Clinical features of patients with carcinoma soft tissue metastases as surgical indications: a retrospective cohort study.

BACKGROUND: Soft-tissue metastasis of carcinoma is rare. In the present study, we investigated the surgical indications and clinical features of patients with soft tissue metastases of carcinoma. METHODS: In this retrospective cohort study, we enrolled 26 patients with soft tissue carcinoma metastasis referred to our department for treatment. Sex, age, location, size, depth, pain due to the tumor, primary origin, serum C-reactive protein (CRP) level, MRI examinations, diagnosis by a previous physician, carcinoma markers from blood, history of carcinoma, other metastases, performance status (PS), and surgical procedures were documented. Associations between variables and surgery were statistically analyzed. RESULTS: The primary cancer origin was found to be the lung (n = 10), kidney (n = 7), esophagus (n = 2), stomach (n = 1), breast (n = 1), liver (n = 1), ureter (n = 1), anus (n = 1), and unknown (n = 2). The mean CRP level of all patients was 2.3 mg/dL. Seven tumors (26.9%) were originally suspected to be soft tissue metastases of carcinoma, while 19 tumors (73.1%) were considered soft tissue sarcomas or inflammatory lesions by the previous treating physician. Twenty patients (76.9%) had other metastases. The PS of the 12 patients (46.2%) was zero. Eleven patients (42.3%) underwent surgery for soft tissue metastases. Diagnosis of soft tissue metastasis by a previous physician and good PS (p < 0.05) were significantly associated with surgery. CONCLUSION: Overall, the present results show that surgical indications for soft tissue metastasis of carcinoma include diagnosis by the referring physician or good PS of the patients.

The plasma EBV DNA load with IL-6 and VEGF levels as predictive and prognostic biomarker in nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is often diagnosed at a very advanced stage due to its location and non-specific initial symptoms. Moreover, no clinically useful serological marker has been established so far for early detection of NPC. In this study, we have investigated the clinical significance of plasma Epstein-Barr virus DNA load along with interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF) levels to evaluate if these three all together can be useful as a strong serological marker for early detection and prediction of treatment response in patients with NPC. Plasma EBV DNA load, IL-6 level, VEGF expressions were measured in 24 patients with NPC at presentation and various time points during and after treatment. There was a positive correlation between high plasma EBV DNA load with higher IL-6 and VEGF expression, which was closely associated with therapeutic response as well. Persistent or recurrent plasma EBV load with higher IL-6 and VEGF levels can potentially predict disease progression and may be useful to select patients for additional therapy and longer follow-up.

Circulating Polyploid Giant Cancer Cells, a Potential Prognostic Marker in Patients with Carcinoma.

Polyploid Giant Cancer Cells (PGCCs) have been recognized as tumor cells that are resistant to anticancer therapies. However, it remains unclear whether their presence in the bloodstream can be consistently detected and utilized as a clinical marker to guide therapeutic anticancer regimens. To address these questions, we conducted a retrospective study involving 228 patients diagnosed with six different types of carcinomas (colon, gastric, NSCLC, breast, anal canal, kidney), with the majority of them (70%) being non-metastatic. Employing a highly sensitive liquid biopsy approach, ISET®, and cytopathological readout, we isolated and detected circulating PGCCs in the patients' blood samples. PGCCs were identified in 46 (20.18%) out of 228 patients, including in 14.47% of 152 non-metastatic and 29.85% of 67 metastatic cases. Patients were subsequently monitored for a mean follow up period of 44.74 months (95%CI: 33.39-55.79 months). Remarkably, the presence of circulating PGCCs emerged as a statistically significant indicator of poor overall survival. Our findings suggest that circulating PGCCs hold promise as a reliable prognostic indicator. They underscore the importance of further extensive investigations into the role of circulating PGCCs as a prognostic marker and the development of anti-PGCC therapeutic strategies to improve cancer management and patient survival.

Tumour markers with clinically controlled cut-offs for suspected cancer.

BACKGROUND: Due to insufficient scientific evidence, panels of tumour markers (TMs) are currently not recommended for use in suspected cancer. However, recent well-designed studies have revealed a potential clinical value in lung cancer. We analysed the diagnostic accuracy of a panel of 11 circulating TMs with clinically controlled thresholds in the differentiation of cancer from nonmalignant diseases. METHODS: We prospectively recruited 4776 consecutive patients presenting with focal or nonspecific symptoms suggestive of cancer who underwent testing for 11 serum TMs before diagnosis was known. The study abided by 2015 STARD guidelines. Tumour markers included, among others, carbohydrate antigen 19-9, carcinoembryonic antigen, alpha-fetoprotein, squamous cell carcinoma-associated antigen, prostate-specific antigen (males), neuron-specific enolase, progastrin-releasing peptide and carbohydrate antigen 125. Thresholds were adjusted for the presence of kidney failure, liver disease, effusions and dermatological disorders. Results showing ≥1 TMs with concentrations above threshold were considered positive. RESULTS: Benign diseases were diagnosed in 3281 (68.7%) patients and cancer in 1495 (31.3%), with epithelial cancers in 1214 (77% at stage IV). When applying criteria for controlled thresholds, overall specificity was 98%. Overall sensitivity of the panel in epithelial cancers was 72.2%, positive predictive value 93% and negative predictive value 90.5%. The area under the receiver operating characteristic curve was 0.920 (95% confidence interval, 0.902-0.924). CONCLUSIONS: By using clinically controlled cut-offs, the combined panel demonstrated an excellent ability to discriminate epithelial cancers from nonmalignant diseases. However, its use in clinical practice would need formal validation through a multicentre controlled trial assessing a panel-guided strategy vs. standard diagnosis.

Assessment of retroperitoneal lymph node status in locally advanced cervical cancer.

BACKGROUND: The assessment of retroperitoneal lymph node status in patients with locally advanced cervical cancer is still a problem. This study aimed to explore the choice of these assessment methods. METHODS: Laparoscopic retroperitoneal lymphadenectomy was performed in 96 patients with advanced cervical cancer. The positive rates of lymph node metastasis were analyzed. The values of computed tomography lymph node minimum axial diameter (MAD) and squamous cell carcinoma antigen (SCC-Ag), and their combination in predicting retroperitoneal lymph node metastasis were compared. High-risk factors for common iliac lymph node (CILN) and/or para-aortic lymph node (PALN) metastasis were analyzed. RESULTS: The lymph node metastasis rate was 62.50% and the CILN and/or PALN metastasis rate was 31.25%. Overall, 96 patients had 172 visible lymph nodes. The positive rate of lymph node metastasis was significantly higher in the MAD ≥1.0 cm group (83.33%) than in the 0.5 cm ≤ MAD < 1.0 cm group (26.82%). The critical values of MAD and SCC-Ag in determining lymph node metastasis were 1.0 cm and 5.2 ng/mL, respectively. The accuracy, specificity, and Youden index of MAD ≥1.0 cm combined with SCC-Ag ≥ 5.2 ng/mL for evaluating lymph node metastasis were 75.71%, 100%, and 0.59, respectively, and were significantly different from the values for the MAD ≥1.0 cm (72.09%, 80.56%, and 0.47, respectively) and SCC-Ag ≥ 5.2 ng/mL (71.43%, 68.97%, and 0.42, respectively) groups. Correlation analysis showed that non-squamous cell carcinoma, pelvic lymph node (PLN) MAD ≥1.0 cm plus number ≥ 2, and 1 PLN MAD ≥1.0 cm with CILN and/or PALN MAD 0.5-1.0 cm were risk factors for CILN and/or PALN metastasis. CONCLUSION: Patients with MAD ≥1.0 cm and SCC-Ag ≥ 5.2 ng/mL, as well as high risk factors for CILN and/or PALN metastasis, should undergo resection of enlarged lymph nodes below the common iliac gland and lymphadenectomy of CILN/PALN to reduce tumor burden and to clarify lymph node metastasis status for accurate guidance in follow-up treatment. Patients with MAD < 1.0 cm and SCC-Ag < 5.2 ng/mL may be treated with chemoradiotherapy directly based on imaging, given the low lymph node metastasis rate.

Global profile of tRNA-derived small RNAs in gastric cancer patient plasma and identification of tRF-33-P4R8YP9LON4VDP as a new tumor suppressor.

Transfer RNA (tRNA)-derived small RNAs (tsRNAs) have been found to play important roles in the occurrence and development of cancers. However, the tsRNA profile in gastric cancer is unknown. In this study, we aimed to identify the global tsRNA profile in plasma from gastric cancer patients and elucidate the role of tRF-33-P4R8YP9LON4VDP in gastric cancer. Differentially expressed tsRNAs in the plasma of gastric cancer patients and healthy controls were investigated using RNA sequencing. The expression levels of tRF-33-P4R8YP9LON4VDP in the plasma of gastric cancer patients, healthy controls and gastric cancer cell lines were first detected by quantitative reverse transcription-polymerase chain reaction. The effects of tRF-33-P4R8YP9LON4VDP overexpression or downregulation in gastric cancer cells on proliferation, migration, apoptosis, and cell cycle were analyzed using the Cell Counting Kit-8, scratch assay, Transwell assay, and flow cytometry, respectively. There were 21 upregulated and 46 downregulated tsRNAs found in plasma from gastric cancer patients. The significantly upregulated tsRNAs included tRF-18-S3M83004, tRF-31-PNR8YP9LON4VD, tRF-19-3L7L73JD, tRF-33-P4R8YP9LON4VDP, tRF-31-PER8YP9LON4VD, tRF-18-MBQ4NKDJ, and tRF-31-PIR8YP9LON4VD. The significantly downregulated tsRNAs included tRF-41-YDLBRY73W0K5KKOVD, tRF-18-07QSNHD2, tRF-28-86J8WPMN1E0J, tRF-29-86V8WPMN1EJ3, tRF-31-6978WPRLXN4VE, tRF-30-MIF91SS2P46I, tRF-26-MI7O3B1NR8E, tRF-30-RRJ89O9NF5W8, tRF-26-XIP2801MK8E, and tRF-35-V0J8O9YEKPRS93, In vitro studies showed that tRF-33-P4R8YP9LON4VDP inhibited proliferation of gastric cancer cells. In conclusion, tsRNAs such as tRF-33-P4R8YP9LON4VDP could serve as a novel diagnostic biomarker and target for gastric cancer therapeutics.

Potential contrasting effects of platelets on the migration and invasion of sarcomas versus carcinomas.

The ability of platelets to promote carcinoma and melanoma progression has been thoroughly studied and occurs in numerous ways. In contrast, the effect of platelets on sarcomas, tumors arising from mesenchymal cells, has received very little attention. This study was undertaken to simultaneously compare the effects of platelets on murine and human sarcomas and carcinomas. In contrast to their effect on carcinomas, platelets inhibited the invasion of some murine- and all human sarcomas tested in vitro. Further invasion studies with TGFß treatment only partially recapitulated the results seen with whole platelets. In a spontaneous tumor growth and lung metastasis model, platelets promoted 4T1 mammary carcinoma metastasis but not MCA-1 fibrosarcoma metastasis. Gene expression analysis of the platelet-promoted MDA-MB-231 breast carcinoma, and the platelet-inhibited HT1080 fibrosarcoma cell lines revealed that exposure of MDA-MB-231 to platelets, resulted in upregulation of oncogenes and EMT-associated genes whereas in HT1080 a tumor-suppressor gene was significantly upregulated. Thus, this study has revealed a potential diametrically opposing effect of platelets on mesenchymal and epithelial cancers, a finding that warrants further investigation.

Locoregional recurrence of parathyroid carcinoma: how to identify this rare but fatal condition using ultrasonography.

Parathyroid carcinoma (PC) is a rare condition with propensity to relapse. The purpose of this study was to evaluate the sonographic findings of locoregional recurrences of parathyroid carcinoma, in order to facilitate diagnosis of this condition using ultrasound (US). This was a retrospective observational study including 21 patients confirmed with pathologically confirmed locoregional recurrence of parathyroid carcinoma. All patients had undergone preoperative US examination at a tertiary center. The imaging, clinical and laboratory data of each case were collected. Sonographic appearance of the largest lesion at each recurrence was evaluated by two experienced radiologists according to a pre-agreed protocol. Overall, 29 relapses occurred in 21 patients. The median age of the patients was 45 years (range 24-71 years). The median size of the largest recurrent lesion at each relapse was 1.8 cm (range 0.8-3.8 cm). Ultrasound images showed hypoechoic solid nodules in 28 relapses (96.6%), inhomogeneous echo-texture in 28 relapses (96.6%), intralesional echogenic septa-like structures in 21 relapses (72.4%), intralesional cystic change in two relapses (6.9%), infiltrative or blurred boundary in 20 relapses (69.0%), irregular shape in 22 relapses (75.9%), marked vascularization on color Doppler imaging in 19 relapses (65.5%), multiple lesions in 26 relapses (89.7%), contralateral recurrence in 3 relapses (10.3%), and subcutaneous recurrence in 10 relapses (34.5%). None of the recurrent lesions exhibited calcification. The total size of all the recurrent lesions at each relapse fairly correlated with the serum intact parathyroid hormone levels (r = 0.450; p = 0.014).

Carcinoma of unknown primary origin with isolated adrenal metastasis: a report of two cases.

The adrenal glands are one of the most common sites of malignant tumor metastasis. However, metastatic adrenal carcinoma of unknown primary origin with localized adrenal gland involvement is an extremely rare condition. Herein, we reported two cases of carcinoma of unknown primary origin with isolated adrenal metastasis. In the first case, back pain was the trigger; while in the second case, the triggers were low fever and weight loss. Metabolic abnormalities such as hypertension and obesity were not detected in either case. Neither patient had relevant previous medical histories, including malignancy. However, both had a long-term history of smoking. Systemic imaging studies revealed only adrenal tumors and surrounding lesions. Primary adrenocortical carcinoma was initially suspected, and chemotherapy including mitotane was considered. However, due to difficulty in complete resection of the tumor, core needle tumor biopsies were performed. Histopathological examination of biopsy specimens led to the diagnosis of carcinoma of unknown primary origin with isolated adrenal metastasis. In both cases, additional laboratory testing showed high levels of serum squamous cell carcinoma-related antigen and serum cytokeratin fragment. Malignant lesions confined to the adrenal glands are rare. As in our cases, it could be occasionally difficult to differentiate non-functioning primary adrenocortical carcinoma from metastatic adrenal carcinoma of unknown primary origin localized to the adrenal gland. If the lesion is unresectable and there are elevated levels of several tumor markers with no apparent hormonal excess, core needle tumor biopsy should be considered to differentiate the primary tumor from the metastatic tumor.

Sequencing-based counting and size profiling of plasma Epstein-Barr virus DNA enhance population screening of nasopharyngeal carcinoma.

Circulating tumor-derived DNA testing for cancer screening has recently been demonstrated in a prospective study on identification of nasopharyngeal carcinoma (NPC) among 20,174 asymptomatic individuals. Plasma EBV DNA, a marker for NPC, was detected using real-time PCR. While plasma EBV DNA was persistently detectable in 97.1% of the NPCs identified, ∼5% of the general population had transiently detectable plasma EBV DNA. We hypothesized that EBV DNA in plasma of subjects with or without NPC may have different molecular characteristics. We performed target-capture sequencing of plasma EBV DNA and identified differences in the abundance and size profiles of EBV DNA molecules within plasma of NPC and non-NPC subjects. NPC patients had significantly higher amounts of plasma EBV DNA, which showed longer fragment lengths. Cutoff values were established from an exploratory dataset and tested in a validation sample set. Adopting an algorithm that required a sample to concurrently pass cutoffs for EBV DNA counting and size measurements, NPCs were detected at a positive predictive value (PPV) of 19.6%. This represented superior performance compared with the PPV of 11.0% in the prospective screening study, which required participants with an initially detectable plasma EBV DNA result to be retested within 4 weeks. The observed differences in the molecular nature of EBV DNA molecules in plasma of subjects with or without NPC were successfully translated into a sequencing-based test that had a high PPV for NPC screening and achievable through single time-point testing.

Elevated Expression of T-Cell Immunoglobulin and Mucin Domain 3 on T Cells from Peripheral Blood in Patients with Cervical Carcinoma.

OBJECTIVE: To investigate the expression of T-cell immunoglobulin and mucin domain 3 (TIM-3) on peripheral T cells of cervical carcinoma patients. METHODS: Peripheral blood samples from 15 high-grade cervical squamous intraepithelial lesion (HSIL) patients, 24 cervical carcinoma patients, and 21 healthy controls were collected. TIM-3 expressions on the surface of peripheral CD4+ T cells and CD8+ T cells were analyzed with flow cytometry. RESULTS: There was significantly lower expression of CD4+ T cells and CD8+ T cells in HSIL patients and cervical carcinoma patients compared with healthy controls. We also found that TIM-3 expression on peripheral CD4+ T and CD8+ T cells of both HSIL patients and cervical carcinoma patients was significantly increased compared to the control group. Further analyses revealed that the expression of TIM-3 on peripheral CD4+ T and CD8+ T cells significantly increased in stage III-IV cervical carcinoma patients compared to stages I-II. CONCLUSION: The increased expression of TIM-3 on CD4+ T cells and CD8+ T cells of patients with cervical carcinoma and HSIL suggests the potential role of TIM-3 in the development and progression of cervical carcinoma, which may be a novel therapy target for cervical carcinoma.

Immune phenotype of patients with stage IV metastatic inflammatory breast cancer.

BACKGROUND: Inflammatory breast cancer (IBC) is a rare but aggressive carcinoma characterized by severe erythema and edema of the breast, with many patients presenting in advanced metastatic disease. The "inflammatory" nature is not due to classic immune-mediated inflammation, but instead results from tumor-mediated blockage of dermal lymphatic ducts. Previous work has shown that expression of PD-L1 on tumor cells can suppress T cell activation in triple-negative (TN) non-IBC breast cancer. In the present work, we investigated immune parameters in peripheral blood of metastatic IBC patients to determine whether cellular components of the immune system are altered, thereby contributing to pathogenesis of the disease. These immune parameters were also compared to PD-1 and PD-L1 expression in IBC tumor biopsies. METHODS: Flow cytometry-based immune phenotyping was performed using fresh peripheral blood from 14 stage IV IBC patients and compared to 11 healthy age-similar control women. Immunohistochemistry for CD20, CD3, PD-1, and PD-L1 was performed on tumor biopsies of these metastatic IBC patients. RESULTS: IBC patients with Stage IV disease had lymphopenia with significant reductions in circulating T, B, and NK cells. Reductions were observed in all subsets of CD4+ T cells, whereas reductions in CD8+ T cells were more concentrated in memory subsets. Immature cytokine-producing CD56bright NK cells expressed higher levels of FcγRIIIa and cytolytic granule components, suggesting accelerated maturation to cytolytic CD56dim cells. Immunohistochemical analysis of tumor biopsies demonstrated moderate to high expression of PD-1 in 18.2% of patients and of PD-L1 in 36.4% of patients. Interestingly, a positive correlation was observed between co-expression levels of PD-L1 and PD-1 in tumor biopsies, and higher expression of PD-L1 in tumor biopsies correlated with higher expression of cytolytic granule components in blood CD4+ T cells and CD56dim NK cells, and higher numbers of CD8+ effector memory T cells in peripheral blood. PD-1 expression in tumor also correlated with increased infiltration of CD20+ B cells in the tumor. CONCLUSIONS: Our results suggest that while lymphocyte populations are severely compromised in stage IV IBC patients, an immune response toward the tumor had occurred in some patients, providing biological rationale to evaluate PD-1/PD-L1 immunotherapies for IBC.

Serum ghrelin and esophageal and gastric cancer in two cohorts in China.

Ghrelin is a hormone produced in the oxyntic glands of the stomach. Previous work by our group has suggested that serum ghrelin concentrations are inversely associated with gastric and esophageal cancer risk. We measured ghrelin concentrations in the Linxian General Population Nutrition Intervention Trial (NIT), and the Shanghai Women's Health Study (SWHS). In NIT, we analyzed serum samples from 298 esophageal squamous cell carcinoma (ESCC) cases, 518 gastric cardia adenocarcinoma (GCA) cases, 258 gastric noncardia adenocarcinoma (GNCA) cases and 770 subcohort controls (case-cohort). In SWHS, we measured ghrelin in plasma samples from 249 GNCA cases and 498 matched controls (nested case-control). Ghrelin was measured using radioimmunoassay. In NIT and SWHS, low ghrelin concentrations were associated with an increased risk of developing GNCA and GCA. The hazard ratio (HR Q1:Q4 ) for GNCA in NIT was 1.35 (95% CI: 0.89-2.05; p-trend = 0.02); the odds ratio in SWHS was 1.66 (95% CI: 1.02-2.70; p-trend = 0.06). Low ghrelin was associated with a twofold increase of GCA (HR Q1:Q4 = 2.00, 95% CI: 1.45-2.77; p-trend<0.001). In contrast, a lower risk of ESCC (NIT ESCC HR Q1:Q4 = 0.65, 95% CI: 0.45-0.92; p-trend = 0.02) was found in NIT. Low baseline ghrelin concentrations were associated with an increased risk for GNCA and GCA in the NIT and the SWHS. In contrast, low ghrelin concentrations at baseline were associated with a reduced risk of developing ESCC in the NIT. Ghrelin may be an early marker of future cancer risk for developing upper gastrointestinal cancer in regions of high incidence.

The genomic profile of parathyroid carcinoma based on whole-genome sequencing.

Parathyroid carcinoma (PC) is a rare endocrine malignancy with poor outcomes. Although some mutations such as CDC73 have been found in patients, the molecular mechanism of PC still needs extensive data to clarify. Whole-genome sequencing (WGS) was performed with frozen samples from 23 PC patients. Peripheral leukocytes were collected from 14 patients and served as controls. Somatic and germline gene alterations, copy number abnormalities and structural variants were detected. Inactivating CDC73 mutations were identified in 39.1% of patients, but only one germline inactivating mutation was found. Other cancer-related mutations identified in more than one case were MAF (2/23), NEB (6/23), NCOR1 (2/23), TTK (2/23), GRIN3A (4/23), TRIO (2/23), MAP1B (2/23), TJP2 (2/23) and FAM20A (2/23). In the seven wild-type CDC73 samples, the mutated genes were enriched in pathways involving antigen presentation, allograft rejection or autoimmune disease. More copy number variants were found in patients with cancer recurrence (P = .006) and CDC73 mutations (P = .022) than in those without these characteristics. PIK3CA loss was found in one sample, which also harboured a CDC73 mutation. Gene alterations in the PI3K/AKT/mTOR pathway were found in 78.3% (18/23) of tumours. The most prominent cancer-predisposing mutations were PDE4DIP (15/23), MAP3K1 (13/23) and CDC42EP1 (10/23). In conclusion, the PI3K/AKT/mTOR pathway may be pivotal in PC. CDC73 mutation correlated with an increased mutational burden and tumour relapse. PC patients with wild-type CDC73 harboured mutations relevant to antigen presentation and autoimmune diseases. A molecular classification based on the CDC73 mutation may help to manage follow-up and therapy for PC patients.

Circulating biomarkers for the detection of tumor recurrence in the postsurgical follow-up of differentiated thyroid carcinoma.

PURPOSE OF REVIEW: To discuss advances and challenges in thyroglobulin and Tg-antibody (TgAb) measurement and their impact on clinical management of differentiated thyroid carcinoma (DTC). RECENT FINDINGS: Basal high-sensitive Tg (hsTg) measurement avoids the need for stimulation and greatly simplifies DTC patients' management. In addition, patients with undetectable hsTg after thyroid ablation are at a very low risk of recurrence and can be safely managed by periodic hsTg measurement alone. When TgAb is present, its trend over time serves as primary (surrogate) tumor marker. However, an undetectable hsTg measurement appears to indicate a complete remission of DTC even in the presence of TgAb. Finally, reliable reference values are not yet available for low-risk DTC who are treated with less than total thyroid ablation, and caution is needed before well-designed studies addressing these issues have been published. SUMMARY: The use of hsTg assays has changed paradigms for DTC monitoring even in the presence of TgAb, and greatly reduced patients' discomfort and overall case-management costs. Reliable Tg interpretation criteria are urgently needed for patients treated with less than total thyroid ablation.

Low Geriatric Nutritional Risk Index as a Poor Prognostic Marker for Second-Line Pembrolizumab Treatment in Patients with Metastatic Urothelial Carcinoma: A Retrospective Multicenter Analysis.

BACKGROUND: We evaluated the prognostic efficacy of the Geriatric Nutritional Risk Index (GNRI) in second-line pembrolizumab (PEM) therapy for patients with metastatic urothelial carcinoma (mUC). PATIENTS AND METHODS: From January 2018 to October 2019, 52 mUC patients, treated previously with platinum-based chemotherapy, underwent second-line PEM therapy. Peripheral blood parameters were measured at the start of treatment: serum neutrophil-to-lymphocyte ratio (NLR), serum albumin, serum C-reactive protein (CRP), and body height and weight. PEM was intravenously administered (200 mg every 3 weeks). The patients were organized into two groups based on their GNRI (<92 [low GNRI] and ≥92 [high GNRI]), and the data were retrospectively analyzed. Adverse events (AEs) were evaluated and imaging studies assessed for all patients. Analyses of survival and recurrence were performed using Kaplan-Meier curves. Potential prognostic factors affecting cancer-specific survival (CSS) were assessed by univariate and multivariate Cox regression analyses. RESULTS: patients' baseline characteristics, except for their BMI and objective response rate, did not significantly differ between the two groups. The median total number of cycles of PEM therapy was significantly higher for the high-GNRI group (n [range]: 6 [2-20] vs. 3 [1-6]). The median CSS with second-line PEM therapy was 3.6 months (95% confidence interval [CI]: 2.5-6.1) and 11.8 months (95% CI: 6.2-NA) in the low-GNRI and the high-GNRI group (p < 0.01), respectively. Significant differences in CSS between the low- and high-CRP or -NRL groups were not found. Multivariate Cox proportional-hazards regression analysis revealed that a poor Eastern Cooperative Oncology Group performance status, visceral metastasis, and a low GNRI were significant prognostic factors for short CSS (95% CI: 1.62-6.10, HR: 3.14; 95% CI: 1.13-8.11, HR: 3.03; 95% CI: 1.32-8.02, HR: 3.25, respectively). Of the AEs, fatigue showed a significantly higher incidence in the low-GNRI group. CONCLUSIONS: For mUC patients receiving second-line PEM therapy, the GNRI is a useful predictive biomarker for survival outcome.

Association between adipokines and thyroid carcinoma: a meta-analysis of case-control studies.

BACKGROUND: The incidence of thyroid carcinoma is increasing all over the world. Some studies have suggested that the change of adipokines expression can induce thyroid carcinoma. However, other studies have come to the opposite conclusion. Therefore, we studied the relationship between adipokines and thyroid carcinoma. METHODS: Databases-PubMed, Cochrane Library, SinoMed, CNKI, Wanfang, and clinical trial registries were searched. A meta-analysis was then performed through a fixed or random-effects model to calculate I values for heterogeneity analysis. RESULTS: Twenty-nine articles were finally included for analysis. The level of serum tumor necrosis factor-alpha (TNF-α) [standardized mean difference (SMD) =1.31, 95% confidence interval (95% CI): 0.35 to 2.28, I2 = 98%, P = 0.008] and the ratio of TNF-α immunoreactivity in tissues [odds ratios (OR) =6.36, 95% CI: 1.92 to 21.05, I2 = 66%, P = 0.002] in thyroid carcinoma are significantly higher than those in control. The serum interleukin-6 (IL-6) in patients with thyroid carcinoma is higher than that in control (SMD = 1.04, 95% CI: 0.40 to 1.67, I2 = 96%, P = 0.001). There is no significant difference of the ratio of IL-6 immunoreactivity in tissues between carcinoma and control (OR = 1.23, 95% CI: 0.62 to 2.43, I2 = 86%, P = 0.55). The ratio of leptin immunoreactivity in tissues is significantly associated with the risk of thyroid carcinoma (OR = 12.21, 95% CI: 3.36 to 44.40, I2 = 85%, P < 0.00001). However, after analyzing the expression level of serum adiponectin in three studies, no significant difference is found between thyroid carcinoma and the control (P = 0.81). CONCLUSIONS: Adipokines (TNF-α, IL-6 and leptin) show a strong relationship between elevated concentrations (in serum and/or tissue) and thyroid carcinoma. However, the association between adiponectin and thyroid carcinoma needs further research.

tRFs as Potential Exosome tRNA-Derived Fragment Biomarkers for Gastric Carcinoma.

BACKGROUND: Gastric Carcinoma (GC) is one of the common diseases induced by the interaction of genes and environment. Exosomes are potential markers for several health problems, which contain lipids, proteins, long non-coding RNAs, microRNAs (miRNAs), and tRNA-derived fragments (tRFs). The roles of mRNAs and miRNAs in GC have been studied comprehensively; however, little research was focused on the function of plasma exosomal tRFs. METHODS: We collected plasma samples from fifty healthy controls and fifty GC patients, and all exosomes were isolated with a combined centrifugation and characterized by electron microscopy, western blot, and flow cytometry. The small RNA sequence was performed to detect the plasma exosomal tRFs, and tRFs markers were validated by real-time quantitative PCR. Three exosomal diagnostic tRFs were confirmed by receiver operating characteristic analyses. RESULTS: In this study, we found higher plasma exosomal tRF-25, tRF-38, tRF-18 expression in GC than in controls. Plasma exosomal tRF-25, tRF-38, and tRF-18 showed better accuracy for GC diagnosis. CONCLUSIONS: Our results suggest that plasma exosomal tRF-25, tRF-38, and tRF-18 were biomarkers for GC detection; tRF-25, tRF-38 and tRF-18 might be predictive of GC prognosis.

Plasma miRNA profile is a biomarker associated with urothelial carcinoma in chronic hemodialysis patients.

The incidence of urothelial carcinoma (UC) is higher in patients undergoing chronic dialysis than in the general population. This study investigated plasma miRNA profiling as the ancillary diagnosis biomarker associated with UC in patients undergoing chronic hemodialysis. We successfully screened out and detected miRNA expression from plasma in eight patients undergoing dialysis through quantitative real-time PCR array analysis and identified eight candidate miRNAs. The candidate miRNAs were then validated using single quantitative RT-PCR assays from 52 plasma samples. The miRNA classifier for ancillary UC detection was developed by multiple logistic regression analyses. Moreover, we validated the classifier by testing another nine samples. Expression levels of miR-150-5p, miR-150-5p/miR-155-5p, miR-378a-3p/miR-150-5p, miR-636/miR-150-5p, miR-150-5p/miR-210-3p, and miR-19b-1-5p/miR-378a-3p were shown to be significantly different between UC and non-UC samples (P = 0.035, 0.0048, 0.016, 0.024, 0.038, and 0.048). Kaplan-Meier curve analysis also showed that low miR-19b-1-5p expression was associated with a worse prognosis (P = 0.0382). We also developed a miRNA classifier based on five miRNA expression levels to predict UC and found that the area under curve was 0.882. The classifier had a sensitivity of 80% (95% confidence interval: 0.5191% to 0.9567%) and a specificity of 83.7% (95% confidence interval: 0.6799% to 0.9381%). This classifier was tested by nine samples with 100% accuracy. The miRNA classifier offers higher sensitivity and specificity than the existing makers. Thus, this approach will improve the prospective diagnosis of UC in patients undergoing chronic hemodialysis.

Molecular characterisation and liquid biomarkers in Carcinoma of Unknown Primary (CUP): taking the 'U' out of 'CUP'.

Cancers of Unknown Primary (CUP) comprise a heterogeneous clinical entity of confirmed metastatic cancer where the primary site of origin is undetectable. It has a poor prognosis with limited treatment options. CUP is historically under-researched; however, understanding its biology has the potential to not only improve treatment and survival by implementation of biomarkers for patient management, but also to greatly contribute to our understanding of carcinogenesis and metastasis across all cancer types. Here we review the current advances in CUP research and explore the debated hypotheses underlying its biology. The evolution of molecular profiling and tissue-of-origin classifiers have the potential to transform the diagnosis, classification and therapeutic management of patients with CUP but robust evidence to support widespread use is lacking. Precision medicine has transformed treatment strategy in known tumour types; in CUP, however, there remains a clinical need for a better understanding of molecular characteristics to establish the potential role of novel or existing therapeutics. The emergence of liquid biopsies as a source of predictive and prognostic biomarkers within known tumour types is gaining rapid ground and this review explores the potential utility of liquid biopsies in CUP.