Systemic Recurrence Regardless of Location or Blood Vessel Type in Patients with Lung Adenocarcinoma.

BACKGROUND: Presence of blood vessel invasion (BVI) is one of the prognostic indicators for lung cancer patients with surgical resection. However, prognostic roles of the location and the type of the involved blood vessel have not been fully evaluated yet. PATIENTS AND METHODS: We retrieved the data of 217 cases of surgically resected lung adenocarcinoma from Asan Medical Center. Clinicopathologic features, including BVI, were reassessed. The location (tumor center and/or periphery) and involved blood vessel types (large and/or small vessels; arteries and/or veins) of BVI were separately examined on standard hematoxylin-eosin slides and confirmed by van Gieson elastic staining. RESULTS: BVI was identified in 35% of cases (76/217), with the tumor center (intratumoral) as the location in more than half of the cases (42/76, 55.3%). The presence of BVI was significantly associated with higher pathologic stage, increased size of invasive components, frequent pleural invasion, lymphatic permeation, and spread through alveolar spaces. BVI was significantly associated with poor overall survival (OS) and recurrence-free survival (RFS) both in univariate and multivariate survival analyses [for OS, hazard ratio (HR) 1.92, 95% confidence interval (CI) 1.06-3.48, P = 0.031; for RFS, HR 2.65, 95% CI 1.64-4.28; P < 0.001]. BVI subgroups, according to location and type of the involved blood vessels, invariably displayed significantly poor RFS; however, the results for OS varied. CONCLUSION: Regardless of their location or blood vessel type, presence of BVI is a useful predictor for postoperative survival outcomes, which should be carefully evaluated on pathologic examination.

Prognostic Molecular Indices of Resectable Hepatocellular Carcinoma: Implications of S100P for Early Recurrence.

BACKGROUND: Although hepatocellular carcinomas (HCCs) often recur in patients undergoing hepatectomy, there are no reliable biomarkers of this undesirable event. Recent RNA-based efforts have developed valuable genetic indices prognostic of cancer outcomes. We aimed to identify molecular predictors of early recurrence after resection of HCC, and reveal the genomolecular structure of the resected tumors. METHOD: Based on the transcriptomic and genomic datasets of 206 HCC samples surgically resected in the Asan Medical Center (AMC), we performed a differential gene expression analysis to identify quantitative markers associated with early recurrence and used the unsupervised clustering method to classify genomolecular subtypes. RESULTS: Differential gene expression profiling revealed that S100P was the highest-ranked overexpressed gene in HCCs that recurred within 2 years of surgery. This trend was reproduced in immunohistochemical studies of the original cohort and an independent AMC cohort. S100P expression also independently predicted HCC-specific mortality post-resection (adjusted hazard ratio 1.09, 95% confidence interval 1.01-1.19; p = 0.042). Validation in a Chinese cohort and in in vitro experiments confirmed the prognostic value of S100P in HCC. We further identified five discrete molecular subtypes of HCC; a subtype with stem cell features ('AMC-C4') was associated with the worst prognosis, both in our series and another two Asian datasets, and S100P was most strongly upregulated in that subtype. CONCLUSION: We identified a promising prognostic biomolecule, S100P, associated with early recurrence after HCC resection, and established the genomolecular architecture of tumors affecting clinical outcomes, particularly in Asian patients. These new insights into molecular mediators should contribute to effective care for affected patients.

Progressive fibrosing interstitial lung disease: prevalence and clinical outcome.

BACKGROUND: The progressive fibrosing (PF) phenotype of interstitial lung disease (ILD) is characterised by worsening respiratory symptoms, lung function, and extent of fibrosis on high-resolution computed tomography. We aimed to investigate the prevalence and clinical outcomes of PF-ILD in a real-world cohort and assess the prognostic significance of the PF-ILD diagnostic criteria. METHODS: Clinical data of patients with fibrosing ILD other than idiopathic pulmonary fibrosis (IPF) consecutively diagnosed at a single centre were retrospectively reviewed. A PF phenotype was defined based on the criteria used in the INBUILD trial. RESULTS: The median follow-up duration was 62.7 months. Of the total of 396 patients, the mean age was 58.1 years, 39.9% were men, and rheumatoid arthritis-ILD was the most common (42.4%). A PF phenotype was identified in 135 patients (34.1%). The PF-ILD group showed lower forced vital capacity and total lung capacity (TLC) than the non-PF-ILD group. The PF-ILD group also showed poorer survival (median survival, 91.2 months vs. not reached; P < 0.001) than the non-PF-ILD group. In multivariable Cox analysis adjusted for age, DLCO, HRCT pattern, and specific diagnosis, PF phenotype was independent prognostic factor (hazard ratio, 3.053; P < 0.001) in patients with fibrosing ILD. Each criterion of PF-ILD showed similar survival outcomes. CONCLUSIONS: Our results showed that approximately 34% of patients with non-IPF fibrosing ILD showed a progressive phenotype and a poor outcome similar to that of IPF, regardless of the diagnostic criteria used.

Computed tomography patterns predict clinical course of idiopathic pulmonary fibrosis.

BACKGROUND: A new clinical guideline for idiopathic pulmonary fibrosis (IPF) uses high-resolution computed tomography (HRCT) patterns for diagnostic purposes. However, it is unknown how they relate to the IPF clinical course. We aimed to investigate whether HRCT patterns could be used to predict lung function changes and survival in patients with IPF. METHODS: Clinical data were retrospectively reviewed in 337 patients with IPF (all biopsy-proven cases). HRCT patterns were classified according to the 2018 IPF diagnostic criteria. RESULTS: The median follow-up was 46.9 months. The mean age was 62.5 years, and 74.2% were men. Among the HRCT patterns, usual interstitial pneumonia (UIP), probable UIP, indeterminate for UIP, and an alternative diagnosis were identified in 163 (48.4%), 110 (32.6%), 33 (9.8%), and 31 (9.2%) patients, respectively. The indeterminate for UIP group showed higher lung function and exercise capacity and better prognosis than the other groups. They also had a lesser decline in lung function than the other groups during follow-up. In the multivariate Cox analysis, which was adjusted by age, smoking status, lung function, exercise capacity, and use of antifibrotic agents, indeterminate for UIP pattern was found to be an independent prognostic factor (hazard ratio 0.559, 95% confidence interval 0.335-0.933, P = 0.026). However, the probable UIP group had similar lung function changes and prognosis when compared the UIP group. CONCLUSIONS: Our results suggest that indeterminate for UIP pattern on HRCT may predict a more favorable clinical course in patients with IPF, supporting the validity of the new IPF diagnostic guidelines.

Long-term clinical course and outcomes of immunoglobulin G4-related lung disease.

BACKGROUND: Immunoglobulin G4-related lung disease (IgG4-RLD) is the pulmonary manifestation of a systemic fibroinflammatory disease characterized by lymphoplasmacytic infiltration with an abundance of IgG4-positive plasma cells. Long-term clinical course and outcomes of IgG4-RLD remain unclear. We aimed to identify clinical characteristics, treatment outcomes, and longitudinal pulmonary function changes in patients with IgG4-RLD according to the radiologic classification. METHODS: Chest computed tomography findings of 37 subjects were classified into five subtypes: solid nodular, bronchovascular, alveolar interstitial, round ground glass opacity, and alveolar consolidative. Radiologic treatment outcomes and longitudinal pulmonary function changes were compared among the different radiologic subtypes. RESULTS: The mean age of the subjects was 55.6 years, and 78.4% were male. Among the five radiologic subtypes, alveolar consolidative and solid nodular type were most common, accounting for approximately 29.7% each of the total cases. Prednisone with or without azathioprine was administered to 31 patients (median treatment duration 14 months). In the treated patients, serial images showed complete response or partial response in 77.4%. However, relapse was documented in 25.0% of those who showed complete or partial response. In patients whose longitudinal lung function data were available (n = 20), the lung function was found to be stable during follow-up. Alveolar consolidative type showed the highest complete response rate, whereas alveolar interstitial type showed the lowest response rate, either complete or partial. CONCLUSIONS: Most patients showed a favorable outcome with regards to radiologic improvement and maintenance of pulmonary function; however, the response differed according to the radiologic subtype.

Comparison between neuroendocrine carcinomas and well-differentiated neuroendocrine tumors of the pancreas using dynamic enhanced CT.

OBJECTIVES: To identify CT features distinguishing neuroendocrine carcinomas (NECs) of pancreas from well-differentiated neuroendocrine tumors (NETs) according to the World Health Organization 2017 and 2019 classification systems. METHODS: This retrospective study included 69 patients with pathologically confirmed pancreatic neuroendocrine neoplasms who underwent dynamic CT (17, 17, 18, and 17 patients for well-differentiated grade 1, 2, 3 NET and NEC, respectively). CT was used to perform qualitative analysis (component, homogeneity, calcification, peripancreatic infiltration, main pancreatic ductal dilatation, bile duct dilatation, intraductal extension, and vascular invasion) and quantitative analysis (interface between tumor and parenchyma [delta], arterial enhancement ratio [AER], portal enhancement ratio [PER], and dynamic enhancement pattern). Uni- and multivariate logistic regression analyses were performed to identify features indicating NEC. Optimal cutoff values for enhancement ratios were determined. RESULTS: NECs demonstrated significantly higher frequencies of main pancreatic ductal dilatation, bile duct dilatation, vascular invasion, and significantly lower delta (i.e., lower conspicuity), AER, and PER than well-differentiated NET (p < 0.05). On multivariate analysis, PER was the only independent factor selected by the model for differentiation of NEC from well-differentiated NET (odds ratio, < 0.001; 95% confidence interval [CI], < 0.001-0.012). PER < 0.8 showed the sensitivity of 94.1% (95% CI, 71.3-99.9) and the specificity of 88.5% (95% CI, 76.6-95.6). When three significant CT features were combined, the sensitivity and specificity for diagnosing NEC were 88.2% and 88.5%, respectively. CONCLUSIONS: Tumor-parenchyma enhancement ratio in portal phase is a useful CT feature to distinguish NECs from well-differentiated NETs. Combining qualitative and quantitative CT features may aid in achieving good diagnostic accuracy in the differentiation between NEC and well-differentiated NET. KEY POINTS: • Neuroendocrine carcinoma of the pancreas should be distinguished from well-differentiated neuroendocrine tumor in line with the revised grading and staging system. • Neuroendocrine carcinoma of the pancreas can be differentiated from well-differentiated neuroendocrine tumor on dynamic CT based on assessment of the portal enhancement ratio, arterial enhancement ratio, tumor conspicuity, dilatation of the main pancreatic duct or bile duct, and vascular invasion. • Tumor-parenchyma enhancement ratio in portal phase of dynamic CT is a useful feature, which may help to distinguish neuroendocrine carcinoma from well-differentiated neuroendocrine tumor of the pancreas.

Involvement of the TNF-α Pathway in TKI Resistance and Suggestion of TNFR1 as a Predictive Biomarker for TKI Responsiveness in Clear Cell Renal Cell Carcinoma.

BACKGROUND: Mechanism and predictive biomarkers for tyrosine kinase inhibitor (TKI) resistance of advanced clear cell renal cell carcinoma (ccRCC) have not been fully evaluated. METHODS: We performed gene expression profiling on samples from an acquired TKI resistance cohort that consisted of 10 cases of TKI-treated ccRCC patients with matched tumor tissues harvested at pre-treatment and TKI-resistant post-treatment periods. In addition, a public microarray dataset from patient-derived xenograft model for TKI-treated ccRCC (GSE76068) was retrieved. Commonly altered pathways between the datasets were investigated by Ingenuity Pathway Analysis using commonly regulated differently expressed genes (DEGs). The significance of candidate DEG on intrinsic TKI resistance was assessed through immunohistochemistry in a separate cohort of 101 TKI-treated ccRCC cases. RESULTS: TNFRSF1A gene expression and tumor necrosis factor (TNF)-α pathway were upregulated in ccRCCs with acquired TKI resistance in both microarray datasets. Also, high expression (> 10% of labeled tumor cells) of TNF receptor 1 (TNFR1), the protein product of TNFRSF1A gene, was correlated with sarcomatoid dedifferentiation and was an independent predictive factor of clinically unfavorable response and shorter survivals in separated TKI-treated ccRCC cohort. CONCLUSION: TNF-α signaling may play a role in TKI resistance, and TNFR1 expression may serve as a predictive biomarker for clinically unfavorable TKI responses in ccRCC.

Epithelial-mesenchymal transition as a mechanism of resistance to tyrosine kinase inhibitors in clear cell renal cell carcinoma.

Tyrosine kinase inhibitors (TKIs) are widely accepted as treatment for metastatic clear cell renal cell carcinoma (ccRCC). However, most patients eventually experience disease progression despite TKI treatment, even if the initial response is favorable. To define the underlying mechanism of TKI resistance, 10 TKI-treated metastatic ccRCC cases in which tumor samples were harvested before treatment and immediately after disease progression were examined. Gene expression profiles and copy number variations of matched pre- and post-treatment tumor samples were investigated. Altered biologic characteristics were confirmed in sunitinib-resistant ccRCC cell lines, which were generated by long-term treatment with sunitinib-containing media. Gene transcript levels related to the cell cycle and epithelial-mesenchymal transition (EMT) were significantly upregulated in the treated tumor samples compared with the pre-treatment samples. The mitotic count and sarcomatoid component were significantly increased in treated tumor samples. Alteration of EMT-related genes was also demonstrated in a sunitinib-resistant ccRCC cell line that showed enhanced migration and invasion compared to the parent cell line. siRNA-induced inhibition of EMT-related gene expression significantly suppressed the migration and invasion capacity of TKI-resistant cell lines. The present study shows that both ccRCC cases that progressed after TKI treatment and sunitinib-resistant ccRCC cell lines demonstrated alteration of EMT-related gene expression and enhancement of EMT-related behavior. These results suggest that EMT may explain the aggressive behavior of TKI-resistant ccRCC.

Immunogenomic landscape of hepatocellular carcinoma with immune cell stroma and EBV-positive tumor-infiltrating lymphocytes.

BACKGROUND & AIMS: The immunogenomic characteristics of hepatocellular carcinomas (HCCs) with immune cell stroma (HCC-IS), defined histologically, have not been clarified. We investigated the clinical and molecular features of HCC-IS and the prognostic impact of Epstein-Barr virus (EBV) infection. METHODS: We evaluated 219 patients with conventional HCC (C-HCC) and 47 with HCC-IS using in situ hybridization for EBV, immunohistochemistry, multiplex immunofluorescence staining, and whole exome and transcriptome sequencing. Human leukocyte antigen types were also extracted from the sequencing data. Genomic and prognostic parameters were compared between HCC-IS and C-HCC. RESULTS: CD8 T cell infiltration was more frequent in HCC-IS than C-HCC (mean fraction/sample, 22.6% vs. 8.9%, false discovery rate q <0.001), as was EBV positivity in CD20-positive tumor-infiltrating lymphocytes (TILs) (74.5% vs. 4.6%, p <0.001). CTNNB1 mutations were not identified in any HCC-IS, while they were present in 24.1% of C-HCC (p = 0.016). Inhibitory and stimulatory immune modulators were expressed at similar levels in HCC-IS and EBV-positive C-HCC. Global hypermethylation, and expression of PD-1 and PD-L1 in TILs, and PD-L1 in tumors, were also associated with HCC-IS (p <0.001), whereas human leukocyte antigen type did not differ according to HCC type or EBV positivity. HCC-IS was an independent factor for favorable recurrence-free survival (adjusted hazard ratio [aHR] 0.23; p = 0.002). However, a subgroup of tumors with a high density of EBV-positive TILs had poorer recurrence-free (aHR 25.48; p <0.001) and overall (aHR 9.6; p = 0.003) survival, and significant enrichment of CD8 T cell exhaustion signatures (q = 0.0296). CONCLUSIONS: HCC-IS is a distinct HCC subtype associated with a good prognosis and frequent EBV-positive TILs. However, paradoxically, a high density of EBV-positive TILs in tumors is associated with inferior prognostic outcomes. Patients with HCC-IS could be candidates for immunotherapy. LAY SUMMARY: Hepatocellular carcinomas with histologic evidence of abundant immune cell infiltration are characterized by frequent activation of Epstein-Barr virus in tumor-infiltrating lymphocytes and less aggressive clinical behavior. However, a high density of Epstein-Barr virus-positive tumor-infiltrating lymphocytes is associated with inferior prognostic outcomes, possibly as a result of immune escape due to significant CD8 T cell exhaustion.

Efficacy and safety of lanreotide in Korean patients with metastatic, well-differentiated gastroenteropancreatic-neuroendocrine tumors: a retrospective analysis.

Lanreotide autogel is a long-acting somatostatin analogue with proven efficacy and safety in patients with well-differentiated (WD) gastroenteropancreatic-neuroendocrine tumors (GEP-NETs) in a prior randomized phase III trial (CLARINET). However, the CLARINET study only enrolled patients with Ki-67 index <10%, and few patients of Asian ethnicity were included. We retrospectively analyzed the efficacy and safety of lanreotide in Korean patients with GEP-NETs in the daily practice setting. Between January 2015 and May 2018, 64 patients with metastatic WD GEP-NETs received lanreotide at Asan Medical Center, Seoul, Korea. Of them, 45 (70.3%) patients who received lanreotide as monotherapy were included in the current analysis. The most common primary tumor site was the pancreas (n = 22, 48.9%), followed by the rectum (10, 22.2%) and the small bowel (7, 15.6%). According to RECIST v1.1, a partial response was achieved in one patient (2.2%) and stable disease was achieved in 40 patients (88.9%). The median progression-free survival (PFS) was 16.4 months (95% confidence interval, 9.5-23.3 months). There were no differences in PFS according to the primary tumor site (p = 0.77). Hepatic tumor volume > 25% and prior systemic therapy were significantly associated with poorer PFS in the multivariate analysis. Lanreotide is well-tolerated and effective for Korean patients with GEP-NETs in the daily practice setting.

The cell-of-origin classification of diffuse large B cell lymphoma in a Korean population by the Lymph2Cx assay and its correlation with immunohistochemical algorithms.

Cell-of-origin (COO) classification of diffuse large B cell lymphoma (DLBCL) is increasingly important due to its prognostic significance and the development of subtype-specific therapeutics. We compared the clinical utility of the Lymph2Cx assay against four widely used immunohistochemical algorithms in 150 R-CHOP-treated DLBCL patients using archival tissue. In contrast to the predominance of germinal center B cell-like (GCB) subtype in Western populations, Lymph2Cx assay classified more than half of the Korean cases as the activated B cell-like (ABC) subtype (ABC, 83/150 [55.3%]; GCB, 51/150 [34.0%]; unclassifiable, 16/150 [10.7%]). Predominance of ABC subtype tended to be more pronounced in the nodal lymphomas than in the extranodal lymphomas. However, among the primary extranodal sites, ABC subgroups predominated in primary testicular, breast, and adrenal gland lymphomas. The classification of COO by Lymph2Cx assay did not show any significant association with clinical parameters. The overall concordance rates of the immunohistochemical algorithms with the Lymph2Cx ranged from 78.0 to 84.3%. However, 47.1-66.7% of the cases of the Lymph2Cx-defined GCB subgroup were misclassified as the non-GCB class by the IHC algorithms. The survival of Lymph2Cx-classified COO subtypes was not significantly different in the present cohort. In conclusion, ABC subtype predominated over GCB in Korean patients. There are significant discrepancies between the immunohistochemistry and Lymph2Cx classifications, especially in GCB subtype.

Endoscopic features and clinical outcomes of colorectal mucosa-associated lymphoid tissue lymphoma.

BACKGROUND AND AIMS: Colorectal mucosa-associated lymphoid tissue (MALT) lymphoma is a rare disease. The purpose of this study was to investigate the clinical and endoscopic features of colorectal MALT lymphoma. METHODS: Patients diagnosed with colorectal MALT lymphoma at Asan Medical Center from 2002 to 2016 were eligible. Medical records were reviewed to investigate clinical features and treatment outcomes. Endoscopic pictures were assessed to characterize the endoscopic features of colorectal MALT lymphoma. RESULTS: A total of 51 patients were enrolled. The median age was 60 years (interquartile range, 55-71), and 21 (41%) were men. Twenty-six patients (51%) were asymptomatic. Forty-four patients (86%) were in early disease stages, namely Lugano stages I, II, and IIE. Endoscopic appearances were classified as 4 distinct types: subepithelial tumor type (26 patients, 51%), polyposis type (10 patients, 20%), epithelial mass type (7 patients, 14%), and ileitis type (8 patients, 16%). The rectum (20 patients, 39%) was the most common location, followed by the ileocecal area (15 patients, 30%). An initial endoscopic impression of lymphoma was made in only 7 patients. Forceps biopsy sampling as the initial tissue acquisition method could histologically diagnose MALT lymphoma in 28 of 35 patients (80%). Polypectomy as the initial histologic diagnosis could diagnose MALT lymphoma in 16 of 16 patients. Progression-free and overall survival rates at 5 years were 92% and 94%, respectively. CONCLUSIONS: Colorectal MALT lymphomas show various endoscopic appearances, complicating the endoscopic suspicion of colorectal MALT lymphoma. The prognosis of colorectal MALT lymphoma was excellent.

Outcomes after endoscopic ultrasound-guided ethanol-lipiodol ablation of small pancreatic neuroendocrine tumors.

BACKGROUND AND AIM: Little is known about the standard care of small (<2 cm in diameter) pancreatic neuroendocrine tumors (PNET). The aim of the present study was to determine the clinical outcomes of small PNET after endoscopic ultrasound (EUS)-guided ethanol-lipiodol ablation (EUS-ELA). METHODS: In this prospective cohort study, consecutive patients who underwent EUS-ELA for PNET were enrolled and were followed for ≥3 years. Treatment efficacy was the primary outcome measure. RESULTS: In total, 33 patients who had 40 pathologically confirmed PNET (<2 cm in diameter) were enrolled for final analysis. A total of 63 EUS-ELA sessions were successfully carried out (mean, 1.9 sessions per patient, 1.6 sessions per tumor), which included 40 initial sessions and 23 repeated sessions owing to incomplete ablation. Median actual volume of ethanol-lipiodol mixture injected per session was 1.1 mL (IQR 0.8-1.9 mL). Complete ablation was achieved in 24 of 40 tumors (60%) with one (18 tumors, 45%) or two (24 tumors, 60%) sessions of EUS-ELA. Lipiodol retention within tumor had better treatment outcomes (P = 0.004). Rate of procedure-related adverse events was 3.2%. No malignancy or lymph node metastasis was discovered during a median follow up of 42 months (IQR 39-46 months). CONCLUSIONS: We found that EUS-ELA was a safe and effective alternative option in the management of PNET <2.0 cm in diameter; 60% of patients achieved complete ablation. Lipiodol retention within tumor may be a useful early predictor of treatment effectiveness. Trial registered at ClinicalTrials.gov (NCT 01902238).

A new extranodal scoring system based on the prognostically relevant extranodal sites in diffuse large B-cell lymphoma, not otherwise specified treated with chemoimmunotherapy.

Extranodal involvement is a well-known prognostic factor in patients with diffuse large B-cell lymphomas (DLBCL). Nevertheless, the prognostic impact of the extranodal scoring system included in the conventional international prognostic index (IPI) has been questioned in an era where rituximab treatment has become widespread. We investigated the prognostic impacts of individual sites of extranodal involvement in 761 patients with DLBCL who received rituximab-based chemoimmunotherapy. Subsequently, we established a new extranodal scoring system based on extranodal sites, showing significant prognostic correlation, and compared this system with conventional scoring systems, such as the IPI and the National Comprehensive Cancer Network-IPI (NCCN-IPI). An internal validation procedure, using bootstrapped samples, was also performed for both univariate and multivariate models. Using multivariate analysis with a backward variable selection, we found nine extranodal sites (the liver, lung, spleen, central nervous system, bone marrow, kidney, skin, adrenal glands, and peritoneum) that remained significant for use in the final model. Our newly established extranodal scoring system, based on these sites, was better correlated with patient survival than standard scoring systems, such as the IPI and the NCCN-IPI. Internal validation by bootstrapping demonstrated an improvement in model performance of our modified extranodal scoring system. Our new extranodal scoring system, based on the prognostically relevant sites, may improve the performance of conventional prognostic models of DLBCL in the rituximab era and warrants further external validation using large study populations.

Body mass index as a prognostic factor in Asian patients treated with chemoimmunotherapy for diffuse large B cell lymphoma, not otherwise specified.

Obesity was recently reported to confer a survival advantage in diffuse large B cell lymphoma (DLBCL) among Western populations. Given ethnic differences, previous studies recommended a revision of the WHO classification of obesity for Asians. We investigated the prognostic impact of body mass index (BMI) using modified WHO criteria in a retrospective cohort of 562 Korean patients with DLBCL. Patients were categorized into five groups according to BMI: 26 (4.6 %) as underweight (<18.5 kg/m(2)), 230 (40.9 %) as normal weight (18.5-22.9 kg/m(2)), 129 (23.0 %) as overweight (23.0-24.9 kg/m(2)), 160 (28.5 %) as obese (25.0-29.9 kg/m(2)), and 17 (3.0 %) as severely obese (≥30 kg/m(2)). As BMI increased, the relative hazard ratio (HR) decreased sharply, reaching the lowest value in the overweight group, and then rose again in the obese and severely obese. On univariate analysis, both overall survival (OS) and progression-free survival (PFS) were best in the overweight group, followed by normal > obese > severely obese > underweight groups. Multivariate analysis showed a significantly shorter survival in the underweight (OS: HR 2.90, 95 % confidence interval (CI) 1.35-6.19, P = 0.006; PFS: HR 3.08, 95 % CI 1.55-6.09, P = 0.001) and severely obese groups (OS: HR 2.93, 95 % CI 1.08-7.95, P = 0.035; PFS: HR 2.59, 95 % CI 1.06-6.36, P = 0.038). We show that being underweight or, contrary to findings in Western patients, being severely obese has a deleterious prognostic impact in DLBCL in Koreans. Revising the BMI criterion that defines obesity according to the patient's ethnic differences could therefore better delineate DLBCL risk groups in Asian patients.

Endoscopic and pathologic findings associated with clinical outcomes of melanoma in the upper gastrointestinal tract.

BACKGROUND: Melanoma that involves the upper gastrointestinal (GI) tract is rare and studies relating to endoscopic and pathologic findings with clinical outcomes are lacking. We reviewed the gross and microscopic patterns of the upper GI tract in primary and metastatic melanoma, and examined their association with clinical outcomes. METHODS: Twenty-nine cases of primary esophageal (n = 19) and metastatic gastric and/or duodenal melanoma (n = 10) that were detected during upper GI endoscopy between 1995 and 2011 were retrospectively analyzed. RESULTS: Three types of gross patterns were recognized-nodular pattern in 7 cases, mass-forming pattern in 18 cases, and flat pigmented pattern in 4 cases. In primary esophageal melanoma, 13 patients (68.4 %) underwent surgery and 9 received palliative therapy. Of all cases, 22 patients (75.9 %) died of disease progression; the median overall survival period was 12 months (interquartile range [IQR] 4.5-24.5 months), and from recognition of upper GI tract melanoma the median overall survival period was 9 months (IQR 3.5-17.0 months). In primary esophageal cases, skin melanoma stage better discriminated the patients with good prognosis than the esophageal cancer stage. The flat pigmented gross pattern proved to be a good prognostic factor in primary and metastatic GI tract melanomas (p = 0.016 and p = 0.046, respectively). CONCLUSIONS: Melanoma of the GI tract is a highly aggressive disease with a poor prognosis, both in primary and metastatic cases. However, in primary esophageal melanoma, careful inspection of the mucosa during endoscopic examination followed by surgical resection may result in extended survival.

Intestinal diffuse large B-cell lymphoma: an evaluation of different staging systems.

The gastrointestinal tract is the most common primary extranodal site for diffuse large B-cell lymphoma (DLBCL). However, there is no consensus on the most appropriate staging system for intestinal DLBCL. We evaluated the utility of the modified Ann Arbor system, the Lugano system, and the Paris staging system (a modification of the Tumor, Node, Metastases [TNM] staging for epithelial tumors) in 66 cases of resected intestinal DLBCL. The cases were treated with surgery, plus either cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) chemotherapy alone (n=26) or with the addition of rituximab immunotherapy (n=40). Median follow-up time was 40.4 months (range, 2.1-171.6 months). Fifty-six patients (84.8%) achieved complete remission. The overall 5-yr survival rate was 86.4% (57/66). Of the stage categories defined for each staging system, only the T stage of the Paris classification showed prognostic significance for overall survival by univariate analysis. However, none of the stage parameters was significantly correlated with patient survival on multivariate analysis. In conclusion, the results suggest that the T stage of the Paris classification system may be a prognostic indicator in intestinal DLBCL. The results also imply that in surgically resected intestinal DLBCL, the addition of rituximab to the CHOP regimen does not confer significant survival advantage.