5-fluorouracil therapeutic drug monitoring and adverse events in a Romanian population.

Fluoropyrimidines represent the backbone of many chemotherapy protocols and the standard treatment for many types of tumors. Toxicity associated with fluoropyrimidines can occur in up to 40% of cases. Background and purpose: The objective of this study was to analyze the correlation between the plasma concentration of 5-fluorouracil and the adverse events that patients might experience during this therapy. Methods: A total of 58 patients received 5-fluorouracil-based chemotherapy. A blood sample was collected from each patient during the drug infusion, in order to assess the area under the curve for 5-fluorouracil. The occurring adverse events were evaluated through medical recordings of the patients' reported symptoms, clinical and paraclinical examinations. Results: In our study, the majority of patients experienced some type of toxicity. Moreover, we found a correlation between 5-FU plasma concentration (expressed as AUC) and adverse events, a stronger one with hematological adverse reactions and a weaker one with gastrointestinal and cardiovascular toxicity. Conclusion: Determining the plasma concentration of 5-FU in patients with severe toxicities could represent a method of individualizing the treatment and improving the safety profile.

RediScore: Prospective validation of a pipeline for homologous recombination deficiency analysis.

Tumors harboring homologous recombination deficiency (HRD) are considered optimal candidates for poly(ADP-ribose) polymerase 1 (PARP) inhibitor treatment. Such deficiency can be detected by analyzing breast cancer type (BRCA)1/2 gene mutations, as well as mutations in other genes of the homologous recombination pathway. The algorithmic measurement of the HRD effect by identifying genomic instability (GI) has been used as biomarker. As compared with the direct measurement of somatic gene alterations, this approach increases the number of patients who could benefit from PARP inhibitor treatment. In the present study, the performance of the Oncoscan CNV assay, accompanied by appropriate bioinformatic algorithms, was evaluated for its performance in GI calculation and was compared with that of a validated next-generation sequencing (NGS) test (myChoice HRD test). In addition, the clinical utility of the GI score (GIS) and BRCA1/2 tumor analysis were investigated in a cohort of 444 patients with ovarian cancer. For that reason, single nucleotide polymorphism (SNP) arrays and appropriate bioinformatics algorithms were used to calculate GIS in 29 patients with ovarian cancer with known GIS status using a validated NGS test. Furthermore, BRCA1/2 analysis results were compared between the aforementioned assay and the amplicon-based Oncomine™ BRCA Research Assay. BRCA1/2 analysis was performed in 444 patients with ovarian cancer, while GIS was calculated in 175 BRCA1/2-negative cases. The bioinformatics algorithm developed for GIS calculation in combination with NGS BRCA1/2 analysis (RediScore), and the OncoscanR pipeline exhibited a high overall agreement with the validated test (93.1%). In addition, the Oncomine NGS assay had a 100% agreement with the validated test. The BRCA1/2 mutation frequency was 26.5% in the examined patients with ovarian cancer. GIS was positive in 40% of the BRCA1/2-negative cases. The RediScore bioinformatics algorithm developed for GIS calculation in combination with NGS BRCA1/2 analysis is a viable and effective approach for HRD calculation in patients with ovarian cancer, offering a positive prediction for PARP inhibitor responsiveness in 55% of the patients.

An insight into lung cancer: a comprehensive review exploring ALK TKI and mechanisms of resistance.

Implementation of precision medicine in lung cancer has benefited from intense research in the past years, developing subsequently an improved quality of life and increased overall survival of the patients. Targeted therapy has become one of the most important therapeutic innovations for the non-small cell lung cancer (NSCLC) category with anaplastic lymphoma kinase (ALK) gene rearrangement. The aim of this review is to provide a through overview of the main molecules of ALK tyrosine kinase inhibitors (TKI) with their general and particular mechanisms of resistance, the main methods of ALK gene detection, each with advantages and limits and the future perspectives currently under research which try to overcome the mechanisms of resistance. We have used two of the most reliable medical databases EMBASE and PubMed to properly select the latest and the most relevant articles for this topic. Encouraged by the promising results, the clinical practice was enriched by the approval of tyrosine kinase inhibitor molecules, three generations being developed, each one with more powerful agents than the previous ones. Unfortunately, the resistance to TKI eventually occurs and it may be induced by several mechanisms, either known or unknown. Crizotinib was the most intensely studied TKI , becoming the first molecule approved into clinical practice and although four other drugs have been broadly used (alectinib, ceritinib, brigatinib and lorlatinib) it seems that even the most recently developed one remains imperfect due to the resistance mutations that developed. There are two types of resistance generally described for the entire class and for the particular drugs, but half of them remain unknown.

Adrenal Gland Primary Neuroblastoma in an Adult Patient: A Case Report and Literature Review.

Neuroblastoma (NB) is an undifferentiated malignant tumor of the sympathetic ganglia, occurring in children under 5 years of age. However, it is a rare histology in adult patients, occurring once per every 10 million patients per year. We present the case of a 68-year-old male patient presented to our department for right lumbar pain, asthenia, loss of weight and altered general status. The contrast-enhanced abdominal computer tomography revealed bilateral adrenal tumoral masses of 149 mm and 82 mm on the right and left sides, respectively, with invasion of the surrounding organs. The patient underwent right 3D laparoscopic adrenalectomy and right radical nephrectomy. The pathological result concluded that the excised tumor was a neuroblastoma of the adrenal gland. The patient followed adjuvant oncological treatment; however, due to disease progression, he passed away 22 months after the surgery. To our knowledge, less than 100 cases of adrenal NB in adult patients have been published, the eldest case being diagnosed at 75 years of age; meanwhile, the largest reported tumor measured 200 mm, and was excised through open surgery. Minimally invasive techniques have been limited so far to smaller, organ-confined diseases, thus making the present case the largest adrenal NB removed entirely laparoscopically. Neuroblastoma in the adult population is a rare finding, with worse prognosis compared to pediatric patients. The available literature does not provide enough data for standardized, multimodal management, as the patients are treated following adapted pediatric protocols, thus reinforcing the need for international, multidisciplinary boards for rare tumors.

Nigella sativa: Valuable perspective in the management of chronic diseases.

OBJECTIVES: Over the past 20 years, increasing interest in the use of medicinal plants as alternative or adjuvant treatments of several chronic diseases was observed. Accordingly, Nigella sativa or black cumin, a medicinal plant rich in bioactive compounds, has been used worldwide for food purposes or in traditional medicines. This paper aims to reveal N. sativa potential as adjunct treatment in cardiovascular diseases, diabetes, and hematological malignancies, due to their increasing prevalence and difficult management in everyday life. MATERIALS AND METHODS: Databases like PubMed, Web of Science, Science Direct, Scopus, and Google Scholar were used to search the literature data. Keywords like anti-inflammatory effect, anti-oxidant effect, antihypertensive effects, hypolipidemic effects and hematological malignancies were used in combination with N. sativa. RESULTS: Because of its numerous pharmacological actions, but especially for its anti-oxidant and anti-inflammatory properties, in vivo and in vitro studies demonstrated N. sativa positive effect against diabetes, hypertension, and hypercholesterolemia, all of them associated to cardiovascular diseases progression. Also, it was proved to have marked anti-proliferative, cytotoxic, pro-apoptotic, and anti-metastatic effects, in both solid cancers and hematological malignancies. CONCLUSION: N. sativa used as complementary treatment to classical medications can improve the management of several chronic diseases.

Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for the Treatment of Peritoneal Carcinomatosis: Our Initial Experience.

Introduction: Peritoneal carcinomatosis represents an advanced stage of tumor dissemination of abdominal cancers in general and colorectal cancer in particular. The only therapeutic methods currently available for the treatment of this pathology are systemic chemotherapy (palliative character) and cytoreductive surgery (CR) with intraperitoneal chemotherapy. After evaluation of evidence-based medical literature and current guide lines we can state that CR + HIPEC procedure is considered to be the treatment of choice in case of patients with peritoneal carcinomatosis of colorectal, ovarian and mucinous appendicular origin. Material and method: In the present study we prospectively analyzed the immediate postoperative results obtained in the first 50 patients that were treated by our team for peritoneal carcinomatosis of different origin. We described the protocol of selection, the patients characteristics that were included in our CR+HIPEC program and analyzed the complications and death rate. Results: From January 2015 till Dec 2018 we evaluated 98 patients with peritoneal carcinomatosis. From them, 51 received radical CR+HIPEC treatment, 33 were not suitable for surgery because of the exclusion criteria's and 15 had only exploratory laparotomies. In regard with the histopathological diagnosis, 30 patients had ovarian cancer and 19 had colorectal cancer or peritoneal pseudomixoma of appendicular origin. There was no 30 days postoperative mortality. The incidence of significant postoperative complications was 15%. Conclusions: Cytoreductive surgery followed by hyperthermic intraperitoneal chemotherapy is a complex technique accompanied by an acceptable rate of complications and postoperative deaths, the results being optimized by a standardized perioperative management and patient selection. The initial results obtained by our team emphasize the feasibility of this procedure, with immediate good results, as a result of a standardization protocol of patient selection and perioperative care.

Incidental findings during follow-up scans in oncological patients.

BACKGROUND AND AIM: To assess the prevalence of incidental findings during follow-up scans of patients with oncologic pathology. METHODS: 499 follow-up scans from different patients with cancer pathology were retrospectively analyzed. Findings which were not suspected by the clinician or known from previous scans were considered as incidental lesions. We excluded lesions that were already suspected by the clinician or were already recorded in the patient's history before the initial computed tomography (CT) scan. The CT scans were performed on two different machines ("Siemens Somatom Sensation, 64 slices, Erlangen, Germany" and "Siemens Somatom Emotion, 16 slices, Erlangen, Germany").Most of the patients had a native scan followed by a thoraco-abdominal-pelvic image acquisition after the injection of intravenous contrast media. RESULTS: 28% of the patients had unsuspected incidental findings. The prevalence of incidental findings was similar: 56.6% of them were found in men and 43.4% in female patients. In 6 cases (1.2%) the presence of unsuspected pulmonary embolism was discovered. From these cases, 5 (83.3%) had metastatic disease at the moment of the follow-up CT scan and 1 (16.6%) had metastasis-free disease. In 17 patients out of 499 (3.4%) we incidentally made an important discovery which either changed the cancer therapy or required immediate treatment. CONCLUSION: Incidental findings are not rare in oncological patients and the radiologist has to be aware of their presence in order not to overlook them and to correctly diagnose them.

Hyperthermic intraperitoneal chemotherapy (HIPEC). Mechanisms of action and the role of HIPEC in the treatment of peritoneal carcinomatosis.

Peritoneal carcinomatosis represents the advanced, final stage of peritoneal malignancy, although it is often not accompanied by systemic neoplasia. The development of the pharmaceutical industry in combination with advanced surgery techniques has helped to improve the outcome of these patients, considered for a long time without radical resources. Tumoral cytoreduction followed by hypertermic intraperitoneal chemotherapy (HIPEC) is the treatment of choice for these patients, of course, this beeing done in a multimodal treatment, carefully chosen, following a multidisciplinary consensus. In this article we reviewed the main aspects of HIPEC procedure, describing the main chemotherapeutic agents used, highlighting the role that they play in this oncological treatment. Finally, we have pinpointed the main research lines in this field, which although have a well-established role in recent guidelines, have a great potential for development, with a maximum impact on the prognosis of patients with peritoneal metastases. KEY WORDS: Cytoreductive surgery, Hyperthermia, Intraperitoneal chemotherapy, Pharmacology, Peritoneal metastasis.

The role of the diffusion sequence in magnetic resonance imaging for the differential diagnosis between hepatocellular carcinoma and benign liver lesions.

BACKGROUND AND AIM: To assess the role of diffusion weighted imaging sequence (DWI), routinely used in hepatic magnetic resonance imaging (MRI) for the differentiation of hepatocellular carcinoma (HCC) from benign liver lesions. METHODS: A number of 56 liver MRI examinations were retrospectively analyzed independently by two experienced radiologists, blinded to each other results. A total number of 70 Focal Liver Lesions (FLLs) assessed by liver MRI in 56 patients were included in the present study. All lesions were retrospectively analyzed by two experienced radiologists, independently from each other and who were not aware of the previous results given by using different imaging techniques. All included FLLs had a final histological diagnosis, or the final diagnosis was based on consensus reading by two experienced radiologists. The signal of the included FLLs was qualitatively appreciated on the b-800 sequences and on the apparent diffusion coefficient (ADC) map. The ADC value of each FLL was measured and the ADC ratio between the ADC value of the assessed FLL and that of the surrounding liver parenchyma was calculated. RESULTS: The mean ADC value for benign FLLs as assessed by the two independent readers was 1.75 × 10(-3) and 1.72 × 10(-3). The mean ADC value for HCC nodules was 0.92 × 10(-3) for the first reader and 0.91 × 10(-3) for the second reader respectively. The mean ADC ratio for benign FLLs was 1.81 and 1.84 for the two readers, respectively. The ADC ratio for HCC nodules was 0.91 and 0.91, respectively. The ADC value is an indicator which is less prone to interobserver variability (correlation of 0.919→1). The ADC ratio has, as the analysis of the ROC curve shows, the best predictive value for differentiation between benign FLLs and HCC nodules. Analysis of the signal intensity on the DWI b-800 image alone is of no significance in differentiating benign FLLs from HCC nodules (p>0.005). CONCLUSIONS: The ADC value and the ADC ratio assessed on liver DWI are useful diagnostic tools in the differential diagnosis of benign FLLs vs HCC nodules. Quantitative methods such as calculating the ADC value or ADC ratio have better diagnostic value than qualitative techniques.

Diffusion Weighted Magnetic Resonance Imaging for the Classification of Focal Liver Lesions as Benign or Malignant.

BACKGROUND AND AIMS: To assess the role of diffusion weighted imaging sequence (DWI), routinely used in hepatic magnetic resonance imaging (MRI) for the differentiation of focal liver lesions (FLLs) as benign or malignant. METHOD: 99 FLLs assessed by liver MRI in 80 patients were included in the present study. All lesions were retrospectively analyzed by two experienced radiologists, independent from each other, who were not aware of the previous results obtained by using different imaging techniques. All included FLLs had a final histological diagnosis or a final diagnosis based on consensus reading by two experienced radiologists and follow-up at 6 months. The FLLs signal was qualitatively appreciated on the b-800 sequences and on the apparent diffusion coefficient (ADC) map. The ADC value of each FLL was measured and the ADC ratio between the ADC value of the assessed FLL and that of the surrounding liver parenchyma were calculated. RESULTS: The mean ADC value for benign FLLs as assessed by the two independent readers was 1.78 x 10¯³ and 1.72 x 10¯³, respectively. The mean ADC value for malignant FLLs was 0.92 x 10¯³ for the first reader and 0.95 x 10¯³ for the second reader. The mean ADC ratio for benign FLLs was 1.91 and 1.85 for the two readers and for malignant FLLs was 0.91 and 0.94, respectively. Using an ADC value lower than 1.024 x 10¯³ offers a specificity of 100% and a sensitivity of 62.5% for the diagnosis of malignant FLLs. The ADC value is an indicator which is less prone to interobserver variability (correlation of 0.919→1). The ADC ratio has, as the analysis of the ROC curve shows, the best predictive value for differentiation between benign and malignant FLLs. Analysis of the signal intensity on the DWI b-800 image alone is of no significance in differentiating benign from malignant FLLs (p>0.05). CONCLUSIONS: The ADC value and the ADC ratio assessed on liver DWI are useful diagnostic tools in the differential diagnosis of benign vs. malignant FLLs. Quantitative methods such as calculating the ADC value or ADC ratio have better diagnostic value than the qualitative techniques.