Melatonin promotes sorafenib-induced apoptosis through synergistic activation of JNK/c-jun pathway in human hepatocellular carcinoma.

Melatonin has been shown to exert anticancer activity on hepatocellular carcinoma (HCC) through its antiproliferative and pro-apoptotic effect in both experimental and clinical studies, and sorafenib is the only approved drug for the systemic treatment of HCC. Thus, this study was designed to investigate the combined effect of melatonin and sorafenib on proliferation, apoptosis, and its possible mechanism in human HCC. Here, we found that both melatonin and sorafenib resulted in a dose-dependent growth inhibition of HuH-7 cells after 48 hours treatment, and the combination of them enhanced the growth inhibition in a synergistic manner. Colony formation assay indicated that co-treatment of HuH-7 cells with melatonin and sorafenib significantly decreased the clonogenicity compared to the treatment with single agent. Furthermore, FACS and TUNEL assay confirmed that melatonin synergistically augmented the sorafenib-induced apoptosis after 48 hours incubation, which was in accordance with the activation of caspase-3 and the JNK/c-jun pathway. Inhibition of JNK/c-jun pathway with its inhibitor SP600125 reversed the phosphorylation of c-jun and the activation of caspase-3 induced by co-treatment of HuH-7 cells with melatonin and sorafenib in a dose-dependent manner. Furthermore, SP600125 exhibited protective effect against apoptosis induced by the combination of melatonin and sorafenib. This study demonstrates that melatonin in combination with sorafenib synergistically inhibits proliferation and induces apoptosis in human HCC cells; therefore, supplementation of sorafenib with melatonin may serve as a potential therapeutic choice for advanced HCC.

Multiple gastrointestinal metastases of Merkel cell carcinoma.

Merkel cell carcinoma is an aggressive skin malignancy. Primary Merkel cell carcinomas are treated by wide radical excision with or without adjuvant radiotherapy, while benefits of adjuvant chemotherapy remain doubtful. There are only several cases of gastrointestinal metastases of Merkel cell carcinoma reported so far. We report a case of recurrent Merkel cell carcinoma with metastases to the stomach and the small intestines after wide excision of primary Merkel cell carcinoma.

Glycine inhibits angiogenic signaling in human hepatocellular carcinoma cells.

Hepatocellular carcinoma (HCC) is a highly vascularized tumor with limited susceptibility to chemotherapy. Modern targeted therapies are aimed at specific properties of this neoplasm. Glycine is a simple non-essential amino acid with potential antiangiogenic effects. In this study, the amino acid's effect on angiogenic signaling in an in vitro model of HCC was evaluated. HepG2 and Huh7 cells were treated with glycine-free DMEM supplemented with 0, 0.01, 0.1, 1.0, 2.0, 5.0 and 10 mM glycine. The direct effects of glycine on the viability of HCC cells were monitored using MTT assay. To detect angiogenic signaling, mRNA and protein levels of vascular endothelial growth factor (VEGF-A) were measured using RT-PCR and Western Blot assays. To determine whether or not glycine receptors (GlyR) played a significant role, the specific antagonist, strychnine, was used as a direct inhibitor. Western Blotting was performed to show the presence of GlyR. While there was no direct pro- or antiproliferative effect of either glycine or strychnine in both cell lines, glycine was shown to significantly decrease VEGF-A expression on mRNA and protein level up to 63 % in both cell lines. This effect was blunted by the presence of strychnine. GlyR was also identified in both cell lines. Glycine decreases GlyR-dependent, VEGF-A-mediated, angiogenic signaling in human HCC and thus might be a promising additive to chemotherapy treatment strategies for highly vascularized tumors.

Observation Safely Reduces the Use of the Computerized Tomography in Medium-to-Low-Risk Patients with Suspected Acute Appendicitis: Results of a Randomized Controlled Trial.

Objectives-The objective was to compare the effectiveness of observation in standard-of-care computed tomography (CT) in adult patients with suspected acute appendicitis (AA). Methods-Patients with clinically suspected AA and inconclusive diagnosis after primary clinical examination, laboratory examination, and transabdominal ultrasound (TUS) were eligible for the study, and they were randomized (1:1) to parallel groups: observation-group patients were observed for 8-12 h and then, repeated clinical and laboratory examinations and TUS were performed; CT group (control group) patients underwent abdominopelvic CT scan. The study utilized Statistical Analysis System 9.2 for data analysis, including tests, logistic regression, ROC analysis, and significance evaluation. Patients were enrolled in the study at Vilnius University Hospital Santaros Klinikos in Lithuania between December 2018 and June 2021. Results-A total of 160 patients (59 men, 101 women), with a mean age of 33.7 ± 14.71, were included, with 80 patients in each group. Observation resulted in a reduced likelihood of a CT scan compared with the CT group (36.3% vs. 100% p < 0.05). One diagnostic laparoscopy was performed in the observation group; there were no cases of negative appendectomy (NA) in the CT group. Both conditional CT and observation pathways resulted in high sensitivity and specificity (97.7% and 94.6% vs. 96.7% and 95.8%). Conclusions-Observation including the repeated evaluation of laboratory results and TUS significantly reduces the number of CT scans without increasing NA numbers or the number of complicated cases.

Suspected and Confirmed Acute Appendicitis During the COVID-19 Pandemic: First and Second Quarantines-a Prospective Study.

Purpose: COVID-19 posed an unprecedented modern global healthcare crisis affecting both elective and urgent surgeries. The aim of this study is to evaluate the difference in the presentation of acute appendicitis (AA) before and during the COVID-19 era, the first and second quarantines. Methods: We performed a prospective study from December 2018 to May 2021. Two cohorts were analysed, one with patients who presented to the emergency department (ED) with suspected AA and the second with confirmed AA. Both cohorts were divided into four groups: before COVID-19, during the first quarantine, between the first and second quarantine, and during the second quarantine. Data such as demographics, the time to first contact with the healthcare provider and time to operation, laboratory tests, clinical stage of AA, length of stay, and COVID-19 status were collected. A total of 469 patients were enrolled. Results: A total of 209 patients were male (45%) and 260 were female (55%), with the median age being 33 years (24-45). In the first cohort of suspected AA, there was no difference in sex; however, more older patients presented to the ED during the first quarantine (41 years) compared with other groups (28.5, 36, and 32.5 years), p < 0.000. Before the pandemic, there was a shorter duration of symptoms to first contact with the healthcare provider (13 h) compared with other groups, p = 0.001. In the second cohort of confirmed AA, there was a shorter period of time to operation from first symptoms before the pandemic (22 h) compared with other groups (30, 35, 30.5 h), p < 0.000. There were more complicated gangrenous, perforated appendicitis or periappendicular abscess in Group 2 and 3 (26, 22 and 10%, and 26, 22 and 2%, respectively) compared with Group 1 (20, 4 and 3%) and Group 4 (22, 12, and 2%), p = 0.009. Hospital stay was longer during the first quarantine (3 days) compared with other groups (2 days), p = 0.009. Six patients were COVID-19 positive: one from Group 3 and five from Group 4 (p > 0.05). Conclusions: Our study suggests that during the first quarantine of the COVID-19 pandemic, there was delayed presentation to the ED with suspected AA and there was a greater proportion of complicated appendicitis and longer hospitalization in confirmed cases as well.

Bratislava Statement: consensus recommendations for improving pancreatic cancer care.

Pancreatic cancer is one of the most lethal tumours, and it is the fourth cause of cancer death in Europe. Despite its important public health impact, no effective treatments exist, nor are there high-visibility research efforts to improve care. This alarming situation is emblematic of a larger group of cancer diseases, known as neglected cancers. To address the impact of these diseases, the European Commission-supported Innovative Partnership for Action Against Cancer launched a multi-stakeholder initiative to determine key steps that healthcare systems can rapidly implement to improve their response. A working group comprising 20 representatives from European medical societies, patient associations, cancer plan organisations and other relevant European healthcare stakeholders was organised. A consensus process based on the results of different studies, discussion of research outcomes, and development and endorsement of draft statements resulted in 22 consensus recommendations (the Bratislava Statement). The statement argues that substantial improvements can be achieved in patient outcomes by centralising pancreatic cancer care around state-of-the-art reference centres, staffed by expert multidisciplinary teams capable of providing high-quality care. This organisational model requires a specific care framework encompassing primary, palliative and survivorship care, and a policy environment prioritising the use of quality criteria and performance assessments as well as research investments dedicated to prevention, risk prediction, early detection and diagnosis. In order to address the challenges posed by neglected cancers in general and pancreatic cancer in particular, a specific control strategy tailored to this reality is required.

Proteomic Identification of FLT3 and PCBP3 as Potential Prognostic Biomarkers for Pancreatic Cancer.

BACKGROUND/AIM: Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest types of cancer, particularly due to its aggressive course and challenging diagnostics in early-stage disease. The aim of this study was to discover new potential prognostic and diagnostic pancreatic cancer biomarkers. MATERIALS AND METHODS: The proteomes of 37 samples from pancreatic cancer, inflammatory or healthy pancreatic tissue derived through in-depth differential proteomic analysis were compared. RESULTS: A set of candidate proteins as pancreatic cancer-specific diagnostic or prognostic biomarkers were identified. Survival data of patients after two-year follow-up indicated FLT3 and PCBP3 proteins as potential biomarkers for favourable pancreatic cancer prognosis. The levels of PCBP3 correlated with tumour stage and FLT3 levels, were evaluated as independent prognostic marker. CONCLUSION: FLT3 and PCBP3 represent potential biomarkers for improved individualized pancreatic cancer prognosis. Moreover, FLT3 may play a role in future treatment selection.

Laparoscopically assisted colonoscopic polypectomy - viable option for curative surgery in elderly patients.

INTRODUCTION: Colorectal cancer (CRC) is the third most common cancer worldwide and the fourth most frequent cause of cancer-related death in the world. CRC screening programs have been widely introduced worldwide, allowing for early detection and removal of precancerous lesions and avoiding major surgical intervention. However, not all polyps are suitable for conventional and advanced colonoscopic polypectomy. Thus, laparoscopically assisted colonoscopic polypectomy (LACP) was introduced to clinical practice as a method of choice for these polyps and adenomas. AIM: To overlook our experience in laparoscopically assisted colonoscopic polypectomies and evaluate effectiveness and quality of the procedure. MATERIAL AND METHODS: A retrospective analysis of a prospectively maintained database was performed. using the Vilnius University Hospital Santariskiu Klinikos patient database for the period from 2010 to 2016, resulting in 21 cases in which LACP was performed. All procedures were performed using combined laparoscopy and videocolonoscopy techniques. Morphology of adenomas was classified according to the Paris classification during the procedure. Creation of the database was approved by the Lithuanian Bioethics committee. RESULTS: Twenty-two adenomas were removed from 21 patients, aged 65.33 ±8.9. There was no difference between male and female age, but occurrence of adenomas in females was 2-fold higher. The majority of removed lesions were localized in the cecum and mean size was 27.2 ±11.1 mm. The morphology of adenomas was distributed equally between 0-Is, 0-Ip, and 0-IIa, except one, which belonged to 0-III. Histological analysis revealed that tubulovillous adenoma occurrence was 1.4 times higher than tubulous adenoma. There was only one postoperative complication - bleeding from the adenoma resection site, which was managed by conservative means. One patient developed G2 adenocarcinoma at the polyp resection site and was referred for radical surgery. CONCLUSIONS: The LACP is a safe procedure with minimal risk to the elderly patient. Patient follow-up is essential for detection of recurrence.

Metabolomics in pancreatic cancer biomarkers research.

Pancreatic cancer is one of the worst prognoses of all malignancies. More than 40,000 deaths a year from this disease are observed in European Union alone. The only possibly curative treatment of pancreatic cancer is surgery, yet only 15-20% of patients have operable disease and even patients, which go through surgery and adjuvant chemotherapy, survival is less than 30%. The sensitive and specific biomarkers which could be used for the advance of early diagnostics are needed and constantly researched. Metabolomics is a technology which analyzes the concentrations of low-molecular-weight metabolites (the metabolome) has lately effectively developed due to the improvements in analytical technology. Metabolome analysis can be a one of the useful approaches for the biomarker discovery and disease diagnosis. Here we discuss recent discoveries in the field of pancreatic cancer metabolomics as well as the most promising biomarkers for diagnostics, prognosis and prediction.

Therapeutic potential and adverse events of everolimus for treatment of hepatocellular carcinoma - systematic review and meta-analysis.

Everolimus is an orally administrated mammalian target of rapamycin (mTOR) inhibitor. Several large-scale randomized controlled trials (RCTs) have demonstrated the survival benefits of everolimus at the dose of 10 mg/day for solid cancers. Furthermore, mTOR-inhibitor-based immunosuppression is associated with survival benefits for patients with hepatocellular carcinoma (HCC) who have received liver transplantation. However, a low rate of tumor reduction and some adverse events have been pointed out. This review summarizes the antitumor effects and adverse events of everolimus and evaluates its possible application in advanced HCC. For the meta-analysis of adverse events, we used the RCTs for solid cancers. The odds ratios of adverse events were calculated using the Peto method. Manypreclinical studies demonstrated that everolimus had antitumor effects such as antiproliferation and antiangiogenesis. However, some differences in the effects were observed among in vivo animal studies for HCC treatment. Meanwhile, clinical studies demonstrated that the response rate of single-agent everolimus was low, though survival benefits could be expected. The meta-analysis revealed the odds ratios (95% confidence interval [CI]) of stomatitis: 5.42 [4.31-6.73], hyperglycemia: 3.22 [2.37-4.39], anemia: 3.34 [2.37-4.67], pneumonitis: 6.02 [3.95-9.16], aspartate aminotransferase levels: 2.22 [1.37-3.62], and serum alanine aminotransferase levels: 2.94 [1.72-5.02], respectively. Everolimus at the dose of 10 mg/day significantly increased the risk of the adverse events. In order to enable its application to the standard conventional therapies of HCC, further studies are required to enhance the antitumor effects and manage the adverse events of everolimus.