Role of sex in liver tumor occurrence and clinical outcomes: a comprehensive review

Circulating glucocorticoids increase during stress. Chronic stress, characterized by a sustained increase in serum levels of cortisol, has been associated in different cases with an increased risk of cancer and a worse prognosis. Glucocorticoids can promote gluconeogenesis, mobilization of amino acids, fat breakdown, and impair the body’s immune response. Therefore, conditions that may favor cancer growth and the acquisition of radio- and chemo-resistance. We found that glucocorticoid receptor knockdown diminishes the antioxidant protection of murine B16-F10 (highly metastatic) melanoma cells, thus leading to a drastic decrease in their survival during interaction with the vascular endothelium. The BRAFV600E mutation is the most commonly observed in melanoma patients. Recent studies revealed that VMF/PLX40-32 (vemurafenib, a selective inhibitor of mutant BRAFV600E) increases mitochondrial respiration and reactive oxygen species (ROS) production in BRAFV600E human melanoma cell lines. Early-stage cancer cells lacking Nrf2 generate high ROS levels and exhibit a senescence-like growth arrest. Thus, it is likely that a glucocorticoid receptor antagonist (RU486) could increase the efficacy of BRAF-related therapy in BRAFV600E-mutated melanoma. In fact, during early progression of skin melanoma metastases, RU486 and VMF induced metastases regression. However, treatment at an advanced stage of growth found resistance to RU486 and VMF. This resistance was mechanistically linked to overexpression of proteins of the Bcl-2 family (Bcl-xL and Mcl-1 in different human models). Moreover, melanoma resistance was decreased if AKT and NF-κB signaling pathways were blocked. These findings highlight mechanisms by which metastatic melanoma cells adapt to survive and could help in the development of most effective therapeutic strategies.

/pdf/survival-mechanisms-of-metastatic-melanoma-cells-the-link-qopl9vxd.pdf

Survival Mechanisms of Metastatic Melanoma Cells: The Link between Glucocorticoids and the Nrf2-Dependent Antioxidant Defense System

Background: A palliative or symptomatic treatment is indicated for 7080% of patients with Klatskins tumor because of the advanced lesion volume and the patients grave condition. Hepatic arterial infusion chemotherapy, chemoembolization, radioembolization are successfully used in the treatment of hepatocellular carcinoma and liver metastases. 
Aim: to estimate the immediate and long-term results of photodynamic therapy (PDT) and its combination with hepatic arterial infusion in inoperable patients with Klatskin tumors. 
Methods: Between 2010 and 2021, 83 palliative PDT sessions (from 1 to 8, average 2.4) were performed in 82 patients as a single treatment or in combination with hepatic arterial infusion. In all cases, percutaneous transhepatic biliary drainage was previously performed; no chemotherapy was applied. Two groups of 48 patients were stratified according to the ECOG status (23) and the numbers of PDT sessions (no more than two). The treatment group of the combination therapy consisted of 24 patients (13 male, 11 female) aged 38 to 85 (mean 63) years with the ECOG status of 24 (mean 2.4). This group received PDT with hepatic arterial infusion using a GemCis regimen. On average, 1.4 PDT sessions were performed, the treatment started on the 89th (27225) day after the biliary drainage. The hepatic arterial infusion was performed on the 2d3th day after the PDT. The control group received only PDT and consisted of 24 patients (13 male, 11 female) aged 51 to 83 (66 on average) years, with the ECOG status of 23 (mean 2.6). On average, 1.4 PDT sessions were performed, starting on the 106th (32405) day after the biliary drainage. 
Results: There were no serious adverse events associated with PDT in both groups. Toxic complications of hepatic arterial infusion were observed in 13 of 24 patients (54%): III grade hematological (54%) and gastrointestinal (69%); all were eliminated with medical therapy. Complications of the percutaneous transhepatic biliary drainage in three patients (hemobilia, n=2, and sepsis, n=1) were estimated as grade III by the CIRSE classification (2017) and successfully treated without surgery. In the combination treatment group, the overall mean survival and median survival were higher than those in the control group: 327.939.8 days (10.9 mo) versus 246.931.2 days (8.2 mo) and 275 days versus 244 days. However, these differences did not reach the statistical significance (p=0.12). 
Conclusions: PDT is a safe method of a palliative treatment of critically ill patients with Klatskin tumor (ECOG 23). PDT alone has limited clinical efficacy. A combination of PDT and hepatic arterial infusion does not cause serious complications and may increase the survival rates.

Intraductal photodynamic therapy and its combination with intra-arterial chemoinfusion in the treatment of inoperable patients with Klatskin tumor

Aim To explore the predictive value of lymph node ratio (LNR) for the prognosis of medullary thyroid carcinoma (MTC) patients, and constructed prediction models for the 5-year, 10-year and 20-year mortality of MTC patients based on LNR and other predictors. Methods This cohort study extracted the data of 2,093 MTC patients aged ≥18 years undergoing total thyroidectomy and neck lymph nodes dissection. Kaplan-Meier curves and log-rank tests were performed to compare survival curves between LNR < 15% group and LNR ≥ 15% group. All data was divided into the training set (n = 1,465) and the testing set (n = 628). The random survival forest model was constructed in the training set and validated in the testing set. The area under the curve (AUC) was employed for evaluating the predictive ability of the model. Results The 5-year, 10-year and 20-year overall survival (OS) and cause-specific survival (CSS) of MTC patients with LNR <15% were higher than those with LNR ≥15%. The OS was 46% and the CSS was 75% after 20 years' follow-up. The AUC of the model for the 5-year, 10-year, and 20-year OS in MTC patients was 0.878 (95%CI: 0.856–0.900), 0.859 (95%CI: 0.838–0.879) and 0.843 (95%CI: 0.823–0.862) in the training set and 0.845 (95%CI: 0.807–0.883), 0.841 (95%CI: 0.807–0.875) and 0.841 (95%CI: 0.811–0.872) in the testing set. In the training set, the AUCs were 0.869 (95%CI: 0.845–0.892), 0.843 (95%CI: 0.821–0.865), 0.819 (95%CI: 0.798–0.840) for the 5-year, 10-year and 20-year CCS in MTC patients, respectively. In the testing set, the AUCs were 0.857 (95%CI: 0.822–0.892), 0.839 (95%CI: 0.805–0.873) and 0.826 (95%CI: 0.794–0.857) for the 5-year CCS, 10-year CCS and 20-year CCS in MTC patients, respectively. Conclusion The models displayed good predictive performance, which might help identify MTC patients might have poor outcomes and appropriate interventions should be applied in these patients.

A prediction model for the 5-year, 10-year and 20-year mortality of medullary thyroid carcinoma patients based on lymph node ratio and other predictors

Simple Summary Primary liver cancer is currently the sixth most common cancer and the third common cause of cancer-related mortality worldwide. Incidences have increased in recent year, especially in high-income countries. The epidemiology of predisposing risk factors for hepatobiliary carcinomas have changed significantly, while treatment and therapeutic options have markedly improved. Here, we provide an update of incidence, mortality, and survival trends in recent years, in Austria. While age-adjusted incidence rates remained stable in almost all hepatobiliary carcinoma subtypes—except for gall-bladder cancer—the overall survival improved significantly. Abstract Using national registries, we investigated the epidemiological trends of hepatobiliary carcinomas in Austria between 2010 and 2018 and compared them to those reported for the periods of 1990–1999 and 2000–2009. In total, 12,577 patients diagnosed with hepatocellular carcinoma (n = 7146), intrahepatic cholangiocarcinoma (n = 1858), extrahepatic cholangiocarcinoma (n = 1649), gallbladder carcinoma (n = 1365), and ampullary carcinoma (n = 559), between 2010 and 2018, were included. The median overall survival of all patients was 9.0 months. The best median overall survival was observed in patients with ampullary carcinoma (28.5 months) and the worst median overall survival was observed in patients with intrahepatic carcinoma (5.6 months). The overall survival significantly improved in all entities over the period 2010–2018 as compared with over the periods of 2000–2009 and 1990–1999. Age-adjusted incidence and mortality rates remained stable for most entities in both, men and women; only in gallbladder carcinoma, the incidence and mortality rates significantly decreased in women, whereas, in men, the incidence rates remained stable and mortality rates showed a decreasing trend. We showed that age-adjusted incidence and mortality rates were stable in most entities, except in gallbladder carcinoma. The overall survival improved in almost all entities as compared with those during 1990–2009.

/pdf/changing-epidemiological-trends-of-hepatobiliary-carcinomas-1m64ho9y.pdf

Changing Epidemiological Trends of Hepatobiliary Carcinomas in Austria 2010–2018

Introduction Klatskin tumors (KTs) occur at the confluence of the right and left extrahepatic ducts and are classified based on their anatomical and histological codes in the International Classification of Diseases for Oncology (ICD-O). The second edition of the ICD-O (ICD-O-2) allocated a distinctive histological code to KT, which also included intrahepatic cholangiocarcinoma (CC). This unclear coding may result in ambiguous reporting of the demographic and clinical features of KT. The current study aimed to investigate the demographic, clinical, and pathological factors affecting the prognosis and survival of KT in the light of the updated third edition of ICD-O, Ninth Revision (ICD-O-3). Methods Data of 1,144 patients with KT from the Surveillance, Epidemiology, and End Result (SEER) database (2001-2012) were extracted. Patients with KT were analyzed for age, sex, race, stage, treatment, and long-term survival. The data were analyzed using chi-square tests, t-tests, and univariate and multivariate analyses. The Kaplan-Meier analysis was used to compare long-term survival between KT and subgroups of all biliary CCs. Results Of all biliary CCs, KT comprised 9.35%, with a mean age of diagnosis of 73±13 years, and was more common in men (54.8%) and Caucasian patients (69.5%). Histologically, moderately differentiated tumors were the most common (38.9%) followed by poorly differentiated (35.7%), well-differentiated (23.3%), and undifferentiated tumors (2.2%) (p 4 cm (29.7%) and <2 cm (28.8%) (p<0.001). ICD-O-3 defined most KTs in extrahepatic location (53.5%), while the remainder were in other biliary locations (46.5%) (p<0.001). Most KT patients received no treatment (73%), and for those who were treated, the most frequent modality was radiation (52.7%), followed by surgery (28.1%), and both surgery and radiation (19.2%) (p<0.001). Mean survival time for KT patients treated with surgery was inferior to all CCs of the biliary tree (1.72±2.61 vs. 1.87±2.18 years) (p=0.047). Multivariate analysis identified regional metastasis (OR=2.8; 95% CI=2.6-3.0), distant metastasis (OR=2.1; 95% CI=1.9-2.4), lymph node positivity (OR=1.6; 95% CI=1.4-1.8), Caucasian race (OR=2.0; 95% CI=1.8-2.2), and male sex (OR=1.2; 95% CI=1.1-1.3) were independently associated with increased mortality for KT (p<0.001). Conclusion The ICD-O-3 has permitted a greater understanding of KT. KT is a rare and lethal biliary malignancy that presents most often in Caucasian men in their seventh decade of life with moderately differentiated histology. Surgical resection does not provide any survival advantage compared to similarly treated biliary CCs. In addition, the combination of surgery and radiation appeared to provide no added survival benefits compared to other treatment modalities for KT.

/pdf/klatskin-tumor-in-the-light-of-icd-o-3-a-population-based-31iur14d60.pdf

Klatskin Tumor in the Light of ICD-O-3: A Population-Based Clinical Outcome Study Involving 1,144 Patients from the Surveillance, Epidemiology, and End Result (SEER) Database (2001-2012).

/pdf/prognostic-value-of-lymph-node-ratio-in-cutaneous-melanoma-a-15gdyoipiy.pdf

Prognostic Value of Lymph Node Ratio in Cutaneous Melanoma: A Systematic Review

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Klatskin Tumor in the Light of ICD-O-3: A Population-Based Clinical Outcome Study Involving 1,144 Patients from the Surveillance, Epidemiology, and End Result (SEER) Database (2001-2012).

Prognostic Value of Lymph Node Ratio in Cutaneous Melanoma: A Systematic Review