The Effect of High CDC6 Levels on Predicting Poor Prognosis in Colorectal Cancer

<b><i>Introduction:</i></b> We investigated the function of cell division cycle 6 (CDC6) on the prognosis in colorectal carcinoma (CRC). <b><i>Methods:</i></b> CDC6 protein expression levels in 121 patients with colorectal cancer and adjacent normal mucosa were detected by immunohistochemistry. <b><i>Results:</i></b> Compared to adjacent normal tissues, CDC6 mRNA level was overexpressed in CRC tissues. Moreover, CDC6 protein levels were expressed up to 93.39% (113/121) in CRC tissues in the cell nucleus or cytoplasm. However, there were only 5.79% (7/121) in normal mucosal tissues with nuclear expression. CDC6 expression was significantly correlated with TNM stage and tumor metastasis. The 5-year survival rate was lower in the high CDC6 expression group than the low group. After silencing of CDC6 expression in SW620 cells, cell proliferation was slowed, the tumor clones were decreased, and the cell cycle was arrested in G1 phase. In multivariate analysis, increased CDC6 protein expression levels in colon cancer tissues were associated with cancer metastasis, TNM stage, and patient survival time. <b><i>Conclusion:</i></b> CDC6 is highly expressed in CRC, and downregulation of CDC6 can slow the growth of CRC cells in vitro. It is also an independent predictor for poor prognosis and may be a useful biomarker for targeted therapy and prognostic evaluation.

Azacitidine to Consolidate and Deepen the Therapeutic Response Achieved by Intensive Induction Treatment in a Young Patient Affected by NPM1mut-AML Who Has Become Ineligible for High-Dose Consolidation

Acute myeloid leukemia (AML) is the most common leukemia in adults. In spite of the most recent discoveries about the molecular landscape of this disease, the treatment of elderly and unfit young patients continues to be a great challenge. The hypomethylating agents (HMA) still represent an effective therapeutic option for these categories, especially for the low-risk subgroups. We report the case of a young patient with NPM1^mut-AML who underwent a first cycle of intensive induction treatment, achieving a complete remission, but suffered from a serious life-threatening neurologic toxicity. Due to the ineligibility to further lines of intensive chemotherapy, we decided to consolidate the response with azacitidine, administered according to the regular schedule. The minimal residual disease (MRD), monitored through the NPM1 mutation at diagnosis, progressively decreased and became undetectable after 36 cycles of hypomethylating therapy. After 1 year from discontinuation of azacitidine, MRD remains undetectable. Therefore, HMA might still represent a feasible and effective option for patients with low-risk AML, especially when the standard chemotherapy is not indicated, or as maintenance therapy in nontransplantable patients.

New Frontiers in the Medical Therapy of Hepatocellular Carcinoma

Background: Hepatocellular carcinoma (HCC) is the most common primary liver tumor, and it rates fourth as a cause of cancer-related death. The presence of underlying liver disease and poor chemosensitivity pose major treatment challenges in the management of HCC. However, in the last few years the therapeutic scenario has substantially changed, and immunotherapy in the form of immune checkpoint inhibitors (ICPIs) has become an essential therapeutic strategy in this field. Summary: After controversial results of monotherapy, ICPIs have been mainly investigated in association with anti-angiogenic agents or as dual checkpoint inhibition. The combination of atezolizumab plus bevacizumab has become the new therapeutic standard for unresectable HCC. Currently, a number of ICPIs-based combinations are being studied in phase III clinical trials as front-line therapy for advanced HCC, with growing interest in integration of early-stage disease management in the form of adjuvant or neoadjuvant therapies. With most of the trials investigating ICPIs as first line treatment, the second line scenario relies mainly on tyrosine kinase inhibitors, which however, have not been formally trialed after ICPIs. Key messages: In this review we summarize the main therapeutic advances in the systemic management of HCC focusing on the most relevant ongoing trials. We also discuss the main issues arising from a such rapidly evolving field including therapeutic sequencing and patient stratification.

Sarcopenia in Hepatocellular Carcinoma: Pathogenesis and Management

Background: Sarcopenia is almost constantly observed in patients with cirrhosis and hepatocellular carcinoma. Summary: Chronic liver disease represents a unique pathophysiological scenario in which sarcopenia develops and all factors involved in the pathogenesis should be taken into account for an appropriate management of the disease. No properly designed intervention studies on this topic are available and, thus, no effective strategies have been developed for clinical practice. Apart from any targeted intervention, treatment and optimization of liver disease is crucial. Key Messages: In patients with cirrhosis and hepatocellular carcinoma, nutritional support to maintain and restore nutrition status, a targeted use of branched-chain amino acids and a guided physical exercise, should all be an integral part of the multidimensional assessment and tailored interventions.

Crizotinib versus Alectinib for the Treatment of ALK-Positive Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis

Background: Crizotinib and alectinib are the two most commonly used anaplastic lymphoma kinase (ALK) inhibitors for ALK-positive non-small cell lung cancer (NSCLC). We compared their antitumor efficacies and adverse effects based on a pooled analysis of the ALEX, ALESIA and J-ALEX clinical trials. Methods: Seven databases were searched for eligible articles. The primary endpoints included overall survival (OS), progression-free survival (PFS), central nervous system (CNS)-PFS, drug responses and adverse effects (AEs). Results: Seven articles on three randomized controlled clinical trials (ALEX, ALESIA and J-ALEX) that included 697 patients were included. Compared with crizotinib, alectinib exhibited superior efficacy in PFS (HR [hazard ratio]: 0.35, [0.25-0.49], p < 0.00001), OS (HR: 0.66, [0.47-0.92], p = 0.02), CNS-PFS (HR: 0.17, [0.11-0.24], p < 0.00001), duration of response (HR: 0.31, [0.23-0.42], p < 0.00001), objective response rate (ORR) (risk ratio [RR]: 0.87, [0.80-0.94], p = 0.0003), partial response (PR) (RR: 0.88, [0.81-0.96], p = 0.004), and grade 3-5 AEs (RR: 1.43, [1.09-1.87], p = 0.009). Additionally, compared with crizotinib, alectinib exhibited a survival advantage that increased with its prolongation of survival time. The disease control rate, complete response and total AEs were comparable between the two groups. The crizotinib group reported higher rates of constipation, nausea, diarrhea, vomiting, peripheral edema, dysgeusia, visual impairment and levels of alanine aminotransferase and aspartate aminotransferase as well as greater decreases in appetite and neutrophil count. Conclusions: In both antitumor efficacy and safety, alectinib appears to be superior to crizotinib for the treatment of ALK-positive NSCLC.

Being a Cancer Patient during the Time of COVID-19: Impact of the Pandemic on the Anxiety and the Sleeping Quality of Oncology Patients

<b><i>Objective:</i></b> In this study, we aimed to assess anxiety and sleep quality in cancer patients treated or followed up at our clinic at the time of the outbreak of the COVID-19 pandemic. <b><i>Methods:</i></b> Seven hundred and sixty-one patients who were either treated or followed up at our oncology clinic between April 2020 and May 2020 were included. Patients were assessed with the State-Trait Anxiety Inventory (STAI) and the Pittsburgh Sleep Quality Index (PSQI). <b><i>Results:</i></b> Mean scores of the 761 participants were STAI, 43.45 ± 9.34 (range, 23–75), and PSQI, 5.67 ± 4.24 (range, 0–19). Quality of sleep was found bad in 447 (58.7%) (global score ≥5). Univariate analyses demonstrated statistical differences by stage of cancer, status of treatment, subgroup of treatment, monthly income, and levels of education in anxiety and sleep quality levels. Multivariate analyses showed active treatment (OR: 21.4; 95% CI: 9.08–50.4; <i>p</i> &#x3c; 0.001) as the major independent variable that affected sleep quality; the major independent variable associated with anxiety was low income (OR: 4.43; 95% CI: 1.69–11.5; <i>p</i> = 0.002). <b><i>Conclusion:</i></b> Anxiety and sleep quality levels were found comparable to pre-pandemic reports, and the pandemic was not observed to have additional negative impact on cancer patients. Also, universal basal anxiety and sleep disorder that accompany cancer or active treatment were observed in our study. The accurate effects of the pandemic can be analyzed in further studies using repeated data obtained from the same patient group.

Molecular Characterization, Virulence Determinants, and Antimicrobial Resistance Profile of Methicillin-Resistant Staphylococcus aureus in the North of Iran; a High Prevalence of ST239-SCCmec III/t037 Clone

<b><i>Objectives:</i></b> Emergence and prevalence of methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) have become a major universal health concern, limiting therapeutic options. <b><i>Methods:</i></b> A total number of 37 MRSA isolates, including 19 clinical isolates from hospitalized patients and 18 colonizing isolates from health care workers were identified from 3 hospitals, in Gorgan, North of Iran. Antimicrobial susceptibility test was performed using the disk diffusion method and E-test. The presence of virulence and antibiotic resistance determinants were evaluated by PCR. The genotypical characterization was further analyzed using multi-locus sequence, <i>spa</i>, staphylococcal cassette chromosome, <i>mec</i> (SCC<i>mec)</i>, and <i>agr</i> typing. <b><i>Results:</i></b> The frequency of MRSA among <i>S. aureus</i> isolates was 38.14% (37/97). The most frequent <i>S. aureus</i> resistant isolates were found to be obstinate against penicillin (98%) and gentamicin (82.5%). Additionally, the lowest resistance rates were found against daptomycin (0%), vancomycin (2.7%), and quinupristin-dalfopristin (5.4%). All MRSA isolates were susceptible to daptomycin with minimum inhibitory concentration (MIC)50/MIC90 of 0.25/0.5 μg/mL. One isolate belonging to sequence type 239 (ST239)-SCC<i>mec</i>III/t037 clone (MIC ≥16 μg/mL) was resistant to vancomycin. All but 1 isolate that shares ST22-SCC<i>mec</i> IV/t790 strain were positive for both <i>tsst</i> and <i>pvl</i> genes. The most predominant MRSA isolates (27%) were associated with ST239-SCC<i>mec</i> III/t037, and ST239-SCC<i>mec</i> III/t924 (16.2%) clones, subsequently. In our study, circulating MRSA strains were genetically diverse with a high prevalence of ST239-SCC<i>mec</i> III/t037 clone. <b><i>Conclusion:</i></b> These findings emphasize the need for future and continuous surveillance studies on MRSA to prevent the dissemination of existing multidrug resistance MRSA clones in an effective manner.

Efficacy of the BNT162b2 mRNA COVID-19 Vaccine in Patients with Chronic Lymphocytic Leukemia: A Serologic and Cellular Study

Background: Antibody response following SARS-CoV2 vaccination is somewhat defective in chronic lymphocytic leukemia (CLL). Moreover, the correlation between serologic response and status of cellular immunity has been poorly studied. Objective: This study was undertaken to assess humoral immune and cellular responses to the BNT162b2 messenger RNA (mRNA) COVID-19 vaccination in CLL. Methods: The presence of the spike antibodies was assessed at a median time of 14 days from the second vaccine dose of SARS-CoV2 in 70 CLL followed-up at a single institution. Results: The antibody response rate (RR) in CLL patients was 58.5%, compared to 100% of 57 healthy controls of the same sex and age (P< 0.0001). Patients treatment-naïve and those in sustained clinical remission after therapy had the highest RR (87.0% and 87.7%, respectively). In contrast, patients on therapy with a pathway inhibitor as monotherapy and those treated with an association of anti-CD20 antibody were unlikely to respond to the SARS-CoV-2 vaccine (52% and 10%, respectively). In multivariate analysis, early Rai stage (OR, 0.19 [0.05-0.79]; P=0.02) and no previous therapy (OR, 0.06[0.02-0.27]; P<0.0001) were found to be independent predictors of vaccination response. An increase in absolute NK cells (i.e., CD16/CD56 positive cells) in patients with a serological response was found following the second dose of vaccine (P=0.02). Conclusions: These results confirm that serological response to the BNT162b2 vaccine in patients with CLL is impaired. A third boosting vaccine dosage should be considered for these patients.

Synthesis and Antimicrobial Evaluation of Amino Acid Naphthoquinone Derivatives as Potential Antibacterial Agents

Background: The synthesis and biological evaluation of 1,4-naphthoquinone derivatives are of great interest since these compounds exhibit strong antibacterial, antifungal, antimalarial, and anticancer activities. The electronic properties of naphthoquinones are usually modulated by attaching functional groups containing nitrogen, oxygen and sulfur atoms, which tune their biological potency and selectivity. Methods: A series of 13 amino acid 1,4-naphthoquinone derivatives were synthesized under assisted microwave and ultrasound conditions. The antibacterial activity compounds was tested against American type Culture Collection (ATCC): Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus and Enterococcus faecalis, as well two multidrug resistant pathogens: Escherichia coli and Staphylococcus aureus from clinical isolated. Minimal inhibitory concentration (MIC) was determined using the broth microdilution method. Results: MIC of derivatives 4–11, 14 and 16 showed antimicrobial activity against gram-positive and gram-negative bacteria. Antimicrobial activities of the compounds 4–8 and 14 were ≤MIC 24.7 μg∙mL-1 against all the reference strain, even more the compound 6 showed the most potent activity with a MIC of 3.9 μg∙mL-1 on S. aureus. On the clinical isolated the compounds 7, 8 and 14 showed a MIC of 49.7 and 24.7 μg∙mL-1 against S. aureus y E. coli respectively. About ADME properties and Osiris analysis, the compounds 4-16 presented high gastrointestinal absorption and good characteristics for oral bioavailability and the compound 14 was the less toxic. Conclusion: amino acid 1,4-naphthoquinone derivatives showed good in vitro antibacterial activity against clinical strains, and modifications on C-3 with cloride atom enhanced the efficiency against same pathogens.

Relationship between Carnitine Deficiency and Tyrosine Kinase Inhibitor Use in Patients with Chronic Myeloid Leukemia

Background: Some chemotherapeutic agents cause carnitine deficiency, which confers general fatigue; however, there is no study on carnitine deficiency in patients with chronic myeloid leukemia (CML) during tyrosine kinase inhibitor (TKI) therapy. Objective: This study investigated carnitine concentrations in patients with CML treated with TKIs. Method: This study included patients with well-controlled CML. Total carnitine and free carnitine concentrations were evaluated using the enzyme cycling method. The Brief Fatigue Inventory (BFI) and Cancer Fatigue Scale (CFS) were used to assess general fatigue developed during TKI therapy. Results: Fifty-five patients on TKIs were included; 12 (21.8%) had low free carnitine concentrations. Free carnitine concentrations were higher in men than in women. Younger age was closely associated with lower free carnitine concentrations. TKI type, TKI dose, treatment response, or therapy duration were not associated with free carnitine concentrations. None of the scores (the global fatigue score with the BFI and CFS score) correlated with carnitine concentrations. Concentrations of free carnitine in the treatment-free remission group were slightly higher than those in the TKI group, with only 9.1% having a low concentration of free carnitine. Conclusion: Carnitine deficiency is probably not a major cause of general fatigue, but may occur in patients with CML receiving TKIs.