Molecular Subtypes, microRNAs and Immunotherapy Response in Metastatic Colorectal Cancer.

Currently, only a limited set of molecular traits are utilized to direct treatment for metastatic CRC (mCRC). The molecular classification of CRC depicts tumor heterogeneity based on gene expression patterns and aids in comprehending the biological characteristics of tumor formation, growth and prognosis. Additionally, it assists physicians in tailoring the therapeutic approach. Microsatellite instability (MSI-H)/deficient mismatch repair proteins (MMRd) status has become a ubiquitous biomarker in solid tumors, caused by mutations or methylation of genes and, in turn, the accumulation of mutations and antigens that subsequently induce an immune response. Immune checkpoint inhibitors (ICI) have recently received approval for the treatment of mCRC with MSI-H/MMRd status. However, certain individuals experience either initial or acquired resistance. The tumor-programmed cell death ligand 1 (PD-L1) has been linked to the ability of CRC to evade the immune system and promote its growth. Through comprehensive research conducted via the PUBMED database, the objectives of this paper were to review the molecular characteristics linked to tumor response in metastatic CRC in light of improved patients' outcomes following ICI therapies as seen in clinical trials and to identify particular microRNAs that can modulate the expression of specific oncoproteins, such as PD-L1, and disrupt the mechanisms that allow the immune system to be evaded.

Baseline Expression of Exosomal miR-92a-3p and miR-221-3p Could Predict the Response to First-Line Chemotherapy and Survival in Metastatic Colorectal Cancer.

The status of predictive biomarkers in metastatic colorectal cancer is currently underdeveloped. Our study aimed to investigate the predictive value of six circulating exosomal miRNAs derived from plasma (miR-92a-3p, miR-143-3p, miR-146a-5p, miR-221-3p, miR-484, and miR-486-5p) for chemosensitivity, resistance patterns, and survival. Thirty-one metastatic colorectal cancer patients were selected before receiving first-line irinotecan- or oxaliplatin-based chemotherapy. Blood samples were harvested at baseline and 4-6 months after the initiation of chemotherapy. The levels of exosomal expression for each miRNA were analyzed by qPCR. Our results for patients receiving first-line FOLFOX showed significantly higher baseline levels of miR-92a-3p (p = 0.007 **), miR-146a-5p (p = 0.036 *), miR-221-3p (p = 0.047 *), and miR-484 (p = 0.009 **) in non-responders (NR) vs. responders (R). Of these, miR-92a-3p (AUC = 0.735), miR-221-3p (AUC = 0.774), and miR-484 (AUC = 0.725) demonstrated a predictive ability to discriminate responses from non-responses, regardless of the therapy used. Moreover, Cox regression analysis indicated that higher expression levels of miR-92a-3p (p = 0.008 **), miR-143-3p (p = 0.009 **), miR-221-3p (p = 0.016 *), and miR-486-5p (p = 0.019 *) at baseline were associated with worse overall survival, while patients expressing higher baseline miR-92a-3p (p = 0.003 **) and miR-486-5p (p = 0.003 **) had lower rates of progression-free survival. No predictive values for candidate microRNAs were found for the post-chemotherapy period. In line with these findings, we conclude that the increased baseline exosomal expression of miR-92a-3p and miR-221-3p seems to predict a lack of response to chemotherapy and lower OS. However, further prospective studies on more patients are needed before drawing practice-changing conclusions.

Advances in Cancer Therapy from Research to Clinical Practice-Surgical, Molecular or Systemic Management of Cancer.

Cancer represents one of the most important general health problems of our day [...].

A Systematic Review Investigating the Difference between 1 Cycle versus 2 Cycles of Adjuvant Chemotherapy in Stage I Testicular Germ Cell Cancers.

Standard care for stage I testicular germ cell cancers (seminomatous-STC or non-seminomatous-NSTC) is orchiectomy followed by active surveillance, 1 or 2 cycles of adjuvant chemotherapy, surgery or radiotherapy. The decision on the adjuvant therapeutic approach is guided by the associated risk factors of the patient and the potential related toxicity of the treatment. Currently, there is no consensus regarding the optimal number of adjuvant chemotherapy cycles. Although in terms of overall survival, there is no proven inconsistency regarding the number of cycles of adjuvant chemotherapy, and the rate of relapse may vary.

Ovarian Cancer-Insights into Platinum Resistance and Overcoming It.

Ovarian cancer is the most lethal gynecologic malignancy. Platinum-based chemotherapy is the backbone of treatment for ovarian cancer, and although the majority of patients initially have a platinum-sensitive disease, through multiple recurrences, they will acquire resistance. Platinum-resistant recurrent ovarian cancer has a poor prognosis and few treatment options with limited efficacy. Resistance to platinum compounds is a complex process involving multiple mechanisms pertaining not only to the tumoral cell but also to the tumoral microenvironment. In this review, we discuss the molecular mechanism involved in ovarian cancer cells' resistance to platinum-based chemotherapy, focusing on the alteration of drug influx and efflux pathways, DNA repair, the dysregulation of epigenetic modulation, and the involvement of the tumoral microenvironment in the acquisition of the platinum-resistant phenotype. Furthermore, we review promising alternative treatment approaches that may improve these patients' poor prognosis, discussing current strategies, novel combinations, and therapeutic agents.

Radiopharmaceuticals for PET and SPECT Imaging: A Literature Review over the Last Decade.

Positron emission tomography (PET) uses radioactive tracers and enables the functional imaging of several metabolic processes, blood flow measurements, regional chemical composition, and/or chemical absorption. Depending on the targeted processes within the living organism, different tracers are used for various medical conditions, such as cancer, particular brain pathologies, cardiac events, and bone lesions, where the most commonly used tracers are radiolabeled with 18F (e.g., [18F]-FDG and NA [18F]). Oxygen-15 isotope is mostly involved in blood flow measurements, whereas a wide array of 11C-based compounds have also been developed for neuronal disorders according to the affected neuroreceptors, prostate cancer, and lung carcinomas. In contrast, the single-photon emission computed tomography (SPECT) technique uses gamma-emitting radioisotopes and can be used to diagnose strokes, seizures, bone illnesses, and infections by gauging the blood flow and radio distribution within tissues and organs. The radioisotopes typically used in SPECT imaging are iodine-123, technetium-99m, xenon-133, thallium-201, and indium-111. This systematic review article aims to clarify and disseminate the available scientific literature focused on PET/SPECT radiotracers and to provide an overview of the conducted research within the past decade, with an additional focus on the novel radiopharmaceuticals developed for medical imaging.

Current and New Challenges in the Management of Pancreatic Neuroendocrine Tumors: The Role of miRNA-Based Approaches as New Reliable Biomarkers.

Pancreatic neuroendocrine tumors (PanNETs) are rare tumors; however, their incidence greatly increases with age, and they occur more frequently among the elderly. They represent 5% of all pancreatic tumors, and despite the fact that low-grade tumors often have an indolent evolution, they portend a poor prognosis in an advanced stages and undifferentiated tumors. Additionally, functional pancreatic neuroendocrine tumors greatly impact quality of life due to the various clinical syndromes that result from abnormal hormonal secretion. With limited therapeutic and diagnostic options, patient stratification and selection of optimal therapeutic strategies should be the main focus. Modest improvements in the management of pancreatic neuroendocrine tumors have been achieved in the last years. Therefore, it is imperative to find new biomarkers and therapeutic strategies to improve patient survival and quality of life, limiting the disease burden. MicroRNAs (miRNAs) are small endogenous molecules that modulate the expression of thousands of genes and control numerous critical processes involved in tumor development and progression. New data also suggest the implication of miRNAs in treatment resistance and their potential as prognostic or diagnostic biomarkers and therapeutic targets. In this review, we discusses the current and new challenges in the management of PanNETs, including genetic and epigenetic approaches. Furthermore, we summarize the available data on miRNAs as potential prognostic, predictive, or diagnostic biomarkers and discuss their function as future therapeutic targets.

Absolute and Functional Iron Deficiency in Colon Cancer: A Cohort Study.

Background and Objectives: Iron is an essential micronutrient for many biological functions and has been found to be intimately linked to cancer biology. Although the effects of increased dietary iron consumption in the development of CRC have been previously investigated in several cohort studies, the available evidence on the involvement of iron deficiency in this process is relatively scarce. Previously published papers did not analyze specific outcomes, such as the presence of biologically aggressive histopathological characteristics, that are associated with the subtypes of iron deficiency. The purpose of this study was to investigate the connection between the development of colorectal cancer and the presence of functional iron deficiency (FID), which is defined as insufficient biological availability of iron in the presence of adequate storage reserves, or absolute iron deficiency (AID), which is defined as severely depleted iron storage levels. Materials and Methods: Our paper represents a single center registry-based cohort study. Iron levels were routinely evaluated upon diagnosis of CRC and the collected data were coupled with patient- and tumor-specific data (2018-2022). Spearman's correlation coefficient and the chi-squared test were used to analyze the association. Results: Out of 129 patients, 75 (58.13%) were anemic. AID was identified in 26.35% of cases and FID was encountered in 51.16% of cases. A statistically significant association between FID and lymphatic invasion was encountered. An analysis of the correlation demonstrated a significant association between anemia and right-sided tumor location. Conclusions: Functional iron deficiency seems to be independently associated with lymphatic invasion. Although a statistically significant correlation with the T or N stage was not demonstrated, the analysis suggested a potential positive relationship between the presence of FID and more aggressive tumor characteristics.

Continuous Intravenous Administration of Granulocyte-Colony-Stimulating Factors-A Breakthrough in the Treatment of Cancer Patients with Febrile Neutropenia.

(1) Background: Febrile neutropenia (FN) remains one of the most challenging problems in medical oncology and is a very severe side effect of chemotherapy. Its late consequences, when it is recurrent or of a severe grade, are dose reduction and therapy delays. Current guidelines allow the administration of granulocyte-colony-stimulating factors (G-CSF) for profound FN (except for the case when a pegylated form of G-CSF is administrated with prophylactic intention) in addition to antibiotics and supportive care. (2) Methods: This is a prospective study that included 96 patients with confirmed malignancy, treated with chemotherapy, who developed FN during their oncological therapy, and were hospitalized. They received standard treatment plus a dose of G-CSF of 16 µg/Kg/day IV continuous infusion. (3) Results: The gender distribution was almost symmetrical: Male patients made up 48.96% and 51.04% were female patients, with no significance on recovery from FN (p = 1.00). The patients who received prophylactic G-CSF made up 20.21%, but this was not a predictive or prognostic factor for the recovery time from aplasia (p = 0.34). The median chemotherapy line where patients with FN were included was two and the number of previous chemotherapy cycles before FN was three. The median serological number of neutrophils (PMN) was 450/mm3 and leucocytes (WBC) 1875/mm3 at the time of FN. Ten patients possess PMN less than 100/mm3. The median time to recovery was 25.5 h for 96 included patients, with one failure in which the patient possessed grade 5 FN. Predictive factors for shorter recovery time were lower levels of C reactive protein (p < 0.001) and procalcitonin (p = 0.002) upon hospital admission and higher WBC (p = 0.006) and PMN (p < 0.001) at the time of the provoking cycle of chemotherapy for FN. The best chance for a shorter duration of FN was a short history of chemotherapy regarding the number of cycles) (p < 0.0001). (4) Conclusions: Continuous IV administration of G-CSF could be an alternative salvage treatment for patients with profound febrile neutropenia, with a very fast recovery time for neutrophiles.

MiRNAs roles in the diagnosis, prognosis and treatment of colorectal cancer.

Introduction: The liver is the main location for metastasization in stage IV colorectal cancers. Areas covered: This review intends to comprehensively present the most important studies conducted in the past few years concerning the role of miRNAs in colorectal cancer liver metastases, trying to clarify some aspects regarding tumor biology and favorite liver metastasization site. Expert commentary: Recent advances in tissue and serum RNA extraction has considerably improved the field of microRNAs studies. These molecules known to play a crucial role in the metastatic stage indicate a starting point in the development of clinical biomarkers with a possible role in the stratification of high-risk patients for adequate treatment.

The Impact of miRNA in Colorectal Cancer Progression and Its Liver Metastases.

Colorectal cancer (CRC) is one of the most commonly diagnosed malignancies with a high incidence and mortality rate. An essential challenge in colorectal cancer management is to identify new prognostic factors that could better estimate the evolution and treatment responses of this disease. Considering their role in cancer development, progression and metastasis, miRNAs have become an important class of molecules suitable for cancer biomarkers discovery. We performed a systematic search of studies investigating the role of miRNAs in colorectal progression and liver metastasis published until October 2018. In this review, we present up-to-date information regarding the specific microRNAs involved in CRC development, considering their roles in alteration of Wnt/ßcatenin, EGFR, TGFß and TP53 signaling pathways. We also emphasize the role of miRNAs in controlling the epithelial⁻mesenchymal transition of CRC cells, a process responsible for liver metastasis in a circulating tumor cell-dependent manner. Furthermore, we discuss the role of miRNAs transported by CRC-derived exosomes in mediating liver metastases, by preparing the secondary pre-metastatic niche and in inducing liver carcinogenesis in a Dicer-dependent manner.

The role of biomarkers and echocardiography in the evaluation of cardiotoxicity risk in children treated for leukemia.

PURPOSE: To describe the high-risk profile group, susceptible to develop anthracycline-induced cardiomyopathy in children with acute leukemia. METHODS: The study involved 35 pediatric patients diagnosed with acute lymphoblastic (ALL) or acute myeloblastic leukemia (AML), from March 2014 to December 2016. Serologic markers used for the analysis of cardiac dysfunction were troponin T, NT-proBNP and PCRhs. Also, the patients have had echocardiographic evaluation at the beginning of treatment to determine LVEF, SF and A, E, E' Doppler waves. RESULTS: Positive linear correlation was shown between NT-proBNP and leukocyte values, NT-proBNP and blast cells value, and NT-proBNP and LDH. Significant linear negative correlations between LVEF with leukocyte values, blast cells values, LDH, SF and leukocyte values, LVEF and NT-proBNP values and LVEF and troponin T values were also identified. A weak negative correlation between E/E' ratio and blast cells values has been observed. All of these correlations were statistically significant (p<0.05). CONCLUSIONS: Leukocyte value, as well as the other serological markers assessed (NT-proBNP, Troponin T), are useful tools to evaluate the risk of anthracycline-induced cardiotoxicity. The variation of the biological markers at the beginning of the cytotoxic treatment confirms the presence of an early myocardial dysfunction, emphasizing the importance of systematic evaluation of this particular group of patients.

Platinum derivatives: a multidisciplinary approach.

Cancer is one of the most difficult diseases to be treated. The particularities regarding the tumors' occurrence mechanism, their evolution under chemotherapy, disease-free interval, but also the increasing number of patients make cancer an intensively studied health domain. Although introduced in therapy since the early 80s, platinum derivatives play an essential role in anticancer therapy. Their use in therapy resulted in improving the patient quality of life and prolonging disease-free interval, which makes them still a benchmark for other anticancer compounds. However, adverse reactions and allergic reactions are a major impediment in therapy with platinum derivatives. This paper summarizes data about platinum derivatives through a multidisciplinary approach, starting from a chemical point of view and on to their mechanism of action, mechanism of cellular resistance, predictive factors for the outcome of chemotherapy such as micro RNAs (miRNAs), tumor suppressor protein p53, and the excision repair cross-complementing 1 protein (ERCC1).

Results of third-generation epirubicin/cisplatin/xeloda adjuvant chemotherapy in patients with radically resected gastric cancer.

PURPOSE: The purpose of this study was to evaluate the efficacy and toxicity of a third-generation chemotherapy regimen in the adjuvant setting to radically operated patients with gastric cancer. This proposed new adjuvant regimen was also compared with a consecutive retrospective cohort of patients treated with the classic McDonald regimen. METHODS: Starting in 2006, a non-randomized prospective phase II study was conducted at the Institute of Oncology of Cluj-Napoca on 40 patients with stage IB-IV radically resected gastric adenocarcinoma. These patients were administered a chemotherapy regimen already considered to be standard treatment in the metastatic setting: ECX (epirubicin, cisplatin, xeloda) and were compared to a retrospective control group consisting of 54 patients, treated between 2001 and 2006 according to McDonald's trial. RESULTS: In a previous paper, we reported toxicities and the possible predictive factors for these toxicities; in the present article, we report on the results concerning predictive factors on overall survival (OS) and disease free survival (DFS). The proposed ECX treatment was not less effective than the standard suggested by McDonald's trial. Age was an independent prognostic factor in multivariate analysis. N3 stage was an independent prognostic factor for OS and DFS. N ratio >70% was an independent predictive factor for OS and locoregional disease control. The resection margins were independent prognostic factors for OS and DFS. CONCLUSION: The proposed treatment is not less effective compared with the McDonald's trial. Age was an independent prognostic factor in multivariate analysis. N3 stage represented an independent prognostic factor and N ratio >70% was a predictive factor for OS and DFS. The resection margins were proven to be independent prognostic factors for OS and DFS.

Hypersensitivity reactions to platinum derivatives: findings of new predictive markers.

PURPOSE: Platinum derivatives play a very important role in cancer therapy. Despite their outstanding results in the treatment of tumors with different locations, the occurrence of hypersensitivity reactions raises issues when it comes to therapy decision, because the changing of chemotherapy line could influence the tumor's evolution. Over the years the scientific community has paid particular attention to the mechanism by which this occurs and to identification of predictive factors. The purpose of this case-control, retrospective study was to find new predictive markers for the occurrence of allergic reactions to platinum derivatives. METHODS: We identified 59 cases of allergic reactions to platinum derivatives in the Oncology Institute "Prof. Dr. Ion Chiricuta" from Cluj-Napoca city in 2013. Blood tests data were analyzed before the administration of the cycle on which the allergic reaction occurred, along with the mandatory analyses for the patients and we focused on the values of neutrophils, lymphocytes, monocytes, eosinophils and basophils. RESULTS: When these values were compared with the values of the control group (,which was made at a ratio of 1:2 or 1:3, matched for age, tumor location and chemotherapy cycle) we found that each increase of lymphocytes or doses of platinum and each drop in monocytes number increased the risk for allergic reactions to occur. CONCLUSION: These findings are of a great value for the physicians and represent a starting point for more detailed studies.

Therapeutic Plasma Exchange in Catastrophic Antiphospholipid Syndrome (CAPS): A Rare Case Report and Literature Review.

BACKGROUND/AIM: Catastrophic antiphospholipid syndrome (CAPS) may be the first manifestation ("de novo") of antiphospholipid syndrome (APS) or a complication in the clinical course of patients known to have this syndrome. Approximately 40% of patients had an associated autoimmune disease, mainly, systemic lupus erythematosus (SLE). The trigger can be one of the following: infections, surgical interventions, neoplasms, pregnancy, discontinuation of anticoagulant treatment, and others. CAPS is a medical emergency in which early identification and prompt initiation of aggressive therapy is extremely important. According to the Guidelines for the use of Therapeutic Apheresis in Clinical Practice developed by the American Society for Apheresis (ASFA), last updated in April 2023, in CAPS, the indication for therapeutic plasma exchange (TPE) is category I, grade 2C. CASE REPORT: We present a case of probable CAPS secondary to systemic lupus erythematosus (SLE) in an elderly patient in whom clinical and biological improvement was achieved through a multidisciplinary approach and prompt initiation of TPE. Because TPE is considered first-line therapy in CAPS, we initiated the procedure as soon as the attending rheumatologist raised this suspicion. Four plasmapheresis sessions were performed in the Intensive Care Unit. We used TPE by membrane filtration. Following the therapeutic intervention with TPE, corticotherapy (Solumedrol in puls-therapy), cyclophosphamide and anticoagulant treatment, the evolution was favourable, with clinical and biological improvement. CONCLUSION: The prompt initiation of TPE, because of the suspicion of CAPS, increases the chances of a favourable evolution.

Influenza A, Influenza B, and SARS-CoV-2 Similarities and Differences - A Focus on Diagnosis.

In late December 2019, the first cases of viral pneumonia caused by an unidentified pathogen were reported in China. Two years later, SARS-CoV-2 was responsible for almost 450 million cases, claiming more than 6 million lives. The COVID-19 pandemic strained the limits of healthcare systems all across the world. Identifying viral RNA through real-time reverse transcription-polymerase chain reaction remains the gold standard in diagnosing SARS-CoV-2 infection. However, equipment cost, availability, and the need for trained personnel limited testing capacity. Through an unprecedented research effort, new diagnostic techniques such as rapid diagnostic testing, isothermal amplification techniques, and next-generation sequencing were developed, enabling accurate and accessible diagnosis. Influenza viruses are responsible for seasonal outbreaks infecting up to a quarter of the human population worldwide. Influenza and SARS-CoV-2 present with flu-like symptoms, making the differential diagnosis challenging solely on clinical presentation. Healthcare systems are likely to be faced with overlapping SARS-CoV-2 and Influenza outbreaks. This review aims to present the similarities and differences of both infections while focusing on the diagnosis. We discuss the clinical presentation of Influenza and SARS-CoV-2 and techniques available for diagnosis. Furthermore, we summarize available data regarding the multiplex diagnostic assay of both viral infections.

The Effect of Convalescent Plasma in Patients With Covid-19 in Intensive Care Unit.

BACKGROUND/AIM: Convalescent plasma collected from COVID-19 survivors contains antibodies against receptor binding domains with potent antiviral activity. The use of this therapy for COVID-19 is still under investigation, as the pathophysiological and immunological mechanisms responsible for the evolution of the disease have not been fully identified. PATIENTS AND METHODS: In this retrospective observational study, we included all patients with a confirmed SARS-Cov-2 infection based on positive RT-PCR testing, who received convalescent plasma treatment in addition to standard therapy, between 17.05.2020 and 27.11.2020, following hospitalization in the Anaesthesia and Intensive Care Unit of the Sibiu County Emergency Clinical Hospital, Romania. RESULTS: Convalescent plasma therapy of patients with SARS-Cov-2 infection and severe forms of the disease (requiring only high-flow oxygen therapy or non-invasive ventilation) significantly improved inflammatory markers (CRP, fibrinogen) and ventilatory parameters (SaO2, paO2, paO2/FiO2) reducing the need of supplemental oxygen delivery (p<0.05). Other factors that had a significant influence on the outcome were age and comorbidity. CONCLUSION: Inflammatory markers and ventilatory parameters were significantly improved and the need of supplemental oxygen delivery was reduced in COVID-19 patients treated with convalescent plasma.

MRI Evaluation of Complete and Near-Complete Response after Neoadjuvant Therapy in Patients with Locally Advanced Rectal Cancer.

Purpose To evaluate MRI performance in restaging locally advanced rectal cancers (LARC) after neoadjuvant chemoradiotherapy (nCRT) and interobserver agreement in identifying complete response (CR) and near-complete response (nCR). Methods 40 patients with CR and nCR on restaging MRI, surgery and/or endoscopy were enrolled. Two radiologists independently scored the restaging MRI and reported the presence of split scar sign (SSS) and MRI tumor regression grade (mrTRG). Diagnostic accuracy and ROC curves were calculated for single and combined sequences, with inter-reader agreement. Results Diagnostic performance was good for detecting CR and weaker for nCR. T2WI had the highest AUCs among individual sequences. There was a significant positive correlation between SSS and CR, with high Sp (89.5%/73.7%) and PPV (90%/79.2%) for both Readers. Similar accuracy rates were observed for the combination of sequences, with AUCs of 0.828-0.847 for CR and 0.690-0.762 for nCR. Interobserver agreement was strong for SSS, moderate for T2WI, weak for the combination of sequences. Conclusions Restaging MRI had good diagnostic performance in identifying CR and nCR. SSS had high Sp and PPV in diagnosing CR, with a strong level of interobserver agreement. T2WI with DWI was the optimal combination of sequences for selecting good responders.

Biventricular cardiac metastasis from vulvar squamous cell carcinoma.

Vulvar cancers make up just 3% to 5% of all gynecological cancers, and they are most typically found in postmenopausal women. Vulvar cancer distant metastases are uncommon and usually arise late. Only six cases of vulvar cancer metastasizing to the heart have been reported in the literature, and none of them included both the left and right ventricles. We describe the case of a 68-year-old patient diagnosed with vulvar cancer arising from lichen sclerosus, initially localized, treated with chemotherapy, surgery, and radiation therapy. Less than two months after the end of the treatment sequence, the patient returned to our clinic with bone pain. Imaging investigations have shown multiple disseminated metastases, but not in the heart at that moment. Chemotherapy was initiated, and after two cycles, the patient developed an arrhythmia (atrial fibrillation with rapid ventricular rate), which was later determined to be caused by cardiac metastases discovered by echocardiography and computed tomography. Vulvar cancer metastatic to the heart represents a rare clinical condition, requiring multidisciplinary care. The case's uniqueness is the biventricular metastasis, which resulted in STEMI despite angiographically normal epicardial coronary arteries.