Outcomes of patients with cancer infected with SARS-CoV-2: results from the Ion Chiricuta Oncology Institute series.

BACKGROUND: The evolution of COVID-19 is a controversial topic in cancer patients. They have been designated by international organizations as a vulnerable population at greater risk for contracting SARS-CoV-2 and having a more severe clinical outcome. PATIENTS AND METHODS: Active screening at our institution became routine early in the pandemic. We have examined the clinical data of 341 cancer patients, with a positive RT-PCR SARS-CoV-2 test between April 2020 and February 2021, in the prevaccination era. RESULTS: During the infection, 40.5% remained asymptomatic, 27.6% developed a mild form, 20.5% had a moderate form, and 11.4% a severe/critical form of COVID-19 that led to death in 7.6% of cases. Treatment was adapted to disease severity according to national guidelines. In our series, the incidence of COVID-19 infection was lower in cancer patients compared with the general population (P < 0.001), however, the mortality rate was higher in cancer patients in comparison with the general population (7.6% versus 2.9%, P < 0.001). The prognostic factors were assessed by three distinct univariate and multivariate analyses: (i) evolution to a moderate or severe/critical clinical manifestation, (ii) clinical worsening (severe/critical form or death), and (iii) overall survival. In the multivariate analysis, the prognostic factors associated with the evolution to a moderate or severe/critical clinical manifestation were: performance status (PS) (P < 0.0001) and no active treatment in the previous 3 months (P = 0.031). Factors associated with clinical worsening were: PS (P < 0.0001), peripheral arterial disease (P = 0.03), and chronic liver disease (P = 0.04). Factors associated with impaired overall survival were PS (P < 0.0001), ischemic cardiac disease (P = 0.0126), chronic liver disease (P = 0.001), and radiotherapy (P = 0.0027). CONCLUSION: Our series confirms a more severe evolution for COVID-19 infection in cancer patients, with PS as the most prominent prognostic factor in all three multivariate analyses. By active screening, efforts should be in place to keep cancer units as coronavirus-free sanctuaries.

RARE MALIGNANT FEMALE ADNEXAL TUMOR OF WOLFFIAN ORIGIN (FATWO) WITH MULTIPLE RELAPSES AND CHEMOTHERAPY REGIMENS.

CONTEXT: Female adnexal tumors of probable Wolffian origin (FATWO) represent very rare borderline ovarian tumors with low malignant potential. Only 15 cases of malignant FATWO are described in the current literature, among which, only 5 are reported as being recurrent. OBJECTIVE: Due to the rare presentation of the recurrence of the malignant FATWO and the few cases reported in the scientific database, there are no clear therapy recommendations. This paper should help practitioners to choose the best therapy approach. DESIGN: This paper presents the 6th case of malignant recurrent FATWO and will compare all the cases available in the literature. SUBJECTS AND METHODS: We present a review of the literature comparing the therapeutic approaches and outcomes of all the five cases of recurrent malignant FATWOs. Also, we introduce the case of a stage III Wolffian origin adnexal tumor with multiple recurrences appeared after 6 years of disease free interval. RESULTS: Our case presents the longest survival reported in the literature and underwent most surgical procedures of the recurrences and more than 4 lines of chemotherapy regimens. CONCLUSIONS: This paper shows possible therapeutic approaches to be used as example by the practitioners according to the drug availability in their centers.

GSTM1, GSTT1 and GSTP1 Genetic Variants in Multiple Urologic Cancers.

INTRODUCTION: Glutathione S-transferases (GSTs) are phase 2 enzymes responsible for catalyzing the biotransformation of a wide variety of electrophilic compounds, having a crucial role in the detoxification of active metabolites of procarcinogens produced by phase 1 reactions, tying them to glutathione and promoting their excretion in the urine. OBJECTIVES: we evaluated GSTM1, GSTT1 and GSTP1 genotypes in patients diagnosed with multiple malignancies, of which at least one was found in the prostate, bladder or kidney. MATERIALS AND METHODS: GSTM1, GSTT1 and GSTP1 genotypes were genetically assessed in 34 patients with multiple urologic cancers and 23 patients with urologic cancer associated with another type of cancer. RESULTS: in the group of patients with multiple urologic cancers, GSTT1 null genotype was found in 26.4% of patients compared to 0% in controls, 82.35 % of patients and 47% of witnesses carried at least one GSTM1 or GSTT1 null genotype, and in the group with different cancers, GSTM1 null genotype was found in 52.1% of patients compared to 4.3% witnesses in the control group; GSTT1 null genotype was found in 34.7% of patients compared to 4.3% of witnesses, atleast one GSTM1 or GSTT1 null genotype was found in 73.9% of patients compared to 8.6% of controls. CONCLUSIONS: GSTT1 null genotype is a risk factor for patients with more primitive urologic malignancies (bladder, prostate and kidney); GSTM1 or GSTT1 null genotype is more frequent in patients with multiple urologic tumors; GSTM1 and GSTT1 null genotypes are risk factors in patients with different types of cancer, with at least one affecting the urinary system.

GSTM1, GSTT1 and GSTP1 in patients with multiple breast cancers and breast cancer in association with another type of cancer.

INTRODUCTION: breast cancer has the highest incidence in women.Glutathione S-transferases (GSTs) are a large group of enzymes involved in the metabolism of xenobiotics. The members of this gene superfamily are involved in the development of multiple cancers. OBJECTIVES: the aim of the study was to see whether the GSTM1, GSTT1 and GSTP1 genetic polymorphisms are risk factors for patients diagnosed with multiple malignancies, of which at least one is located in the breast. MATERIALS AND METHODS: in the period between 2005 and 2012,of the 520 patients diagnosed with breast cancer, 69 had multiple primitive malignant tumors, of which at least one was localized in the breast. The research on GSTM1, GSTT1 and GSTP1 genotypes consisted of 59 patients diagnosed with multiple breast cancers or with breast cancer in association with another type of cancer, compared with a group of healthy controls. RESULTS: in the subgroup of patients with breast cancer in association with another type of cancer, the GSTM1 null genotype was present in 61.2% of patients, compared to 29% of controls; the subgroup of metachronous breast cancers, the presence of any of the GSTT1 or GSTM1 null genotypes was statistically significantly different from that of controls (65.2%vs. 28.5%); in the subgroup with synchronous cancers, the GSTM1 null genotype was found in 66.6% of patients compared to 9% for the controls, and the presence of any null genotype (GSTM1 and GSTT1) was also statistically significant in the case group. CONCLUSIONS: the GSTM1 null genotype is a risk factor for synchronous breast cancers and for breast cancer associated with extramammary cancer; the presence of null genotypes(GSTM1 or GSTT1) is a risk factor for multiple breast cancer(bilateral or synchronous); the GSTT1 null genotype and the heterozygous variant allele (Ile105Val) and homozygous variant allele (Val105Val) of GSTP1 are not risk factors for the cases studied.

Multiple malignant tumors.

BACKGROUND: Due to the improvement in diagnosis and therapy for certain malignant tumors, we are now faced with patients who develop in time multiple malignancies. METHODS: We conducted a retrospective analysis of the patients diagnosed with at least two primary cancers that were admitted and treated in Cluj-Napoca Municipal Hospital. The study followed patients for a period of 7.5 years. RESULTS: We included in the present study 217 patients (4.33%) with two or more malignant primary tumors from 5003 cases diagnosed with a primary cancer. The most common sites for multiple malignant tumors were related to the breast, colorectum, urinary bladder, prostate and kidneys. CONCLUSIONS: We should always take into consideration the possibility of synchronous tumors and we have to keep in mind that a successful treatment of cancer might not prevent the onset of another primary mass.

GST gene variants in synchronous colorectal cancers and synchronous association of colorectal cancers with other cancers.

BACKGROUND: the present study evaluates genetic polymorphisms of three glutathione S-transferases (GSTM1, GSTT1and GSTP1) in patients with synchronous malignant colorectal tumors and the association of synchronous colorectal cancers with other cancers. MATERIAL AND METHODS: from 420 patients with a colorectal cancer admitted to our hospital between 2005-2012, we selected for genetic analysis 20 patients with multiple synchronous malignant colorectal tumors and 9 patients with asynchronous association of colorectal cancer with another cancer. We searched for GST genotypes, comparing the results with controls. RESULTS: the genetic analysis was possible only in 19 patients with colorectal synchronous cancers and 9 patients with asynchronous association of colorectal cancer with another cancer; we found a statistically significant difference for null GSTM1 genotype frequency between these patients and the control group; we found no differences regarding the frequency of null GSTT1 genotype and Ile105Val polymorphism of GSTP1 in patients with synchronous cancers compared with the control group. CONCLUSION: in our study we found the null GSTM1 genotype as a risk factor for multiple colorectal synchronous cancers and for an association of synchronous colorectal with other cancers

Identifying molecular features for prostate cancer with Gleason 7 based on microarray gene expression profiles.

Prostate cancer represents the first leading cause of cancer among western male population, with different clinical behavior ranging from indolent to metastatic disease. Although many molecules and deregulated pathways are known, the molecular mechanisms involved in the development of prostate cancer are not fully understood. The aim of this study was to explore the molecular variation underlying the prostate cancer, based on microarray analysis and bioinformatics approaches. Normal and prostate cancer tissues were collected by macrodissection from prostatectomy pieces. All prostate cancer specimens used in our study were Gleason score 7. Gene expression microarray (Agilent Technologies) was used for Whole Human Genome evaluation. The bioinformatics and functional analysis were based on Limma and Ingenuity software. The microarray analysis identified 1119 differentially expressed genes between prostate cancer and normal prostate, which were up- or down-regulated at least 2-fold. P-values were adjusted for multiple testing using Benjamini-Hochberg method with a false discovery rate of 0.01. These genes were analyzed with Ingenuity Pathway Analysis software and were established 23 genetic networks. Our microarray results provide new information regarding the molecular networks in prostate cancer stratified as Gleason 7. These data highlighted gene expression profiles for better understanding of prostate cancer progression.

The clinical implications of platelet derived growth factor B, vascular endothelial growth factor and basic fibroblast growth factor in colorectal cancer.

Colorectal cancer (CRC) remains a major health problem worldwide. Angiogenesis is a key process for tumor growth and metastasis. The conversion of tumor cells to an angiogenic phenotype involves the change in the balance of angiogenic growth factors and angiogenesis inhibitors. In our study we evaluated by qRT-PCR the level of expression of 3 growth factors involved in angiogenesis: platelet derived growth factor-B (PDGFb), vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (bFGF) in patients with different stages of colon cancer. Our results showed the level of VEGF increased on all tumor without difference, statistically significant according with tumor stage whereas the others the levels of bFGF and PDGF were higher, statistically significant, on tumor classified stage B compared with stage C. The early implication of these molecules in colon carcinogenesis justifies the development of new biologic individualized therapies.

Expression of VEGF, VEGFR, EGFR, COX-2 and MVD in cervical carcinoma, in relation with the response to radio-chemotherapy.

INTRODUCTION: Despite the improvement in the treatment results due to modern irradiation techniques and to the association of chemo-radiotherapy, cervical cancer remains an unsolved problem of oncology both due to the increased rate of local failures and of the distant metastasis. Efforts to implement new therapeutic strategies in order to obtain better results in patients with cervical cancer appear justified. Neovascularization is an important step in the tumor progression and the therapeutic targeting of the tumor blood vessels appears to be a good strategy to follow in the anti-cancer treatment. Thus, even in an incipient phase of the clinical research process, the combination between the anti-angiogenic aimed therapies and the current radio-chemotherapy seems to represent a new, feasible and promising approach. The aim of the present study was to determine the prognostic and/or predictive value of some biological markers of tumor angiogenesis and of their implication in increasing the efficacy of current treatments for this cancer. MATERIALS AND METHODS: So far, 54 women were included in a prospective trial: 44 having an advanced cervical carcinoma and 10 healthy women, as controls. A tumor biopsy and a blood sample were obtained from each patient before the start of therapy. The density of microvascularization was assessed using CD34 monoclonal antibody (hot spot technique), the expression of angiogenic factors VEGFR, EGFR and COX-2 were determined in tumor biopsies by specific immunohistochemistry techniques, using primary antibodies anti-EGFR, anti-VEGF and anti-COX-2 respectively. The quantitative polymerase chain reaction (Real Time PCR) was employed for assessing the expression level of the genes involved. Serum VEGF was determined by quantitative ELISA technique. RESULTS: Among the studied clinical and molecular factors, we found to be predictive for the type of response the following factors: tumor size at diagnosis (p=0.01), VEGFR2 expression (p=0.02) and a tendency to significance for patients' age (p=0.06). From the large panel of studied markers it was observed correlation between MVD expression with stromal COX-2 (p=0.01) and a tendency with epithelial COX-2 (p=0.06). Stromal COX-2 has higher correlation with VEGFR2 (p=0.01) and MVD (p=0.01) and also has a lower correlation with tumor size (p=0.08). CONCLUSIONS: Univariate analysis demonstrates that the response to radio-chemotherapy in cervical cancer is related to a set of clinical and molecular factors as: the tumor size, the expression of VEGFR2 as mRNA level and the patients' age. Unfortunately, the multivariate analysis by logistic model selects only VEGFR2 expression for prediction of tumor response. The interrelations between the different biomarkers demonstrate the complexity of the tumor progression process and the necessity of further studies to identify new therapeutic targets.

Oxaliplatin in patients with metastatic colorectal cancer: efficacy and pharmacokinetics parameters.

PURPOSE: The aim of this study was to investigate the efficiency of the FOLFOX-4 regimen and to evaluate the pharmacokinetics of oxaliplatin in untreated patients with metastatic colorectal cancer. METHODS: 43 patients were enrolled in the study. Patients received oxaliplatin 85 mg/m(2) as 2-h i.v. infusion, on day 1, and bolus 5-fluorouracil (5FU) 400 mg/m(2) plus leucovorin (LV) 200 mg/m(2) followed by 5FU 600 mg/m(2) as 22-h infusion on day 1 and 2, every 2 weeks. The pharmacokinetics of oxaliplatin evaluated in 4 patients was performed in blood, plasma and ultrafiltered plasma (UFT) by Inductively Coupled Plasma Mass Spectrometry (ICP-MS). RESULTS: The overall response rate and the median time to progression (TTP) were 53.49% and 7.1 months, respectively. Grade 3-4 toxic effects were observed in 11 (25.5%) patients. Grade 3 neuropathy was observed in 13.95% of the cases. In univariate analysis only Eastern Cooperative Oncology Group (ECOG) performance status (PS) was correlated with response. No correlation was found between grade 3-4 adverse events and the patient characteristics. The area under the time-concentration curve (AUC) in UFT was 4.8 + or - 0.72 standard deviation (SD) microg h/ml and the total clearance 30.17 + or - 7.75 l/min. The values for volume of distribution and the maximum concentration were 567 + or - 20 liters and 0.38 + or - 0.17 ug/ml, respectively. CONCLUSION: FOLFOX-4 was an effective regimen with good tolerability in previously untreated metastatic colorectal cancer patients. The pharmacokinetics of oxaliplatin was triphasic with a short initial distribution phase and a long terminal elimination phase.

p53 gene therapy using RNA interference.

p53 gene, discovered almost 35 years ago, keeps the main role in cell cycle control, apoptosis pathways and transcription. p53 gene is found mutated in more than 50% of all human cancers in different locations. Many structures from viral to non viral were designed to incorporate and deliver in appropriate conditions forms of p53 gene or its transcripts, systemically to target tumor cells and to eliminate them through apoptosis or to restore the normal tumor suppressor gene role. Each delivery system presents advantages and low performance in relation to immune system recognition and acceptance. One of the major discoveries in the last years, silencing of RNA, represents a powerful tool for inhibiting post transcriptional control of gene expression. According to several studies, the RNA silencing technology for p53 transcripts together with other carriers or transporters at nano level can be used for creating new therapeutic models. RNA interference for p53 uses different double-stranded (ds) molecules like short interfering (si) RNA and, despite the difficulty of introducing them into mammalian cells due to immune system response, it can be exploited in cancer therapy.