Factor For Disease-specific Survival Research Articles

Loss of DDX3X Function Promotes CLL Progression By Facilitating NOTCH1 mRNA Translation

A variety of driver genes are present in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), and those with high mutation frequencies include SF3B1, NOTCH1, and TP53, which are involved in the development of CLL/SLL and are associated with poor prognosis. The biological significance of some driver genes, such as DDX3X, has not yet been elucidated. DDX3X is located on the X chromosome. As one of the members of the DEAD-box helicase family, it is expressed ubiquitously in human tissues and participates in many biological processes. Here, we described the mapping of the DDX3X abnormalities and demonstrated its clinical significance in CLL/SLL. We also explored the effect and mechanism of DDX3X dysregulation on tumorigenesis and development of CLL by in vitro experiments. To examine the mutational landscape of DDX3X, we performed next-generation sequencing on 402 CLL/SLL patients, and 17 patients (4.2%) had DDX3X mutations. Six patients were frameshift mutations and 2 were nonsense mutation, which caused truncation of DDX3X. Among the 7 cases of missense mutations, 4 cases involved the ATP-binding or C-terminal domain, which may affect the function of DDX3X. The remaining two cases are deletion mutation and splicing mutation. Next, we evaluated the clinical significance and prognostic role of DDX3X mutation. The patients with DDX3X mutations are mostly male (94.1% vs 66.5%, P=0.017), and had more adverse prognostic indicators: unmutated IGHV (88.2% vs 48.6%, P=0.002), 17p deletion (42.9% vs 11.4%, P=0.041), and 11q deletion (46.7% vs 15.7%, P=0.006). DDX3X mutation was an independent risk factor for disease specific survival of CLL/SLL in the competing-risk regression. Also, we found all (14/14) the mutated patients and 15.2% (5/33) of the non-mutated patients had low expression of DDX3X in bone marrow samples by immunohistochemistry. Overall, these results indicates that dysregulation of DDX3X are common in CLL/SLL and may contribute to its progression. To delineate the functional consequences of DDX3X loss in CLL, we used CRISPR/cas9 system to construct stable DDX3X knockout (DDX3X-KO) MEC-1 and JVM-3 cells. DDX3X-KO cells showed significantly increased proliferation and reduced spontaneous apoptosis compared to vector control. Additionally, DDX3X-KO cells showed higher rates of cell viability and reduced apoptosis after treatment of ibrutinib or venetoclax. We further found that DDX3X-KO cells had higher expression level of phosphorylated BTK and MCL-1, which may explain the resistance to ibrutinib and venetoclax, respectively. Moreover, DDX3X-KO cells showed increased expression level of CXCR4 and enhanced chemotaxis in response to CXCL-12. In summary, loss of DDX3X function promotes progression of CLL by mediating more invasive biological behaviors of CLL cells. To evaluate the mechanisms by which DDX3X deletion affects CLL, we detected key signaling pathways in the tumorigenesis and development of CLL in DDX3X-KO and control cells. We found increased expression of NOTCH1 and its downstream target proteins in DDX3X-KO cells (Figure 1), indicating that loss of DDX3X activated the NOTCH1 pathway. Considering that DDX3X is an RNA-binding protein and mainly regulates translation, we speculated that DDX3X may regulate the translation of NOTCH1. We performed RNA binding protein immunoprecipitation assay and found that DDX3X directly interacted with NOTCH1 mRNA (Figure 2A, B). Dual-luciferase reporter assay showed enhanced activity of NOTCH1 5‘ UTR in DDX3X-KO cells (Figure 2C), further suggesting that DDX3X may regulate translation of NOTCH1 mRNA through binding to the 5‘ UTR. Finally, polysome profiling demonstrated that DDX3X knockout resulted in increased NOTCH1 mRNAs in polysome fractions (Figure 2D), confirming that loss of DDX3X function facilitates NOTCH1 mRNA translation. In conclusion, DDX3X abnormalities are common in CLL and associated with poor prognosis. DDX3X dysregulation is involved in the progression of CLL by facilitating NOTCH1 mRNA translation through binding to the 5' UTR.

Prognostic factors for pure ovarian immature teratoma and the role of adjuvant chemotherapy in stage I diseases

Background The prognostic factors for patients with pure ovarian immature teratoma (POIT) and the role of adjuvant chemotherapy in stage IA G2-G3 and IB-IC POIT remains controversial. Methods We conducted a retrospective study of 155 POIT patients treated in our hospital between 2000 and 2022. The recurrence-free survival (RFS), disease-specific survival (DSS), and potential prognostic factors of POIT patients were evaluated. Subgroup analysis was conducted in stage I other than stage IA G1 POIT. Results The median age at diagnosis was 23.0 years (range: 4.0 − 39.0), and 126 (81.3%), 2 (1.3%), 26 (16.8%), and 1 (0.6%) patients had FIGO stage I, stage II, stage III, and stage IV disease, respectively. Twenty-three patients relapsed and five died of the diseases after a median follow-up of 7.6 years, with a 5-year RFS and DSS rate of 86.0% and 97.0%, respectively. Multivariate analysis showed that positive postoperative tumour markers (TM) were the risk factor for recurrence in the overall cohort (hazard ratio [HR] 4.058, 95% CI 1.175 − 14.019, p = 0.027) and subgroup (HR 10.237, 95% CI 2.175 − 48.179, p = 0.003), and FIGO stage II–IV was the only factor for DSS in overall cohort (HR 7.751, 95% CI 1.281 − 46.895, p = 0.026). In 110 patients subjected to subgroup analysis, 29 patients received surveillance without chemotherapy and 81 patients were administered adjuvant chemotherapy. Multivariate analysis revealed active surveillance significantly increased the recurrence rate (5-year RFS of 75.7% vs. 93.6%, HR 7.562, 95% CI 2.441 − 23.424, p < 0.001) but not the death related to POIT (p = 0.338). Conclusion Positive postoperative TM and FIGO stage II–IV were the prognostic factors for POIT. Active surveillance in stage I POIT of any grade may be practical for those with negative postoperative TM.

Separating lymph node stations by the surgeon from the gastric cancer specimen improves the quality of nodal status evaluation

BackgroundIn gastric cancer (GC), the pN-stage is an important prognostic factor influencing treatment. Along with the depth of invasion of the tumor, the presence of nodal metastases is one of the most important prognostic factors guiding treatment strategies in gastric cancer. Examining a small number of lymph nodes may lead to understaging of the disease; hence, it is essential for the nodal status to be precisely assessed. In this study, we explored whether dissecting lymph node stations into separate samples by the surgeon from the gastric cancer surgical specimen affects the quality of nodal status evaluation and patient outcome.MethodsThe clinical data of 130 GC patients treated at the Helsinki University Hospital between 2016 and 2019 was reviewed. The performed operations included 59 total and 71 subtotal gastrectomies. The processing of the surgical specimen before the pathological examination was assessed from the operation records and pathology reports.The association of the number of examined lymph nodes with other variables was assessed, and multivariate survival analysis was performed to explore the independent prognostic factors in disease-specific survival.ResultsDissecting lymph node stations into separate specimens before pathological evaluation yielded a significantly greater number of examined lymph nodes compared with a specimen without intervention (median 34.5 vs 21.0, p < 0.001). The pT-stage, the pN-stage, and the extent of lymphadenectomy were identified as independent prognostic factors, whereas dissecting the specimen’s lymph node stations did not associate with survival.ConclusionsDissecting lymph node stations into separate specimens results in a greater number of examined lymph nodes, which has the potential to lead to a more reliable pN-stage assessment.

Cytokine-induced apoptosis inhibitor 1: a comprehensive analysis of potential diagnostic, prognosis, and immune biomarkers in invasive breast cancer.

Cytokine-induced apoptosis inhibitor 1 (CIAPIN1) is strictly associated with the incidence and progress of several malignant tumors, but its effect on invasive breast cancer (IBC) remains unclear. We directed to research the potential diagnostic and prognostic significance of CIAPIN1 in IBC. The Cancer Genome Atlas (TCGA) database and Tumor Immune Estimation Resource (TIMER) database were utilized to examine CIAPIN1 expression level in IBC and its relationship with clinicopathological features. The diagnostic value and prognostic importance of CIAPIN1 in IBC were assessed by Kaplan-Meier analysis, Cox regression analysis, receiver operating characteristic (ROC) curve and nomogram model. The STRING database and enrichment analysis were utilized to discover the interacting proteins, biological roles and possible cellular mechanisms related to CIAPIN1. The methylation status of CIAPIN1 was analyzed using MethSurv database and the University of Alabama at Birmingham Cancer Data Analysis Portal (UALCAN). By using Spearman correlation assessment, how the expression of CIAPIN1 was related to TP53, immune checkpoint genes and immune cell infiltration was determined. CIAPIN1 mRNA and protein levels were overexpressed in IBC, and significantly correlated with T stage, histological type, age, ER status, PR status and PAM50 (P<0.001). CIAPIN1 overexpression significantly decreased overall survival, distant metastasis free survival (DMFS) and relapse free survival in IBC patients (P<0.001). Similarly, hypermethylation of CIAPIN1 was associated with adverse outcomes in IBC patients. Multivariate Cox analysis identified CIAPIN1 as a potential risk factor for disease specific survival (DSS) and progression free survival (PFS) in individuals with IBC. The outcomes of the ROC curve showed that CIAPIN1 had a better accuracy in predicting ER(-), PR(-) and Asian breast cancer subtypes. Furthermore, there was a substantial correlation between the CIAPIN1 expression level in IBC and immune cell infiltration, TP53, and immune checkpoint genes. The high expression of CIAPIN1 in IBC is significantly related to the infiltration status of various tumor immune cells and the poor prognosis of IBC patients. According to this current study, CIAPIN1 is a promising diagnostic and prognostic marker for IBC.

Clinicopathological characteristics and survival outcomes in patients with angiosarcoma of breast.

Angiosarcoma of the breast is a rare malignancy. There are little data evaluating the survival and estimating the prognostic factors. The best surgical management and the role of systemic adjuvant therapy remain ill-defined. This study aimed to investigate the clinicopathological features, survival, and prognostic factors of breast angiosarcoma. The data on patients diagnosed with breast angiosarcoma were extracted from the Surveillance, Epidemiology, and End Results database (1975-2016). Univariate and multivariate Cox regression analyses were used to estimate the influential prognostic factors. The overall survival (OS) and disease-specific survival (DSS) of patients with breast angiosarcoma were evaluated. This study included 656 patients diagnosed with breast angiosarcoma between 1975 and 2016. The 5-year OS rate of all patients was 44.9% (95% CI 40.8-49.0). In both OS and DSS, Kaplan-Meier survival analyses revealed significant differences for both OS and DSS according to age, year at diagnosis, laterality, grade, and stage (all log-rank p < 0.05). Multivariate analysis suggested that lesions of the right breast, poor differentiation, and advanced stage were independent risk factors for OS or DSS (all p < 0.05). Older age was a risk factor in OS, but was protective in DSS. In primary breast angiosarcoma, age, laterality, grade, and stage were independent prognostic factors in OS and DSS (all p < 0.05). Mastectomy was also a risk factor in DSS (p = 0.034). The proportion of patients with grade III and regional disease was larger in the mastectomy group. Angiosarcoma of the breast had a poor prognosis. In our study, age, laterality, histologic grade, and stage were identified as significant prognostic factors. Why patients with angiosarcoma of the right breast had a worse prognosis remains equivocal. Mastectomy was adopted more often by surgeons in this cohort study for patients with advanced primary breast angiosarcoma.

Cell cycle regulatory markers as potential prognostic biomarkers in uterine carcinosarcoma

The relevance of cell cycle regulatory markers with uterine carcinosarcoma was investigated. The immunohistochemical expression of p16, p53, and cyclin D1 were assessed using tissue microarray of 55 eligible patients. p16 and p53 showed a high rate of strong (+3) immune reaction in carcinomatous/sarcomatous components (61.8%/70.9% and 52.7%/56.4%, respectively). Cyclin D1 showed a 14.5%/7.3%of strong immune reaction in the carcinomatous/sarcomatous components. Strong expression of p16 was related to a higher rate of recurrence, lymph node metastasis, and bigger tumor size. Strong expression of cyclin D1 was related to the lower International Federation of Gynecology and Obstetrics (FIGO) stage and recurrence rate. In univariate regression analysis, FIGO stage, lymph node metastasis, p16, and cyclin D1 were prognostic factors for disease-free survival. FIGO stage, p16, p53, and cyclin D1 were prognostic factors for disease specific survival. In a multivariate regression analysis, FIGO stage and p16 in carcinomatous component were independent factors for disease-free survival (odds ratio (OR), 95% confidence interval (CI); 3.2 (1.1–9.6) and 3.5 (1.3–9.7); p = 0.035 and 0.017). p16 was a predictor of lymph node metastasis, tumor size, and prognostic outcome in uterine carcinosarcoma.

MTHFD2 is a potential oncogene for its strong association with poor prognosis and high level of immune infiltrates in urothelial carcinomas of bladder

BackgroundThe bifunctional methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 2, methenyltetrahydrofolate cyclohydrolase (MTHFD2) has been reported to play an oncogenic role in various types of cancers. However, the function of MTHFD2 in urothelial carcinomas of bladder (UCB) and its association with tumor immune infiltration remains unknown. We aim to examine the suitability of MTHFD2 to be a novel biomarker of bladder cancer and whether MTHFD2 is linked to immune infiltration.MethodsRNA sequencing data and clinical information (bladder cancer samples: normal samples = 414: 19) were downloaded from The Cancer Genome Atlas official website. Western blot analysis was performed to detect MTHFD2 expression in human bladder cancer (BLCA) cells and normal urothelial cell line SV-HUC-1. Associations between MTHFD2 expression and clinicopathological features were analyzed using Mann Whitney U test or Kruskal-Wallis H test. The “survival” and “survminer” packages were utilized to plot Kaplan-Meier survival curves. Moreover, the gene set enrichment analysis (GSEA) was conducted using a clusterProfiler package. The correlation of MTHFD2 expression with immune infiltration level was estimated using the single sample GSEA (ssGSEA) algorithm. Furthermore, associations between MTHFD2 and immune checkpoint genes were evaluated using the correlation analysis.ResultsTranscriptome analysis manifested that MTHFD2 was highly expressed in UCB tissues than normal bladder tissues, which was further confirmed by western blot analysis in human BLCA cells and SV-HUC-1 cells. Moreover, MTHFD2 high expression was significantly associated with the advanced disease progression. Also, the high expression of MTHFD2 was correlated with poor prognosis, and MTHFD2 was considered as an independent prognostic factor for disease specific survival. Furthermore, a number of cancer-related pathways were enriched in MTHFD2 high group, including NF-κB activation, JAK/STAT, and cancer immunotherapy by PD1 blockade. Several immune checkpoint molecules were also strongly associated with MTHFD2 expression, including PDCD1, CD274, CTLA4, CD276, LAG3, HAVCR2, and TIGIT.ConclusionsMTHFD2 expression was remarkably elevated in UCB, suggesting that MTHFD2 could be a promising biomarker for BLCA as well as novel target for anti-cancer immunotherapy since its close association with immune infiltration.

The Impact of a Preoperative Staging System on Accurate Prediction of Prognosis in Intrahepatic Cholangiocarcinoma.

Simple SummaryNon-invasive biomarkers detected preoperatively are still inadequate for treatment decision making for patients with intrahepatic cholangiocarcinoma (ICC). In this study, we analyzed preoperative findings to establish a novel preoperative staging system (PRE-Stage) for patients with ICC. A newly invented PRE-Stage was developed using a CRP–albumin–lymphocyte index < 3, central tumor location, and CA19-9 level > 40 U/mL, and it was able to significantly predict DSS and DFS when the patients were stratified into four stages (p < 0.05). The PRE-Stage demonstrated similar accuracy in predicting the prognosis of ICC as that of the Liver Cancer Study Group of Japan stage, which is based on postoperative findings. The PRE-Stage may contribute to appropriate treatment decision making.Background: Non-invasive biomarkers detected preoperatively are still inadequate for treatment decision making for patients with intrahepatic cholangiocarcinoma (ICC). In this study, we analyzed preoperative findings to establish a novel preoperative staging system (PRE-Stage) for patients with ICC. Methods: The clinical data of 227 consecutive patients with histologically confirmed ICC following hepatectomy at five university hospitals were analyzed. Results: Cox proportional hazards regression analysis of survival revealed that a CRP–albumin–lymphocyte index < 3, central tumor location, and CA19-9 level > 40 U/mL were prognostic factors among the preoperatively obtained clinical findings (hazard ratios (HRs) of all three factors for disease-specific survival (DSS) and disease-free survival (DFS: 2.4–3.3 and 1.7–2.9; all p < 0.05). The PRE-Stage was developed using these three prognostic factors, and it was able to significantly predict DSS and DFS when the patients were stratified into four stages (p < 0.05). In addition, the PRE-Stage resulted in similar HRs as those of the Liver Cancer Study Group of Japan (LCSGJ) stage (HRs for DSS: PRE-Stage, 1.985; LCSGJ stage, 1.923; HRs for DFS: LCSGJ stage, 1.909, and PRE-Stage, 1.623, all p < 0.05). Conclusion: The PRE-Stage demonstrated similar accuracy in predicting the prognosis of ICC as that of the LCSGJ stage, which is based on postoperative findings. The PRE-Stage may contribute to appropriate treatment decision making.

Pancreatic fibrosis, acinar atrophy and chronic inflammation in surgical specimens associated with survival in patients with resectable pancreatic ductal adenocarcinoma

BackgroundPancreatic ductal adenocarcinoma (PDAC), one of the most lethal malignancies, is increasing in incidence. However, the stromal reaction pathophysiology and its role in PDAC development remain unknown. We, therefore, investigated the potential role of histological chronic pancreatitis findings and chronic inflammation on surgical PDAC specimens and disease-specific survival (DSS).MethodsBetween 2000 and 2016, we retrospectively enrolled 236 PDAC patients treated with curative-intent pancreatic surgery at Helsinki University Hospital. All pancreatic transection margin slides were re-reviewed and histological findings were evaluated applying international guidelines.ResultsDSS among patients with no fibrosis, acinar atrophy or chronic inflammation identified on pathology slides was significantly better than DSS among patients with fibrosis, acinar atrophy and chronic inflammation [median survival: 41.8 months, 95% confidence interval (CI) 26.0–57.6 vs. 20.6 months, 95% CI 10.3–30.9; log-rank test p = 0.001]. Multivariate analysis revealed that Ca 19–9 > 37 kU/l [hazard ratio (HR) 1.48, 95% CI 1.02–2.16], lymph node metastases N1–2 (HR 1.71, 95% CI 1.16–2.52), tumor size > 30 mm (HR 1.47, 95% CI 1.04–2.08), the combined effect of fibrosis and acinar atrophy (HR 1.91, 95% CI 1.27–2.88) and the combined effect of fibrosis, acinar atrophy and chronic inflammation (HR 1.63, 95% CI 1.03–2.58) independently served as unfavorable prognostic factors for DSS. However, we observed no significant associations between tumor size (> 30 mm) and the degree of perilobular fibrosis (p = 0.655), intralobular fibrosis (p = 0.587), acinar atrophy (p = 0.584) or chronic inflammation (p = 0.453).ConclusionsOur results indicate that the pancreatic stroma is associated with PDAC patients’ DSS. Additionally, the more severe the fibrosis, acinar atrophy and chronic inflammation, the worse the impact on DSS, thereby warranting further studies investigating stroma-targeted therapies.

Disease-Specific Survival of AJCC 8th Stage II Gastric Cancer Patients After D2 Gastrectomy.

The association between the risk factors and long-term prognosis in patients with stage II gastric cancer after radical gastrectomy has been fully revealed. The purpose of this study was to investigate the independent risk factors for treatment failure in stage II gastric cancer. Demographic, clinical, and pathological information of 247 stage II gastric cancer patients who underwent radical D2 gastrectomy in our department between January 2011 and December 2014 were collected and retrospectively analyzed. The relationship between and long-term clinical outcomes of stage II gastric cancer was analyzed using t-tests, chi-square tests, receiver operating characteristic (ROC) analysis, time-dependent ROC analysis, K–M curves, and a Cox regression model. The median follow-up of 247 stage II gastric cancer patients was 5.49 years (range: 0.12–8.62 years). The Kaplan–Meier estimated 3-year and 5-year DSS rates of the study group were 92.7% (95% CI 89.4–95.9) and 88.7% (95% CI 84.7–92.7), respectively. Higher age (>70 vs. ≤70, log-rank p = 0.0406), nerve invasion (positive vs. negative, log-rank p = 0.0133), and non-distal gastrectomy (distal partial gastrectomy vs. other surgical methods, log-rank p = 0.00235) had worse prognoses compared to controls. Univariate and multivariate analyses of disease-specific survival showed that these three factors were independent prognostic factors for patients with stage II disease. The area under time-dependent ROC curve (AUC) is 0.748 of 5-year survival and c-index is 0.696 based on the three-marker model drawn for stage II patients. Subgroup analyses showed an interaction between tumor location and nerve invasion. The age, perineural invasion, and surgical approach are independent prognostic factors for disease-specific survival after radical gastrectomy. Tumor location may be an important confounding factor for outcomes by affecting surgical methods and the hazards of nerve invasion.

Avidity and Outcomes of Radioiodine Therapy for Distant Metastasis of Distinct Types of Differentiated Thyroid Cancer.

The recommendations for radioactive-iodine treatment (RAIT) in metastatic differentiated thyroid cancer (DTC) are mostly based in the experience with papillary histotype and do not consider the differences within the distinct types of DTC, in terms of RAIT uptake and response. This work aims to investigate the association between histology and RAIT avidity and response, and to evaluate whether histotype was an independent prognostic factor in progression-free survival (PFS) and disease-specific survival (DSS) after RAIT for distant metastatic disease. A retrospective analysis was conducted of all DTC patients who underwent RAIT for distant metastatic disease, from 2001 to 2018, at a thyroid cancer referral center. We included 126 patients: 42 (33.3%) classical variant papillary thyroid cancer (cvPTC), 45 (35.7%) follicular variant PTC (fvPTC), 17 (13.5%) follicular thyroid cancer (FTC) and 22 (17.5%) Hürthle cell carcinoma. Main outcome measures included RAIT avidity and response. RAIT avidity was independently associated with histology (P < .001) and stimulated thyroglobulin (Tg) at first RAIT for distant lesions (P = .007). Avidity was lowest in HCC (13.6%), intermediate in cvPTC (21.4%), and highest in fvPTC (75.6%) and FTC (76.5%). Regarding RAIT response, HCC and FTC were not different; both showed significantly more often progression after RAIT than fvPTC and cvPTC. Histology influenced PFS (P = .014), but tumor type was not a significant prognostic factor in DSS. Instead, age at diagnosis, resection status, and stimulated Tg at the first RAIT were significantly associated with DSS. DTC histotype influenced RAIT avidity and PFS. It is crucial to better detect the metastatic patients that may benefit the most from RAIT.

Intraoperative molecular imaging clinical trials: a review of 2020 conference proceedings.

.Significance: Surgery is often paramount in the management of many solid organ malignancies because optimal resection is a major factor in disease-specific survival. Cancer surgery has multiple challenges including localizing small lesions, ensuring negative surgical margins around a tumor, adequately staging patients by discriminating positive lymph nodes, and identifying potential synchronous cancers. Intraoperative molecular imaging (IMI) is an emerging potential tool proposed to address these issues. IMI is the process of injecting patients with fluorescent-targeted contrast agents that highlight cancer cells prior to surgery. Over the last 5 to 7 years, enormous progress has been achieved in tracer development, near-infrared camera approvals, and clinical trials. Therefore, a second biennial conference was organized at the University of Pennsylvania to gather surgical oncologists, scientists, and experts to discuss new investigative findings in the field. Our review summarizes the discussions from the conference and highlights findings in various clinical and scientific trials.Aim: Recent advances in IMI were presented, and the importance of each clinical trial for surgical oncology was critically assessed. A major focus was to elaborate on the clinical endpoints that were being utilized in IMI trials to advance the respective surgical subspecialties.Approach: Principal investigators presenting at the Perelman School of Medicine Abramson Cancer Center’s second clinical trials update on IMI were selected to discuss their clinical trials and endpoints.Results: Multiple phase III, II, and I trials were discussed during the conference. Since the approval of 5-ALA for commercial use in neurosurgical malignancies, multiple tracers and devices have been developed to address common challenges faced by cancer surgeons across numerous specialties. Discussants also presented tracers that are being developed for delineation of normal anatomic structures that can serve as an adjunct during surgical procedures.Conclusions: IMI is increasingly being recognized as an improvement to standard oncologic surgical resections and will likely advance the art of cancer surgery in the coming years. The endpoints in each individual surgical subspecialty are varied depending on how IMI helps each specialty solve their clinical challenges.

Strap muscle invasion in differentiated thyroid cancer does not impact disease-specific survival: a population-based study

The American Joint Committee on Cancer (AJCC) 8th TNM staging system of differentiated thyroid cancer defines gross strap muscle invasion as T3b stage. However, the impact of strap muscle invasion on disease-specific survival (DSS) remains controversial. To elucidate the survival impact of strap muscle invasion of any degree in thyroid cancers, the Surveillance, Epidemiology, and End Results (SEER) database (1973–2018) was queried for thyroid cancer only patients on July 2019 (n = 19,914). The Cox proportional hazard analysis with multivariable adjustment revealed that strap muscle invasion was not a significant factor for DSS in tumors equal to or smaller than 40 mm (hazard ratio (HR) = 1.620 [confidence interval (CI) 0.917 – 2.860]; p = 0.097). The competing risk analysis with multivariable adjustment showed that strap muscle invasion did not significantly impact DSS regardless of tumor size or cause of death (cancer-caused death (Subdistribution HR (SDHR) = 1.567 [CI 0.984 – 2.495]; p = 0.059); deaths to other causes (SDHR = 1.155 [CI 0.842 – 1.585]; p = 0.370). A “modified” staging schema discarding strap muscle invasion as a T stage criterion showed better 10-year DSS distinction between T stages. The modified staging schema may better reflect cancer-caused death risk and may prevent potential overstaging.

Prognostic factors of metastatic myxoid liposarcoma

BackgroundMyxoid liposarcoma (MLS) has the tendency to metastasize extrapulmonary. Although prognostic factors at the initial diagnosis of MLS have been reported, those at diagnosis of metastasis remain unclear. The purpose of this study was to investigate the prognostic factors for disease-specific survival at the initial diagnosis of metastasis.MethodsThis retrospective observational study was conducted at three cancer centers and two university hospitals in Japan. Of 274 MLS patients pathologically diagnosed between 2001 and 2015, 48 metastatic patients were examined.ResultsLung metastases were detected in nine patients (18.8%) and extrapulmonary metastases in 45 (93.8%). Interval from primary diagnosis to the first metastasis was significantly shorter in patients with lung metastases than without (p = 0.007). Median disease-specific survival after diagnosis of metastases was 52.5 months in all patients. In multivariable analysis, liver metastasis (hazard ratio (HR), 2.71 [95% confidence interval (CI), 1.00–7.09]) and no evidence of disease (NED) achieved by radical treatment (resection with or without radiation therapy, or radiation therapy ≥60 Gy) or semi-radical (radiation therapy ≥40 Gy) treatment were significantly related to survival (HR, 0.36; 95%CI [0.13–0.95]). The number of metastases (odds ratio (OR), 0.44; 95%CI [0.25–0.78]) and abdominal/retroperitoneal metastases (OR, 0.09; 95%CI [0.008–0.95]) were the significant inhibitory factors of achieving NED.ConclusionsThis is the first study to statistically demonstrate the importance of achieving NED with surgical resection or radiation therapy for longer survival in metastatic MLS patients. As number of metastases was a significant factor for achieving NED, early detection of metastases might be important.

The role of adjuvant radiotherapy in patients with malignant phyllodes tumor of the breast: a propensity-score matching analysis

Background and objectivesMalignant phyllodes tumor of the breast (MPTB) is a kind of rare tumor. Our objective was to investigate the role of adjuvant radiotherapy (RT) in MPTB patients.MethodsMPTB patients were identified in the Surveillance, Epidemiology and End Results (SEER) database. Kaplan–Meier curves and multivariable Cox proportional hazards analyses were conducted to determine the effect of adjuvant RT on MPTB patients. Propensity-score matching (PSM) method was used to balance the clinicopathological characteristics.ResultsA total of 1353 MPTB patients were included in our study and the median follow-up time was 99 months (range: 0–331 months). 16.7% (226) MPTB patients received adjuvant RT, of which 49.1% (111) received mastectomy and 50.9% (115) underwent breast conservation surgery (BCS). Patients receiving adjuvant RT were more likely to be white, with better differentiation and larger tumors (p < 0.05). Multivariate analysis showed that poorer tumor differentiation grade, larger tumor size, and lymph node metastasis were associated with reduced survival while BCS was a protective factor of disease-specific survival (DSS) (HR 0.297; 95% CI 0.184–0.480) and overall survival (OS) (HR 0.445; 95% CI 0.321–0.616). After PSM, survival curves showed patients did not achieve an improved OS or DSS from adjuvant RT (p > 0.05). In subgroup analysis, no subgroup benefited from adjuvant RT. Exploratory analysis showed a survival benefit trend from adjuvant RT in patients with tumor larger than 50 mm and undergoing BCS.ConclusionsAmong MPTB patients, adjuvant RT did not improve OS or DSS. In patients with tumor larger than 50 mm and receiving BCS, a survival benefit trend from adjuvant RT existed.

High tumor budding is a strong predictor of poor prognosis in the resected perihilar cholangiocarcinoma patients regardless of neoadjuvant therapy, showing survival similar to those without resection

BackgroundTumor budding (TB) is used as an indicator of poor prognosis in various cancers. However, studies on TB in perihilar cholangiocarcinoma are still limited. We examined the significance of TB in resected perihilar cholangiocarcinoma with or without neoadjuvant therapy.MethodsSeventy-eight patients who underwent surgical resection at our institution for perihilar cholangiocarcinoma from 2004 to 2017, (36 with neoadjuvant therapy), were enrolled in this study. TB was defined as an isolated cancer cell or clusters (< 5 cells) at the invasive front and the number of TB was counted using a 20 times objective lens. Patients were classified into two groups according to TB counts: low TB (TB < 5) and high TB (TB ≥5).ResultsIn this 78 patient cohort, high TB was significantly associated with advanced tumor status (pT4: 50.0% vs 22.2%, p = 0.007, pN1/2: 70.8% vs 39.6%, p = 0.011, M1: 20.8% vs 1.9%) and higher histological grade (G3: 25.0% vs 5.7%, p = 0.014). Disease specific survival (DSS) in high TB was significantly inferior compared to that in low TB group (3-y DSS 14.5% vs 67.7%, p < 0.001). Interestingly, DSS in high TB showed similar to survival in unresected patients. In addition, high TB was also associated with advanced tumor status and poor prognosis in patients with neoadjuvant therapy. Multivariate analysis identified high TB as an independent poor prognostic factors for DSS (HR: 5.206, p = 0.001).ConclusionThis study demonstrated that high TB was strongly associated with advanced tumor status and poor prognosis in resected perihilar cholangiocarcinoma patients. High TB can be a novel poor prognostic factor in resected perihilar cholangiocarcinoma regardless of neoadjuvant therapy.

Prognostic value of risk stratification using blood biochemical parameters in Japanese patients with metastatic renal cell carcinoma treated by nivolumab.

724 Background: Nivolumab is a standard treatment for previously treated advanced renal-cell carcinoma (RCC). However, nivolumab is effective in only a limited number of patients; therefore, we evaluated the prognostic value of several biomarkers, including inflammation-based prognostic scores and changes in these scores following nivolumab treatment in Japanese patients with metastatic RCC. Methods: We retrospectively reviewed the medical records of 65 patients with previously treated metastatic RCC and who received nivolumab. MSKCC and IMDC risk, inflammation-based prognostic scores, including neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), lymphocyte/monocyte ratio (LMR), and Glasgow prognostic score before and 6 weeks after the treatment were recorded. Categorical variables influencing disease-specific and overall survival were compared using Cox proportional-hazards regression models. Results: Univariate analysis showed that MSKCC risk score ( P = 0.0052), lactate dehydrogenase (LDH) ( P = 0.0266), LMR ( P = 0.0113), and PLR ( P = 0.0017) had a significant effect on disease-specific survival. Multivariate analyses showed that PLR and LDH were found to be independent prognostic factors for disease-specific survival ( P = 0.0008, RR = 7.95, 95% CI, 2.16–51.64 and P = 0.0123, RR = 3.92, 95% CI, 1.37–10.80, respectively). The combination of PLR and LDH was the most significant prognostic biomarker in metastatic RCC for disease-specific ( P &lt; 0.0001) and overall ( P &lt; 0.0001) survival. Changes in LMR and PLR in response to nivolumab were significant prognostic factors for disease-specific survival ( P &lt; 0.0001 and P = 0.0477, respectively). Conclusions: The combination of PLR and LDH may be a potential biomarker for estimating disease-specific and overall survival in Japanese patients with metastatic RCC treated by nivolumab. If changes of inflammation-based prognostic scores in response to nivolumab treatment might be improved, nivolumab treatment should be continued.

Expression of Pregnancy Up-regulated Non-ubiquitous Calmodulin Kinase (PNCK) in Hepatocellular Carcinoma.

Pregnancy up-regulated non-ubiquitous calmodulin kinase (PNCK) is a member of calmodulin kinase, and overexpression of PNCK with involvement in carcinogenesis have been reported in HER-2 amplified breast cancer, clear cell renal cell carcinoma and nasopharygeal carcinoma. However, the expression of PNCK and its clinical implication have not been elucidated in hepatocellular carcinoma (HCC). We investigated PNCK expression at both the protein and mRNA level using immunohistochemistry (IHC) and microarray gene expression profiling in HCC tissue samples, and evaluated its association with clinicopathological parameters and their potential prognostic significance. High PNCK protein expression and high PNCK mRNA level was observed in 61.7% and 34.7% of total HCC cases, respectively. PNCK mRNA level was higher in tumor tissues than in background non-tumor tissues, and significantly correlated with protein expression by IHC. High PNCK expression was associated with higher Edmondson grade, intrahepatic metastasis, microvascular invasion and higher AFP levels. Patients with high PNCK expression showed shorter recurrence-free survival and disease-specific survival, and high mRNA expression of PNCK was an independent prognostic factor in disease-specific survival. Up-regulation of PNCK expression as well as its association with poor prognosis was demonstrated in HCC. PNCK might be a prognostic biomarker of HCC, and could be a potential candidate therapeutic target.

Retrospective analysis of seven cases of pancreatic mixed adenoneuroendocrine carcinoma from a high-volume center and review of the literature

BackgroundsThe clinicopathologic features and biological behaviors of pancreatic mixed adenoneuroendocrine carcinoma (pMANEC) and its impacts on survival are poorly known.MethodsWe retrospectively reviewed seven pMANEC cases from a single institution from September 2010 to January 2017 along with twenty-one previously reported cases from the literature. Survival and prognostic analyses were conducted using Kaplan-Meier estimates and Cox regression, respectively.ResultsSeven pMANEC cases were identified during the study interval. Among the six patients who underwent operations, five reached R0 resections, one experienced postoperative pancreatic fistula, and two suffered other complications. The median progression-free survival (PFS) and disease-specific survival (DSS) were 7.5 months (2 to 36 months) and 15 months (6 to 36 months), respectively. A total analysis of twenty-eight pMANEC cases showed that patients were mostly older (median age, 59.5 years) and male (64.3%). The two most common symptoms were abdominal pain (53.6%) and obstructive jaundice (35.7%). The majority of pMANECs were non-functional (89.3%) and located in the pancreatic head (64.3%). The median diameter of pMANEC was 3.0 cm, with a wide range (0.5 to 19.0 cm). Lymph node metastasis (P = 0.015) was associated with decreased DSS, while age (P = 0.414), sex (P = 0.125), tumor size (P = 0.392), location (P = 0.913), functional status (P = 0.313), CA19–9 level (P = 0.608), and liver metastasis (P = 0.935) did not show significant prognoses on DSS.ConclusionsWe reported seven pMANEC cases and outlined their clinical behaviors and prognoses with a review of twenty-one cases from the literature. Lymph node metastasis was found to be a negative prognostic factor of DSS based on the present study.

Prognostic Nomogram for Disease-Specific Survival in Patients with Non-metastatic Ampullary Carcinoma After Surgery

ObjectiveThe aim of this study was to establish and validate an individualized nomogram for predicting disease-specific survival (DSS) in patients with non-metastatic ampullary carcinoma after surgery.MethodsThe nomogram was prepared using retrospective data from the Surveillance, Epidemiology, and End Results database, and included 2022 patients (training dataset: 1276; validation dataset: 746 patients) with non-metastatic ampullary carcinoma who were surgically treated between 2004 and 2014. Cox multivariate regression was performed to identify independent risk factors. The predictive accuracy was determined using the concordance index (C-index) and calibration curves. Results were validated internally using bootstrap resampling, and externally against the validation dataset.ResultsThe median follow-up for the training dataset was 25.5 months (range 1–143), the median survival time was 52 months [95% confidence interval (CI) 41.67–62.33], and the postoperative 1-, 3-, and 5-year DSS rates were 86.7%, 57.3%, and 47.2%, respectively. Univariate and multivariate regression analysis demonstrated that age, grade, tumor size, lymph node ratio, extension range, and histology were independent risk factors for DSS. The C-index of the internal validation dataset for predicting DSS was 0.70 (95% CI 0.68–0.72), which was superior to that of the American Joint Committee on Cancer staging, i.e. 0.64 (95% CI 0.62–0.66; p < 0.001). The 5-year DSS and median DSS time for the low-risk group were significantly greater than those for the high-risk group (p < 0.001).ConclusionOur nomogram reliably and accurately predicted DSS in patients with non-metastatic ampullary carcinoma after surgery. This model may help clinicians in their decision making.