Search results for: prognosis

Authors: Tarana Siddika, Ilka U. Heinemann, Patrick O’Donoghue

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Protein kinase B (AKT1) is a serine/threonine kinase and central transducer of cell survival pathways. Typical approaches to study AKT1 biology in cells rely on growth factor or insulin stimulation that activates AKT1 via phosphorylation at two key regulatory sites (Threonine308, Serine473), yet cell stimulation also activates many other kinases and fails to differentiate the effect of the two main activating sites of AKT1 on downstream substrate phosphorylation and cell growth. While both AKT1 activating sites are associated with disease and used as clinical markers, in some cancers, high levels of Threonine308 phosphorylation are associated with poor prognosis while in others poor survival correlates with high Serine473 levels. To produce cells with specific AKT1 activity, a system was developed to deliver active AKT1 to human cells. AKT1 phospho-variants were produced from Escherichia coli with programmed phosphorylation by genetic code expansion. Tagging of AKT1 with an N-terminal cell penetrating peptide tag derived from the human immunodeficiency virus trans-activator of transcription (TAT) helped to enter AKT1 proteins in mammalian cells. The TAT-tag did not alter AKT1 kinase activity and was necessary and sufficient to rapidly deliver AKT1 protein variants that persisted in human cells for 24 h without the need to use transfection reagents. TAT-pAKT1T308, TAT-pAKT1S473 and TAT-pAKT1T308S473 proteins induced selective phosphorylation of the known AKT1 substrate GSK-3αβ, and downstream stimulation of the AKT1 pathway as evidenced by phosphorylation of ribosomal protein S6 at Serine240/244 in transfected cells. Increase in cell growth and proliferation was observed due to the transfection of different phosphorylated AKT1 protein variants compared to cells with TAT-AKT1 protein. The data demonstrate efficient delivery of AKT1 with programmed phosphorylation to human cells, thus establishing a cell-based model system to investigate signaling that is dependent on specific AKT1 activity and phosphorylation.

Keywords: cell penetrating peptide, cell signaling, protein kinase b (AKT1), phosphorylation

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Authors: Elyce Cardonick, Shistri Dhar, Linsdey Seidman

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Background: When breast cancer is diagnosed during pregnancy, the prognosis is comparable to non-pregnant women matched for prognostic indicators when pregnant women receive treatment without delay. Chemotherapy, including taxanes, can be given during pregnancy with normal neonatal development in exposed fetuses. Methods: Cases of primary breast cancer were extracted from the Cancer and Pregnancy Registry and longitudinal study at Cooper Medical School, which collects cases of pregnant women diagnosed and treated for cancer into a single database. Obstetrical, oncology and pediatric records were reviewed, including annual neonatal developmental, behavioral and medical assessments. Results: 270 pregnant women were diagnosed with primary breast cancer at a mean gestational age of 14.7+9weeks. Mean maternal age at diagnosis 34.5+4.5 years. Receptor status is comparable to non-pregnant women of reproductive age. Forty-nine women were advised to terminate. Two hundred two women underwent surgery;244 women received chemotherapy in pregnancy after the first trimester; the majority of Doxorubucin/Cytoxan; 81 of the cases included a taxane. At a mean of 90 months, follow up obtained on 255 newborns.192/255 newborns are meeting developmental milestones. Respiratory illnesses, including asthma, and bronchiolitis, were reported in 64 newborns, the most common medical condition reported. Thirty-one children are undergoing treatment for GERD, 11 for urinary tract infections, and 7 are undergoing treatment for anemia. Twenty-six children with expressive or articulation language delays, 21/26 are mild. Eleven children with gross/ 7 with fine motor delays. Eight children are treated for ADHD, 4 for anxiety and 4 have social skill impairment. The majority of children with developmental, language or motor delays were born preterm. Conclusion: After chemotherapy exposure in utero for breast cancer, the majority of newborns are meeting developmental milestones and are medically healthy. The goal for treating pregnant women with breast cancer is to aim for delivery close to the term.

Keywords: breast cancer, pregnancy, chemotherapy, newborn

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Authors: Shabnam Abdi, Behzad Toosi

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Background: Melanoma is the most lethal type of malignant skin cancer in humans and dogs since it spreads rapidly throughout the body. Despite significant advances in treatment, cancer at an advanced stage has a poor prognosis. Hence, more effective treatments are needed to enhance outcomes with fewer side effects. Erythropoietin-producing hepatocellular receptors are the largest family of receptor tyrosine kinases and are divided into two subfamilies, EphA and EphB, both of which play a significant role in disease, especially cancer. Due to their association with proliferation and invasion in many aggressive types of cancer, Eph receptor tyrosine kinases (Eph RTKs) are promising cancer therapy molecules. Because these receptors have not been studied in canine melanoma, we investigated how EphA2 influences survival and tumorigenicity of melanoma cells. Methods: Expression of EphA2 protein in canine melanoma cell lines and human melanoma cell line was evaluated by Western blot. Melanoma cells were transduced with lentiviral particles encoding Eph-targeting shRNAs or non-silencing shRNAs (control) for silencing the expression of EphA2 receptor, and silencing was confirmed by Western blotting and immunofluorescence. The effect of siRNA treatment on cellular proliferation, colony formation, tumorsphere assay, invasion was analyzed by Resazurin assay Matrigel invasion assay, respectively. Results: Expression of EphA2 was detected in canine and human melanoma cell lines. Moreover, stably silencing EphA2 by specific shRNAs significantly and consistently decreased the expression of EphA2 protein in both human and canine melanoma cells. Proliferation, colony formation, tumorsphere and invasion of melanoma cells were significantly decreased in EphA2 siRNA-treated cells compared to control. Conclusion: Our data provide the first functional evidence that the EphA2 receptor plays a critical role in the malignant cellular behavior of melanoma in both human and dogs.

Keywords: ephA2, targeting, melanoma, human, canine

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Authors: Shadia Al-Bahlani, Ruqaya Al-Rashdi, Shadia Al-Sinawi, Maya Al-Bahri

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Background: Breast cancer is the most common cancer in women worldwide. Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer, which is defined by the absence of Estrogen (ER), Progesterone (PR) and Human epidermal growth factor (Her-2) receptors. The calpain system plays an important role in many cellular processes including apoptosis, necrosis, cell signaling and proliferation. The role of clapins in pathogenesis and tumor progression has been studied in certain cancer types; however, its definite role is not yet established in breast cancer especially in the TNBC subtype. Objectives: This study aims to measure calpain-1 expression and correlate this measurement with the proliferating/apoptotic index as well with the prognostic factors in TNBC patients’ tissue. Materials and Methods: Thirty nine paraffin blocks from patients diagnosed with TNBC were used to measure the expression of calpain-1 and Ki-67 (proliferating marker) proteins using immunohistochemistry. Apoptosis was assessed morphological and biochemically using conventional Haematoxylin and Eosin (H&E) staining method and terminal deoxynucleotidyl transferase-mediate dUTP nick and labeling (TUNEL) assay respectively. Data was statistically analyzed using Pearson X2 test of association. Results: Calpain-1 content was visualized in the nucleus of the TNBC cells and its expression varied from low to high among the patients tissue. Calpain expression showed no significant correlation with the proliferating/apoptotic index as well with the clinicopathological variables. Apoptotic counts quantified by H&E staining showed significant association with the apoptotic TUNEL assay, validating both approaches. Conclusion: Although calpain-1 expression showed no significant association with the clinical outcome, its variable level of expression might indicate a hidden role in breast cancer tissue. Larger number of samples and different mode of assessments are needed to fully investigate such role. Exploring the involvement of calpain-1 in cancer progression might help in considering it as a biomarker of breast cancer.

Keywords: breast cancer, calpain, apoptosis, prognosis

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Authors: Sarah Gounden, Mukesh Dheda, Boikhutso Tlou, Elizabeth Ojewole, Frasia Oosthuizen

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Background: Antiretroviral therapy (ART) has been effective in the reduction of mortality and resulted in an improvement in the prognosis of HIV-infected patients. However, treatment with antiretrovirals (ARVs) has led to the development of many adverse drug reactions (ADRs). It is, therefore, necessary to determine the safety profile of these medicines in a South African population in order to ensure safe and optimal medicine use. Objectives: The aim of this study was to quantify ADRs experienced with the different ARVs currently used in South Africa, to determine the safety profile of ARV medicine in South Africa based on reported ADRs, and to determine the ARVs with the lowest risk profile based on specific patient populations. Methodology: This was a quantitative study. Individual case safety reports for the period January 2010 – December 2013 were obtained from the National Pharmacovigilance Center; these reports contained information on ADRs, ARV medicine, and patient demographics. Data was analysed to find associations that may exist between ADRs experienced, ARV medicines used and patient demographics. Results: A total of 1916 patient reports were received of which 1534 met the inclusion criteria for the study. The ARV with the lowest risk of ADRs were found to be lamivudine (0.51%, n=12), followed by lopinavir/ritonavir combination (0.8%, n=19) and abacavir (0.64%, n=15). A higher incidence of ADRs was observed in females compared to males. The age group 31–50 years and the weight group 61–80 kg had the highest incidence of ADRs reported. Conclusion: This study found that the safest ARVs to be used in a South African population are lamivudine, abacavir, and the lopinavir/ritonavir combination. Gender differences play a significant role in the occurrence of ADRs and both anatomical and physiological differences account for this. An increased BMI (body mass index) in both men and women showed an increase in the incidence of ADRs associated with ARV therapy.

Keywords: adverse drug reaction, antiretrovirals, HIV/AIDS, pharmacovigilance, South Africa

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Authors: Sarocha Vivatvakin, Thanaporn Ratchataswan, Thiratest Leesutipornchai, Komkrit Ruangritchankul, Somboon Keelawat, Virachai Kerekhanjanarong, Patnarin Mahattanasakul, Saknan Bongsebandhu-Phubhakdi

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In this globalization era, much attention has been drawn to various molecular biomarkers, which may have the potential to predict the progression of cancer. Epidermal growth factor receptor (EGFR) is the classic member of the ErbB family of membrane-associated intrinsic tyrosine kinase receptors. EGFR expression was found in several organs throughout the body as its roles involve in the regulation of cell proliferation, survival, and differentiation in normal physiologic conditions. However, anomalous expression, whether over- or under-expression is believed to be the underlying mechanism of pathologic conditions, including carcinogenesis. Even though numerous discussions regarding the EGFR as a prognostic tool in head and neck cancer have been established, the consensus has not yet been met. The aims of the present study are to assess the correlation between the level of EGFR expression and demographic data as well as clinicopathological features and to evaluate the ability of EGFR as a reliable prognostic marker. Furthermore, another aim of this study is to investigate the probable pathophysiology that explains the finding results. This retrospective study included 30 squamous cell laryngeal carcinoma patients treated at King Chulalongkorn Memorial Hospital from January 1, 2000, to December 31, 2004. EGFR expression level was observed to be significantly downregulated with the progression of the laryngeal cancer stage. (one way ANOVA, p = 0.001) A statistically significant lower EGFR expression in the late stage of the disease compared to the early stage was recorded. (unpaired t-test, p = 0.041) EGFR overexpression also showed the tendency to increase recurrence of cancer (unpaired t-test, p = 0.128). A significant downregulation of EGFR expression was documented in advanced stage laryngeal cancer. The results indicated that EGFR level correlates to prognosis in term of stage progression. Thus, EGFR expression might be used as a prevailing biomarker for laryngeal squamous cell carcinoma prognostic prediction.

Keywords: downregulation, epidermal growth factor receptor, immunohistochemistry, laryngeal squamous cell carcinoma

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Authors: Yifat Koren Carmi, Abed Agbarya, Hazem Khamaisi, Raymond Farah, Yelena Shechtman, Roman Korobochka, Jacob Gopas, Jamal Mahajna

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Ovarian cancer (OC), the second most common form of gynecological malignancy, has a poor prognosis and is frequently identified in its late stages. The recommended treatment for OC typically includes a platinum-based chemotherapy, like carboplatin. Nonetheless, OC treatment has proven challenging due to toxicity and development of acquired resistance to therapy. Chemoresistance is a significant obstacle to a long-lasting response in OC patients, believed to arise from alterations within the cancer cells as well as within the tumor microenvironments (TME). Malignant ascites is a presenting feature in more than one-third of OC patients. It serves as a reservoir for a complex mixture of soluble factors, metabolites, and cellular components, providing a pro-inflammatory and tumor-promoting microenvironment for the OC cells. Malignant ascites is also associated with metastasis and chemoresistance. In an attempt to elucidate the role of TME in chemoresistance of OC, we monitored the ability of soluble factors derived from ascites fluids to affect platinum sensitivity of OC cells. This research, compared ascites fluids from non-malignant cirrhotic patients to those from OC patients in terms of their ability to alter the platinum sensitivity of OC cells. Our findings indicated that exposure to OC ascites induces platinum chemoresistance on OC cells in 11 out of 13 cases (85%). In contrast, 75% of cirrhosis ascites (3 out of 4) failed to confer platinum chemoresistance to OC cells. Cytokine array analysis revealed that IL-6, and to a lesser extent HGF were enriched in OC ascites, whereas IL-22 was enriched in cirrhosis ascites. Pharmaceutical inhibitors that target the IL-6/JAK signaling pathway were mildly effective in overcoming the platinum chemoresistance induced by malignant ascites. In contrast, Crizotinib an HGF/c-MET inhibitor, and 2-hydroxyestradiol (2HE2) were effective in restoring platinum chemoresistance to OC. Our findings demonstrate the importance of OC ascites in supporting platinum chemoresistance as well as the potential of a combination therapy with Crizotinib and the estradiol metabolite 2HE2 to regain OC cells chemosensitivity.

Keywords: ovarian cancer, platinum chemoresistance, malignant ascites, tumor microenvironment, IL-6, 2-hydroxyestradiol, HGF, crizotinib

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Authors: F. Polito, M. Cucinotta, A. Conti, C. Lo Giudice, C. Tomasello, F. Angileri, D. La Torre, M. Aguennouz

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Glioblastoma multiforme (GBM) is the most aggressive form of brain tumors, with an extremely poor prognosis. Telomeres lenght is associated with tumor progression in several type of human cancers and telomere elongation is a common molecular feature of advanced malignancies. Among the telomeric shelterin proteins PTOP is required for telomeric protein complex assembly, telomerase recruitment and activity, and telomere length regulation through a PTOP-telomerase interaction. Previous studies suggest that PTOP upregulation is involved in radioresistance and telomere lengthening in colorectal cancer cells. Moreover, in human osteosarcoma cells PTOP deletion led to telomere shortening, increased apoptosis and radiation sensitivity enhancement. However, to date, little is known about the role of PTOP in progression of glioma cancers. In light of this background aim of the study is to investigate the expression of PTOP in different grades of human glioma and its correlation with the pathological grade of gliomas, grades of malignancy, proliferative activity and apoptosis. Fifteen Low Grade Astrocytomas (LGA), 18 Anaplastic Astrocytomas (AA) and 26 Glioblastoma Multiforme (GBM) samples were analyzed. Three samples of normal brain tissue (NBT) were used as controls. The expression levels of PTOP, h-TERT, BIRC1 and cyclin D1 were determined by real time PCR and/or western blot. Results obtained shows that PTOP expression in glioma tissues is tightly correlated with clinical grade ( p < 0.01 ). No correlation was found between PTOP expression and other clinicopathologic parameters. The expression of PTOP was positively correlated with the expression of hTERT and TERF1. Furthermore PTOP positively correlates with cyclin D1 and negatively correlates with the expression of BIRC1. Our findings indicate that PTOP might play key role in the progression of glioma regulating telomerase activity and likely through regulation of cell cycle and apoptosis. In conclusion results obtained prompted us to speculate that PTOP might represents a potential molecular bio marker and a therapeutic target for the treatment of glioblastoma tumors.

Keywords: glioblastoma, PTOP, telomere, brain tumors

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Authors: Soodabeh Shahid Sales, Azam Rastgar Moghadam, Mehrane Mehramiz, Malihe Entezari, Kazem Anvari, Mohammad Sadegh Khorrami, Saeideh Ahmadi Simab, Ali Moradi, Seyed Mahdi Hassanian, Majid Ghayour-Mobarhan, Gordon A. Ferns, Amir Avan

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Background Esophageal cancer has been reported as the eighth most common cancer universal and the seventh cause of cancer-related death in men .recent studies have revealed that cytochrome P450, family 1, subfamily B, polypeptide 1, which plays a role in metabolizing xenobiotics, is associated with different cancers. Therefore in the present study, we investigated the impact of CYP1B1-rs1056836 on esophagus squamous cell carcinoma (ESCC) patients. Method: 317 subjects, with and without ESCC were recruited. DNA was extracted and genotyped via Real-time PCR-Based Taq Man. Kaplan Meier curves were utilized to assess overall and progression-free survival. To evaluate the relationship between patients clinicopathological data, genotypic frequencies, disease prognosis, and patients survival, Pearson chi-square and t-test were used. Logistic regression was utilized to assess the association between the risk of ESCC and genotypes. Results: the genotypic frequency for GG, GC, and CC are respectively 58.6% , 29.8%, 11.5% in the healthy group and 51.8%, 36.14% and 12% in ESCC group. With respect to the recessive genetic inheritance model, an association between the GG genotype and stage of ESCC were found. Also, statistically significant results were not found for this variation and risk of ESCC. Patients with GG genotype had a decreased risk of nodal metastasis in comparison with patients with CC/CG genotype, although this link was not statistically significant. Conclusion: Our findings illustrated the correlation of CYP1B1-rs1056836 as a potential biomarker for ESCC patients, supporting further studies in larger populations in different ethnic groups. Moreover, further investigations are warranted to evaluate the association of emerging marker with dietary intake and lifestyle.

Keywords: Cytochrome P450, esophagus squamous cell carcinoma, dietary intake, lifestyle

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Authors: Kai Pai Huang

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Background: There are several types of plasma cell neoplasms including multiple myeloma, plasmacytoma, lymphoplasmacytic lymphoma, and monoclonal gammopathy of undetermined significance (MGUS) are found in our lab. Today, we want to compare with two cases using the method of capillary electrophoresis. Method: Serum is prepared and electrophoresis is performed at alkaline PH in a capillary using the Sebia® Capillary 2. Albumin and globulins are detected by the detector which is located in the cathode of the capillary and the signals are transformed to peaks. Serum was treated with beta-mercaptoethanol which reducing the polymerized immunoglobulin to monomer immunoglobulin to clarify two M-protein are secreted from the same plasma cell clone in bone marrow. Result: Case 1: A 78-year-old female presenting dysuria, oliguria and leg edema for several months. Laboratory data showed proteinuria, leukocytosis, results of high serum IgA and lambda light chain. A renal biopsy found amyloid fibrils in the glomerular mesangial area. Serum protein electrophoresis shows a major monoclonal peak in the β region and minor small peak in gamma region, and the immunotyping studies for serum showed two IgA/λ type. Case 2: A 55-year-old male presenting abdominal distension and low back pain for more than one month. Laboratory data showed T12 T8 compression fracture, results of high serum IgM and kappa light chain. Bone marrow aspiration showed the cells from the bone marrow are B cells with monotypic kappa chain expression. Bone marrow biopsy found this is lymphoplasmacytic lymphoma (Waldenstrom macroglobulin). Serum protein electrophoresis shows a monoclonal peak in the β region and the immunotyping studies for serum showed IgM/κ type. Conclusion: Plasma cell neoplasm can be diagnosed by many examinations. Among them, using capillary electrophoresis by a lab can separate several types of gammopathy and the quantification of a monoclonal peak can be used to evaluate the patients’ prognosis or treatment.

Keywords: plasma cell neoplasm, capillary electrophoresis, serum protein electrophoresis, immunotyping

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Authors: Umamaheswari Shanmugam, Silvia Ronchi

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Software, artificial intelligence, and machine learning can improve healthcare through innovative and advanced technologies that can use the large amount and variety of data generated during healthcare services every day; one of the significant advantages of these new technologies is the ability to get experience and knowledge from real-world use and to improve their performance continuously. Healthcare systems and institutions can significantly benefit because the use of advanced technologies improves the efficiency and efficacy of healthcare. Software-defined as a medical device, is stand-alone software that is intended to be used for patients for one or more of these specific medical intended uses: - diagnosis, prevention, monitoring, prediction, prognosis, treatment or alleviation of a disease, any other health conditions, replacing or modifying any part of a physiological or pathological process–manage the received information from in vitro specimens derived from the human samples (body) and without principal main action of its principal intended use by pharmacological, immunological or metabolic definition. Software qualified as medical devices must comply with the general safety and performance requirements applicable to medical devices. These requirements are necessary to ensure high performance and quality and protect patients' safety. The evolution and the continuous improvement of software used in healthcare must consider the increase in regulatory requirements, which are becoming more complex in each market. The gap between these advanced technologies and the new regulations is the biggest challenge for medical device manufacturers. Regulatory requirements can be considered a market barrier, as they can delay or obstacle the device's approval. Still, they are necessary to ensure performance, quality, and safety. At the same time, they can be a business opportunity if the manufacturer can define the appropriate regulatory strategy in advance. The abstract will provide an overview of the current regulatory framework, the evolution of the international requirements, and the standards applicable to medical device software in the potential market all over the world.

Keywords: artificial intelligence, machine learning, SaMD, regulatory, clinical evaluation, classification, international requirements, MDR, 510k, PMA, IMDRF, cyber security, health care systems

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Authors: Vitor Rafael Regiani, Carlos Henrique Viesi Do Nascimento Filho, Patricia Matos Biselli-Chicote, Claudia Aparecida Rainho, Luiz Sergio Raposo, José Victor Maniglia, Eny Maria Goloni-Bertollo, Erika Cristina Pavarino

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Promoter hypermethylation of tumor-related genes has been associated with prognosis in early-stage head-and-neck cancers, providing strong evidence that these hypermethylated genes are valuable biomarkers for prognostic evaluation. Hence, we selected the MGMT and RASSF1A genes to examine the methylation status in head and neck squamous cell carcinomas (HNSCC) samples matched with non-tumor tissues (tumor-surrounding tissues or peripheral blood samples). DNA methylation analysis was based on Methylation-Sensitive High Resolution Melting, and the methylation status was correlated with clinic-pathological characteristics of the patients. RASSF1A and MGMT promoter methylation was detected in 43.24% (16/37) and in 44.44% (16/36) of the tumors, respectively. RASSF1A and MGMT methylation was significantly more frequent in tumor tissue than non-tumor tissues, as well as, simultaneous methylation of RASSF1A and MGMT also was higher in tumor tissue than non-tumor tissues. In relation to anatomic site, larynx cancer presented significant methylation of MGMT gene compared to tumor-surrounding tissue. The frequency of RASSF1A and MGMT promoter methylated was higher in tumor tissues in relation to peripheral blood from the same patient. No association was found between methylation and the variables analyzed, including gender, age, smoking or alcohol drinking habits. Clinic-pathological characteristics also showed no association in the presence of methylation. The Kaplan–Meier's method showed no association of methylation and both disease-free and overall survival. In conclusion, the presence of epigenetic abnormalities in normal-appearing tissue corroborates the hypothesis of the ‘field cancerization', or it can reflect preneoplastic and/or preinvasive. Moreover, MGMT methylation may serve as an important laryngeal cancer biomarker because it showed significant difference between laryngeal cancer and surrounding tumor tissues.

Keywords: head and neck cancer, DNA methylation, MGMT promoter methylation, RASSF1A promoter methylation

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Authors: Naridchaya Aberdour, Joanna Kao, Anne Miller, Timothy Shore, Richard Maher, Zhixin Liu

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Background: COVID-19 has and continues to be a strain on healthcare globally, with the number of patients requiring hospitalization exceeding the level of medical support available in many countries. As chest x-rays are the primary respiratory radiological investigation, the Radiological Assessment of Lung Edema (RALE) score was used to quantify the extent of pulmonary infection on baseline imaging. Assessment of RALE score's reproducibility and associations with clinical outcome parameters were then evaluated to determine implications for patient management and prognosis. Methods: A retrospective study was performed with the inclusion of patients testing positive for COVID-19 on nasopharyngeal swab within a single Local Health District in Sydney, Australia and baseline x-ray imaging acquired between January to June 2020. Two independent Radiologists viewed the studies and calculated the RALE scores. Clinical outcome parameters were collected and statistical analysis was performed to assess RALE score reproducibility and possible associations with clinical outcomes. Results: A total of 78 patients met inclusion criteria with the age range of 4 to 91 years old. RALE score concordance between the two independent Radiologists was excellent (interclass correlation coefficient = 0.93, 95% CI = 0.88-0.95, p<0.005). Binomial logistics regression identified a positive correlation with hospital admission (1.87 OR, 95% CI= 1.3-2.6, p<0.005), oxygen requirement (1.48 OR, 95% CI= 1.2-1.8, p<0.005) and invasive ventilation (1.2 OR, 95% CI= 1.0-1.3, p<0.005) for each 1-point increase in RALE score. For each one year increased in age, there was a negative correlation with recovery (0.05 OR, 95% CI= 0.92-1.0, p<0.01). RALE scores above three were positively associated with hospitalization (Youden Index 0.61, sensitivity 0.73, specificity 0.89) and above six were positively associated with ICU admission (Youden Index 0.67, sensitivity 0.91, specificity 0.78). Conclusion: The RALE score can be used as a surrogate to quantify the extent of COVID-19 infection and has an excellent inter-observer agreement. The RALE score could be used to prognosticate and identify patients at high risk of deterioration. Threshold values may also be applied to predict the likelihood of hospital and ICU admission.

Keywords: chest radiography, coronavirus, COVID-19, RALE score

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Authors: Ashenafi Ayele, Shewit Haftu, Tesfalem Araya

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Background: “Post-psychotic depression”, “post schizophrenic depression”, and “secondary depression” have been used to describe the occurrence of depressive symptoms during the chronic phase of schizophrenia. Post-psychotic depression is the most common cause of death due to suicide in schizophrenia patients. Overall lifetime risk for patients with schizophrenia is 50% for suicide attempts and 9-13% lifetime risk for completed suicide and also it is associated with poor prognosis and poor quality of life. Objective: To assess determinant of post psychotic depression in schizophrenia patients ACSH and Mekelle General Hospital, Tigray Ethiopia 2019. Methods: An institutional based unmatched case control study was conducted among 69 cases and 138 controls with the ratio of case to control 1 ratio 2. The sample is calculated using epi-info 3.1 to assess the determinant factors of post-psychotic depression in schizophrenia patients. The cases were schizophrenia patients who have been diagnosed at least for more than one-year stable for two months, and the controls are any patients who are diagnosed as schizophrenia patients. Study subjects were selected using a consecutive sampling technique. The Calgary depression scale for schizophrenia self-administered questionnaire was used. Before the interview, it was assessed the client’s capacity to give intended information using a scale called the University of California, San Diego Brief Assessment of Capacity to Consent (UBACC). Bivariant and multiple Logistic regression analysis was performed to determine between the independent and dependent variables. The significant independent predictor was declared at 95% confidence interval and P-value of less than 0.05. Result: Females were affected by post psychotic depression with the (AOR=2.01, 95%CI: 1.003- 4.012, P= 0.49).Patients who have mild form of positive symptom of schizophrenia affected by post psychotic depression with (AOR =4.05, 95%CI: 1.888- 8.7.8, P=0001).Patients who have minimal form of negative symptom of schizophrenia are affected by post psychotic depression with (AOR =4.23, 95%CI: 1.081-17.092, P=.038). Conclusion: In this study, sex (female) and presence of positive and negative symptoms of schizophrenia were significantly associated. It is recommended that the post psychotic depression should be assessed in every schizophrenia patient to decrease the severity of illness, and to improve patient’s quality of life.

Keywords: determinants, post-psychotic depression, Mekelle city

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Authors: H. N. Alyaseen, S. E. Alalawi, T. Cordoba, É. Delisle, C. Cordoba, A. Odobescu

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Sternal dehiscence is defined as the persistent separation of sternal bones that are often complicated with mediastinitis. Etiologies that lead to sternal dehiscence vary, with cardiovascular and thoracic surgeries being the most common. Early diagnosis in susceptible patients is crucial to the management of such cases, as they are associated with high mortality rates. A recent meta-analysis of more than four hundred thousand patients concluded that deep sternal wound infections were the leading cause of mortality and morbidity in patients undergoing cardiac procedures. Long-term complications associated with sternal dehiscence include increased hospitalizations, cardiac infarctions, and renal and respiratory failures. Numerous osteosynthesis methods have been described in the literature. Surgical materials offer enough rigidity to support the sternum and can be flexible enough to allow physiological breathing movements of the chest; however, these materials fall short when managing patients with extensive bone loss, osteopenia, or general poor bone quality, for such cases, flaps offer a better closure system. Early utilization of flaps yields better survival rates compared to delayed closure or to patients treated with sternal rewiring and closed drainage. The utilization of pectoralis major flaps, rectus abdominus, and latissimus muscle flaps have all been described in the literature as great alternatives. Flap selection depends on a variety of factors, mainly the size of the sternal defect, infection, and the availability of local tissues. Free fibular flaps are commonly harvested flaps utilized in reconstruction around the body. In cases regarding sternal reconstruction with free fibular flaps, the literature exclusively discussed the flap applied vertically to the chest wall. We present a different technique applying the free fibular triple barrel flap oriented in a transverse manner, in parallel to the ribs. In our experience, this method could have enhanced results and improved prognosis as it contributes to the normal circumferential shape of the chest wall.

Keywords: sternal dehiscence, management, free fibular flaps, novel surgical techniques

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Authors: Reena K., Mamatha H. G., Somshekarayya, P. Kumar

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Objectives: The annual proficiency testing of intermediate reference laboratories is conducted by the National Reference Laboratory (NRL) to assess the efficiency of the laboratories to correctly identify Mycobacterium tuberculosis and to determine its drug susceptibility pattern. The proficiency testing results from 2013 to 2017 were analyzed to determine laboratories that were consistent in reporting quality results and those that had difficulty in doing so. Methods: A panel of twenty cultures were sent out to each of these laboratories. The laboratories were expected to grow the cultures in their own laboratories, set up drug susceptibly testing by all the methods they were certified for and report the results within the stipulated time period. The turnaround time for reporting results, specificity, sensitivity positive and negative predictive values and efficiency of the laboratory in identifying the cultures were analyzed. Results: Most of the laboratories had reported their results within the stipulated time period. However, there was enormous delay in reporting results from few of the laboratories. This was mainly due to improper functioning of the biosafety level III laboratory. Only 40% of the laboratories had 100% efficiency in solid culture using Lowenstein Jensen medium. This was expected as a solid culture, and drug susceptibility testing is not used for diagnosing drug resistance. Rapid molecular methods such as Line probe assay and Genexpert are used to determine drug resistance. Automated liquid culture system such as the Mycobacterial growth indicator tube is used to determine prognosis of the patient while on treatment. It was observed that 90% of the laboratories had achieved 100% in the liquid culture method. Almost all laboratories had achieved 100% efficiency in the line probe assay method which is the method of choice for determining drug-resistant tuberculosis. Conclusion: Since the liquid culture and line probe assay technologies are routinely used for the detection of drug-resistant tuberculosis the laboratories exhibited higher level of efficiency as compared to solid culture and drug susceptibility testing which are rarely used. The infrastructure of the laboratory should be maintained properly so that samples can be processed safely and results could be declared on time.

Keywords: annual proficiency testing, drug susceptibility testing, intermediate reference laboratory, national reference laboratory

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Authors: Yosep Chong, Yejin Kim, Jingyun Choi, Hwanjo Yu, Eun Jung Lee, Chang Suk Kang

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For the past decades, immunohistochemistry (IHC) has been playing an important role in the diagnosis of human neoplasms, by helping pathologists to make a clearer decision on differential diagnosis, subtyping, personalized treatment plan, and finally prognosis prediction. However, the IHC performed in various tumors of daily practice often shows conflicting and very challenging results to interpret. Even comprehensive diagnosis synthesizing clinical, histologic and immunohistochemical findings can be helpless in some twisted cases. Another important issue is that the IHC data is increasing exponentially and more and more information have to be taken into account. For this reason, we reached an idea to develop an expert supporting system to help pathologists to make a better decision in diagnosing human neoplasms with IHC results. We gave probabilistic decision tree algorithm and tested the algorithm with real case data of lymphoid neoplasms, in which the IHC profile is more important to make a proper diagnosis than other human neoplasms. We designed probabilistic decision tree based on Bayesian theorem, program computational process using MATLAB (The MathWorks, Inc., USA) and prepared IHC profile database (about 104 disease category and 88 IHC antibodies) based on WHO classification by reviewing the literature. The initial probability of each neoplasm was set with the epidemiologic data of lymphoid neoplasm in Korea. With the IHC results of 131 patients sequentially selected, top three presumptive diagnoses for each case were made and compared with the original diagnoses. After the review of the data, 124 out of 131 were used for final analysis. As a result, the presumptive diagnoses were concordant with the original diagnoses in 118 cases (93.7%). The major reason of discordant cases was that the similarity of the IHC profile between two or three different neoplasms. The expert supporting system algorithm presented in this study is in its elementary stage and need more optimization using more advanced technology such as deep-learning with data of real cases, especially in differentiating T-cell lymphomas. Although it needs more refinement, it may be used to aid pathological decision making in future. A further application to determine IHC antibodies for a certain subset of differential diagnoses might be possible in near future.

Keywords: database, expert supporting system, immunohistochemistry, probabilistic decision tree

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Authors: Priyal Chikhaliwala, Sudeshna Chandra

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Liver cancer is one of the most common malignant tumors with poor prognosis. This is because liver cancer does not exhibit any symptoms in early stage of disease. Increased serum level of AFP is clinically considered as a diagnostic marker for liver malignancy. The present diagnostic modalities include various types of immunoassays, radiological studies, and biopsy. However, these tests undergo slow response times, require significant sample volumes, achieve limited sensitivity and ultimately become expensive and burdensome to patients. Considering all these aspects, electrochemical biosensors based on dendrimer-magnetic nanoparticles (MNPs) was designed. Dendrimers are novel nano-sized, three-dimensional molecules with monodispersed structures. Poly-amidoamine (PAMAM) dendrimers with eight –NH₂ groups using ethylenediamine as a core molecule were synthesized using Michael addition reaction. Dendrimers provide added the advantage of not only stabilizing Fe₃O₄ NPs but also displays capability of performing multiple electron redox events and binding multiple biological ligands to its dendritic end-surface. Fe₃O₄ NPs due to its superparamagnetic behavior can be exploited for magneto-separation process. Fe₃O₄ NPs were stabilized with PAMAM dendrimer by in situ co-precipitation method. The surface coating was examined by FT-IR, XRD, VSM, and TGA analysis. Electrochemical behavior and kinetic studies were evaluated using CV which revealed that the dendrimer-Fe₃O₄ NPs can be looked upon as electrochemically active materials. Electrochemical immunosensor was designed by immobilizing anti-AFP onto dendrimer-MNPs by gluteraldehyde conjugation reaction. The bioconjugates were then incubated with AFP antigen. The immunosensor was characterized electrochemically indicating successful immuno-binding events. The binding events were also further studied using magnetic particle imaging (MPI) which is a novel imaging modality in which Fe₃O₄ NPs are used as tracer molecules with positive contrast. Multicolor MPI was able to clearly localize AFP antigen and antibody and its binding successfully. Results demonstrate immense potential in terms of biosensing and enabling MPI of AFP in clinical diagnosis.

Keywords: alpha-fetoprotein, dendrimers, electrochemical biosensors, magnetic nanoparticles

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Authors: Jiri Kysucan, Dusan Klos, Katherine Vomackova, Pavel Koranda, Martin Lovecek, Cestmir Neoral, Roman Havlik

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Aim: The prognosis of patients with pancreatic cancer is poor. The median of survival after establishing diagnosis is 3-11 months without surgical treatment, 13-20 months with surgical treatment depending on the disease stage, 5-year survival is less than 5%. Radical surgical resection remains the only hope of curing the disease. Early diagnosis with valid establishment of tumor resectability is, therefore, the most important aim for patients with pancreatic cancer. The aim of the work is to evaluate the contribution and define the role of 18F-FDG PET/CT in preoperative staging. Material and Methods: In 195 patients (103 males, 92 females, median age 66,7 years, 32-88 years) with a suspect pancreatic lesion, as part of the standard preoperative staging, in addition to standard examination methods (ultrasonography, contrast spiral CT, endoscopic ultrasonography, endoscopic ultrasonographic biopsy), a hybrid 18F-FDG PET/CT was performed. All PET/CT findings were subsequently compared with standard staging (CT, EUS, EUS FNA), with peroperative findings and definitive histology in the operated patients as reference standards. Interpretation defined the extent of the tumor according to TNM classification. Limitations of resectability were local advancement (T4) and presence of distant metastases (M1). Results: PET/CT was performed in a total of 195 patients with a suspect pancreatic lesion. In 153 patients, pancreatic carcinoma was confirmed and of these patients, 72 were not indicated for radical surgical procedure due to local inoperability or generalization of the disease. The sensitivity of PET/CT in detecting the primary lesion was 92.2%, specificity was 90.5%. A false negative finding in 12 patients, a false positive finding was seen in 4 cases, positive predictive value (PPV) 97.2%, negative predictive value (NPV) 76,0%. In evaluating regional lymph nodes, sensitivity was 51.9%, specificity 58.3%, PPV 58,3%, NPV 51.9%. In detecting distant metastases, PET/CT reached a sensitivity of 82.8%, specificity was 97.8%, PPV 96.9%, NPV 87.0%. PET/CT found distant metastases in 12 patients, which were not detected by standard methods. In 15 patients (15.6%) with potentially radically resectable findings, the procedure was contraindicated based on PET/CT findings and the treatment strategy was changed. Conclusion: PET/CT is a highly sensitive and specific method useful in preoperative staging of pancreatic cancer. It improves the selection of patients for radical surgical procedures, who can benefit from it and decreases the number of incorrectly indicated operations.

Keywords: cancer, PET/CT, staging, surgery

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Authors: Shouta Sora, Shizuki Kuriu, Radhika Mishra, Ariunbuyan Sukhbaatar, Maya Sakamoto, Shiro Mori, Tetsuya Kodama

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Lymph node (LN) metastasis accounts for 20 - 30 % of all deaths in patients with head and neck cancer. Therefore, the control of metastatic lymph nodes (MLNs) is necessary to improve the life prognosis of patients with cancer. In a classical metastatic theory, tumor cells are thought to metastasize hematogenously through a bead-like network of lymph nodes. Recently, a lymph node-mediated hematogenous metastasis theory has been proposed, in which sentinel LNs are regarded as a source of distant metastasis. Therefore, the treatment of MLNs at the early stage is essential to prevent distant metastasis. Radiation therapy is one of the primary therapeutic modalities in cancer treatment. In addition, total body irradiation (TBI) has been reported to act as activation of natural killer cells and increase of infiltration of CD4+ T-cells to tumor tissues. However, the treatment effect of TBI for MLNs remains unclear. This study evaluated the possibilities of low-dose total body irradiation (L-TBI) and middle-dose total body irradiation (M-TBI) for the treatment of MLNs. Mouse breast cancer FM3A-Luc cells were injected into subiliac lymph node (SiLN) of MXH10/Mo/LPR mice to induce the metastasis to the proper axillary lymph node (PALN) and lung. Mice were irradiated for the whole body on 4 days after tumor injection. The L-TBI and M-TBI were defined as irradiations to the whole body at 0.2 Gy and 1.0 Gy, respectively. Tumor growth was evaluated by in vivo bioluminescence imaging system. In the non-irradiated group, tumor activities on SiLN and PALN significantly increased over time, and the metastasis to the lung from LNs was confirmed 28 days after tumor injection. The L-TBI led to a tumor growth delay in PALN but did not control tumor growth in SiLN and metastasis to the lung. In contrast, it was found that the M-TBI significantly delayed the tumor growth of both SiLN and PALN and controlled the distant metastasis to the lung compared with non-irradiated and L-TBI groups. These results suggest that the M-TBI is an effective treatment method for MLNs in the early stage and distant metastasis from lymph nodes via blood vessels connected with LNs.

Keywords: metastatic lymph node, lung metastasis, radiation therapy, total body irradiation, lymphatic system

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Authors: Yasmine Aridi, Lara Nasreddine, Maya Khalil, Arafat Tfayli, Anas Mugharbel, Farah Naja

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Breast cancer is the most commonly diagnosed cancer site among women worldwide and the second most common cause of cancer mortality. Breast cancer rates differ vastly between geographical areas, countries, and within the same country. In Lebanon, the proportion of breast cancer to all other sites of tumor is 38.2%; these rates are still lower than those observed worldwide, but remain the highest among Arab countries. Studies and evidence based reviews show a strong association between breast cancer development and prognosis and dietary habits, specifically the Mediterranean diet (MD). As such, the aim of this study is to examine dietary patterns and adherence to the MD among a sample of 182 breast cancer female patients in Beirut, Lebanon. Subjects were recruited from two major hospitals; a private medical center and a public hospital. All subjects were administered two questionnaires: socio- demographics and Mediterranean diet adherence. Five Mediterranean scores were calculated: MS, MSDPS, PMDI, PREDIMED and DDS. The mean age of the participants was 53.78 years. The overall adherence to the Mediterranean diet (MD) was low since the sample means of 3 out of the 5 calculated scores were less than the scores’ medians. Given that 4 out of the 5 Mediterranean scores significantly varied between the recruitment sites, women in the private medical center were found to adhere more to the MD. Our results also show that the majority of the sample population’s intakes are exceeding the recommendations for total and saturated fat, while meeting the requirements for fiber, EPA, DHA and Linolenic Acid. Participants in the private medical center were consuming significantly more calories, carbohydrates, fiber, sugar, Lycopene, Calcium, Iron and Folate and less fat. After conducting multivariate linear regression analyses, the following significant results were observed: positive associations between MD (CPMDI, PREDIMED) and monthly income & current state of health, while negative associations between MD (MSDPS, PREDIMED) and age & employment status. Our findings indicated a low overall adherence to the MD and identified factors associated with it; which suggests a need to address dietary habits among BC patients in Lebanon, specifically encouraging them to adhere to their traditional Mediterranean diet.

Keywords: Adherence, Breast cancer, Dietary patterns, Mediterranean diet, Nutrition

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Authors: Cherrie Mae S. Sia, Noel J. Belonguel, Jarungchai Anton S. Vatanagul

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Background: Parkinson’s disease (PD) is a chronic progressive, neurodegenerative disorder known for its motor symptoms such as bradykinesia, resting tremor, muscle rigidity, and postural instability. Patients with PD also experience non-motor symptoms (NMS) such as depression, fatigue, and sleep disturbances that are most of the time unrecognized by clinicians. This may be due to the lack of spontaneous reports from the patients or partly because of the lack of systematic questioning from the healthcare professional. There is limited data with regards to these NMS especially that of Filipino patients with PD. Objectives: This study aims to determine the non-motor symptoms of Filipino patients with Parkinson’s disease. Materials and Methods: This is a prospective, cohort study involving thirty-four patients of Filipino-descent diagnosed with PD in three out-patient clinics in Cebu City from April to September 2014. Each patient was interviewed using the Non-Motor Symptom Scale (NMSS). A Cebuano version of the NMSS was also provided for the non-English speaking patients. Interview time was approximately ten to fifteen minutes for each respondent. Results: Of the thirty-four patients with Parkinson’s disease, majority was noted to be males (N=19) and the disease was noted to be more prevalent in patients with a mean age of 62 (SD±9) years old. Hypertension (59%) and diabetes mellitus (29%) were the common co-morbidities in the study population. All patients presented more than one NMS, with insomnia (41.2%), poor memory (23.5%) and depression (14.7%) being the first non-motor symptoms to occur. Symptoms involving mood/cognition (mean=2.21), and attention/memory (mean=2.05) were noted to be the most frequent and of moderate severity. Based on the NMSS, the symptoms that were noted to be mild and often to occur were those that involved the mood/cognition (score=3.84), attention/memory (score=3.50), and sleep/fatigue (score=3.00) domains. Levodopa-Carbidopa, Ropinirole, and Pramipexole were the most frequently used medications in the study population. Conclusion: Non-motor symptoms (NMS) are common in patients with Parkinson’s disease (PD). They appear at the time of diagnosis of PD or even before the motor symptoms manifest. The earliest non-motor symptoms to occur are insomnia, poor memory, and depression. Those pertaining to mood/cognition and attention/memory are the most frequent NMS and they are of moderate severity. Identifying these NMS by doing a questionnaire-guided interview such as the Non-Motor Symptom Scale (NMSS) before they can become more severe and affect the patient’s quality of life is a must for every clinician caring for a PD patient. Early treatment and control of these NMS can then be given, hence, improving the patient’s outcome and prognosis.

Keywords: non motor symptoms, Parkinson's Disease, insomnia, depression

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Authors: Rubai M. Ochieng

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Cancer, which accounts for 7 percent of deaths per year in Kenya, is the third highest cause of death after infectious and cardiovascular diseases. Awareness Campaigns have tended to focus on leading cancers including breast and cervical for women as well as prostrate and Esophageal for men. Consequently, less common cancers such as Acute Myeloid Leukemia (AML) are rarely properly understood by the general population and a section of the medical fraternity. Diagnoses of AML in patients who may not have heard about it sometimes results in shock, denial and confusion not just to the diagnosed, but also to their family and friends. The diagnosed and caregivers are bound to receive a lot of contradicting information about prognosis, care and treatment of AML. This information, which often comes from diverse sources including doctors, friends, internet and social media platforms, causes further confusion and panic. The situation is handled differently by different people. Religious people sometimes resort to prayer. This paper, written from the perspective of a care giver, is based on data collected from a case of Acute Myeloid Leukemia diagnosed in a 32 year old male who lost his life within six weeks of diagnosis. The sample constitutes of 16 people who participated in prayers. Out of this total, 5 were males including the diagnosed and 11 were females. All the 16 were Christians of protestant orientation including Anglicans, Quakers and Church of God members. Data was collected by the researcher herself through participant of observation. Findings discuss how the 16 participants prayed individually at different times, together in an overnight prayer meeting and every morning through a group social media platform. They shared songs and words of encouragement from the bible. The group prayed for healing, peace and strength to the diagnosed and family, financial breakthrough and doctors’ work and decisions, among other challenges that came with the situation. The paper reveals the immense benefits of prayer to the diagnosed and his close relatives and friends. They include acceptance of the condition and a positive attitude in handling the challenges that arose from the disease and treatment processes. The challenges arising from the prayer approach of handling the situation are also discussed. The paper concludes that prayer as therapy goes a long way in cancer management.

Keywords: acute myeloid leukemia, Kenya, participant observation, prayer

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Authors: Vinda B. Manurung, Laila Warkhaida, David Hutabarat, Sentanu Wisnuwardhana, Christovik Simatupang, Dhani Sanjaya, Ashadi, Redha B. Putra, Kiki Yustendi

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The geothermal drilling environment presents many obstacles that have limited the use of directional drilling and logging-while-drilling (LWD) technologies, such as borehole washout, mud losses, severe vibration, and high temperature. The case study presented in this paper demonstrates a practice to enhance data logging in geothermal drilling by deploying advanced telemetry and LWD technologies. This operation is aiming continuous improvement in geothermal drilling operations. The case study covers a 12.25-in. hole section of well XX-05 in Pad XX of the Sorik Marapi Geothermal Field. LWD string consists of electromagnetic (EM) telemetry, pressure while drilling (PWD), vibration (DDSr), and acoustic calliper (ACAL). Through this tool configuration, the operator acquired drilling mechanics and caliper logs in real-time and recorded mode, enabling effective monitoring of wellbore stability. Throughout the real-time acquisition, EM-PPM telemetry had provided a three times faster data rate to the surface unit. With the integration of Caliper data and Drilling mechanics data (vibration and ECD -equivalent circulating density), the borehole conditions were more visible to the directional driller, allowing for better control of drilling parameters to minimize vibration and achieve optimum hole cleaning in washed-out or tight formation sequences. After reaching well TD, the recorded data from the caliper sensor indicated an average of 8.6% washout for the entire 12.25-in. interval. Washout intervals were compared with loss occurrence, showing potential for the caliper to be used as an indirect indicator of fractured intervals and validating fault trend prognosis. This LWD case study has given added value in geothermal borehole characterization for both drilling operation and subsurface. Identified challenges while running LWD in this geothermal environment need to be addressed for future improvements, such as the effect of tool eccentricity and the impact of vibration. A perusal of both real-time and recorded drilling mechanics and caliper data has opened various possibilities for maximizing sensor usage in future wells.

Keywords: geothermal drilling, geothermal formation, geothermal technologies, logging-while-drilling, vibration, caliper, case study

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Authors: Ella Tyuryumina, Alexey Neznanov

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Finding algorithms to predict the growth of tumors has piqued the interest of researchers ever since the early days of cancer research. A number of studies were carried out as an attempt to obtain reliable data on the natural history of breast cancer growth. Mathematical modeling can play a very important role in the prognosis of tumor process of breast cancer. However, mathematical models describe primary tumor growth and metastases growth separately. Consequently, we propose a mathematical growth model for primary tumor and primary metastases which may help to improve predicting accuracy of breast cancer progression using an original mathematical model referred to CoM-IV and corresponding software. We are interested in: 1) modelling the whole natural history of primary tumor and primary metastases; 2) developing adequate and precise CoM-IV which reflects relations between PT and MTS; 3) analyzing the CoM-IV scope of application; 4) implementing the model as a software tool. The CoM-IV is based on exponential tumor growth model and consists of a system of determinate nonlinear and linear equations; corresponds to TNM classification. It allows to calculate different growth periods of primary tumor and primary metastases: 1) ‘non-visible period’ for primary tumor; 2) ‘non-visible period’ for primary metastases; 3) ‘visible period’ for primary metastases. The new predictive tool: 1) is a solid foundation to develop future studies of breast cancer models; 2) does not require any expensive diagnostic tests; 3) is the first predictor which makes forecast using only current patient data, the others are based on the additional statistical data. Thus, the CoM-IV model and predictive software: a) detect different growth periods of primary tumor and primary metastases; b) make forecast of the period of primary metastases appearance; c) have higher average prediction accuracy than the other tools; d) can improve forecasts on survival of BC and facilitate optimization of diagnostic tests. The following are calculated by CoM-IV: the number of doublings for ‘nonvisible’ and ‘visible’ growth period of primary metastases; tumor volume doubling time (days) for ‘nonvisible’ and ‘visible’ growth period of primary metastases. The CoM-IV enables, for the first time, to predict the whole natural history of primary tumor and primary metastases growth on each stage (pT1, pT2, pT3, pT4) relying only on primary tumor sizes. Summarizing: a) CoM-IV describes correctly primary tumor and primary distant metastases growth of IV (T1-4N0-3M1) stage with (N1-3) or without regional metastases in lymph nodes (N0); b) facilitates the understanding of the appearance period and manifestation of primary metastases.

Keywords: breast cancer, exponential growth model, mathematical modelling, primary metastases, primary tumor, survival

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Authors: Yori Gidron, Maartje Mol, Norbert Foudraine, Frits Van Osch, Joop Van Den Bergh, Moshe Farchi, Maud Straus

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Background: The worldwide pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-COV2), which began in 2019, also known as Covid-19, has infected over 136 million people and tragically took the lives of over 2.9 million people worldwide. Many of the complications and deaths are predicted by the inflammatory “cytokine storm.” One way to progress in the prevention of death is by finding a predictive and protective factor that inhibits inflammation, on the one hand, and which also increases anti-viral immunity on the other hand. The vagal nerve does precisely both actions. This study examined whether vagal nerve activity, indexed by heart-rate variability (HRV), predicts survival in patients with Covid-19. Method: We performed a pseudo-prospective study, where we retroactively obtained ECGs of 271 Covid-19 patients arriving at a large regional hospital in The Netherlands. HRV was indexed by the standard deviation of the intervals between normal heartbeats (SDNN). We examined patients’ survival at 3 weeks and took into account multiple confounders and known prognostic factors (e.g., age, heart disease, diabetes, hypertension). Results: Patients’ mean age was 68 (range: 25-95) and nearly 22% of the patients had died by 3 weeks. Their mean SDNN (17.47msec) was far below the norm (50msec). Importantly, relatively higher HRV significantly predicted a higher chance of survival, after statistically controlling for patients’ age, cardiac diseases, hypertension and diabetes (relative risk, H.R, and 95% confidence interval (95%CI): H.R = 0.49, 95%CI: 0.26 – 0.95, p < 0.05). However, since HRV declines rapidly with age and since age is a profound predictor in Covid-19, we split the sample by median age (40). Subsequently, we found that higher HRV significantly predicted greater survival in patients older than 70 (H.R = 0.35, 95%CI: 0.16 – 0.78, p = 0.01), but HRV did not predict survival in patients below age 70 years (H.R = 1.11, 95%CI: 0.37 – 3.28, p > 0.05). Conclusions: To the best of our knowledge, this is the first study showing that higher vagal nerve activity, as indexed by HRV, is an independent predictor of higher chances for survival in Covid-19. The results are in line with the protective role of the vagal nerve in diseases and extend this to a severe infectious illness. Studies should replicate these findings and then test in controlled trials whether activating the vagus nerve may prevent mortality in Covid-19.

Keywords: Covid-19, heart-rate Variability, prognosis, survival, vagal nerve

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Authors: Umamaheswari Shanmugam, Silvia Ronchi, Radu Vornicu

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Software, artificial intelligence, and machine learning can improve healthcare through innovative and advanced technologies that are able to use the large amount and variety of data generated during healthcare services every day. As we read the news, over 500 machine learning or other artificial intelligence medical devices have now received FDA clearance or approval, the first ones even preceding the year 2000. One of the big advantages of these new technologies is the ability to get experience and knowledge from real-world use and to continuously improve their performance. Healthcare systems and institutions can have a great benefit because the use of advanced technologies improves the same time efficiency and efficacy of healthcare. Software-defined as a medical device, is stand-alone software that is intended to be used for patients for one or more of these specific medical intended uses: - diagnosis, prevention, monitoring, prediction, prognosis, treatment or alleviation of a disease, any other health conditions, replacing or modifying any part of a physiological or pathological process–manage the received information from in vitro specimens derived from the human samples (body) and without principal main action of its principal intended use by pharmacological, immunological or metabolic definition. Software qualified as medical devices must comply with the general safety and performance requirements applicable to medical devices. These requirements are necessary to ensure high performance and quality and also to protect patients’ safety. The evolution and the continuous improvement of software used in healthcare must take into consideration the increase in regulatory requirements, which are becoming more complex in each market. The gap between these advanced technologies and the new regulations is the biggest challenge for medical device manufacturers. Regulatory requirements can be considered a market barrier, as they can delay or obstacle the device approval, but they are necessary to ensure performance, quality, and safety, and at the same time, they can be a business opportunity if the manufacturer is able to define in advance the appropriate regulatory strategy. The abstract will provide an overview of the current regulatory framework, the evolution of the international requirements, and the standards applicable to medical device software in the potential market all over the world.

Keywords: artificial intelligence, machine learning, SaMD, regulatory, clinical evaluation, classification, international requirements, MDR, 510k, PMA, IMDRF, cyber security, health care systems.

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Authors: Reuben Mugisha, Stella Bakibinga

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The cervical cancer burden is a global threat, but more so in low income settings where more than 85% of mortality cases occur due to lack of sufficient screening programs. There is consequently a lack of early detection of cancer and precancerous cells among women. Studies show that 3% to 35% of deaths could have been avoided through early screening depending on prognosis, disease progression, environmental and lifestyle factors. In this study, a systematic literature review is undertaken to understand potential barriers and facilitators as documented in previous studies that focus on the application of telehealth in cervical cancer screening programs for early detection of cancer and precancerous cells. The study informs future studies especially those from low income settings about lessons learned from previous studies and how to be best prepared while planning to implement telehealth for cervical cancer screening. It further identifies the knowledge gaps in the research area and makes recommendations. Using a specified selection criterion, 15 different articles are analyzed based on the study’s aim, theory or conceptual framework used, method applied, study findings and conclusion. Results are then tabulated and presented thematically to better inform readers about emerging facts on barriers and facilitators to telehealth implementation as documented in the reviewed articles, and how they consequently lead to evidence informed conclusions that are relevant to telehealth implementation for cervical cancer screening. Preliminary findings of this study underscore that use of low cost mobile colposcope is an appealing option in cervical cancer screening, particularly when coupled with onsite treatment of suspicious lesions. These tools relay cervical images to the online databases for storage and retrieval, they permit integration of connected devices at the point of care to rapidly collect clinical data for further analysis of the prevalence of cervical dysplasia and cervical cancer. Results however reveal the need for population sensitization prior to use of mobile colposcopies among patients, standardization of mobile colposcopy programs across screening partners, sufficient logistics and good connectivity, experienced experts to review image cases at the point-of-care as important facilitators to the implementation of mobile colposcope as a telehealth cervical cancer screening mechanism.

Keywords: cervical cancer screening, digital technology, hand-held colposcopy, knowledge-sharing

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Authors: Ugo Rovigatti

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Neuroblastoma (NBL) has epitomized for at least 40 years our understanding of cancer cellular and molecular biology and its potential applications to novel therapeutic strategies. This includes the discovery of the very first oncogene aberrations and tumorigenesis suppression by differentiation in the 80s; the potential role of suppressor genes in the 90s; the relevance of immunotherapy in the millennium first, and the discovery of additional mutations by NGS technology in the millennium second decade. Similar discoveries were achieved in the majority of human cancers, and similar therapeutic interventions were obtained subsequently to NBL discoveries. Unfortunately, targeted therapies suggested by specific mutations (such as MYCN amplification –MNA- present in ¼ or 1/5 of cases) have not elicited therapeutic successes in aggressive NBL, where the prognosis is still dismal. The reasons appear to be linked to Tumor Heterogeneity, which is particularly evident in NBL but also a clear hallmark of aggressive human cancers generally. The new avenue of cancer immunotherapy (CIT) provided new hopes for cancer patients, but we still ignore the cellular or molecular targets. CIT is emblematic of high-risk disease (HR-NBL) since the mentioned GD2 passive immunotherapy is still providing better survival. We recently critically reviewed and evaluated the literature depicting the genomic landscapes of HR-NBL, coming to the qualified conclusion that among hundreds of affected genes, potential targets, or chromosomal sites, none correlated with anti-GD2 sensitivity. A better explanation is provided by the Micro-Foci inducing Virus (MFV) model, which predicts that neuroblasts infection with the MFV, an RNA virus isolated from a cancer-cluster (space-time association) of HR-NBL cases, elicits the appearance of MNA and additional genomic aberrations with mechanisms resembling chromothripsis. Neuroblasts infected with low titers of MFV amplified MYCN up to 100 folds and became highly transformed and malignant, thus causing neuroblastoma in young rat pups of strains SD and Fisher-344 and larger tumor masses in nu/nu mice. An association was discovered with GD2 since this glycosphingolipid is also the receptor for the family of MFV virus (dsRNA viruses). It is concluded that a dsRNA virus, MFV, appears to provide better explicatory mechanisms for the genesis of i) specific genomic aberrations such as MNA; ii) extensive tumor heterogeneity and chromothripsis; iii) the effects of passive immunotherapy with anti-GD2 monoclonals and that this and similar models should be further investigated in both pediatric and adult cancers.

Keywords: neuroblastoma, MYCN, amplification, viruses, GD2

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Authors: Karen Boaz, C. R. Charan

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Background: The infiltration of tumour stroma by eosinophils, Tumor-Associated Tissue Eosinophilia (TATE), is known to modulate the progression of Oral Squamous Cell Carcinoma (OSCC). Eosinophils have direct tumoricidal activity by release of cytotoxic proteins and indirectly they enhance permeability into tumor cells enabling penetration of tumoricidal cytokines. Also, eosinophils may promote tumor angiogenesis by production of several angiogenic factors. Identification of eosinophils in the inflammatory stroma has been proven to be an important prognosticator in cancers of mouth, oesophagus, larynx, pharynx, breast, lung, and intestine. Therefore, the study aimed to correlate TATE with clinical and histopathological variables, and blood eosinophil count to assess the role of TATE as a prognosticator in Oral Squamous Cell Carcinoma (OSCC). Methods: Seventy two biopsy-proven cases of OSCC formed the study cohort. Blood eosinophil counts and TNM stage were obtained from the medical records. Tissue sections (5µm thick) were stained with Haematoxylin and Eosin. The eosinophils were quantified at invasive tumour front (ITF) in 10HPF (40x magnification) with an ocular grid. Bryne’s grading of ITF was also performed. A subset of thirty cases was also assessed for association of TATE with recurrence, involvement of lymph nodes and surgical margins. Results: 1) No statistically significant correlation was found between TATE and TNM stage, blood eosinophil counts and most parameters of Bryne’s grading system. 2) Statistically significant relation of intense degree of TATE was associated with the absence of distant metastasis, increased lympho-plasmacytic response and increased survival (diseasefree and overall) of OSCC patients. 3) In the subset of 30 cases, tissue eosinophil counts were higher in cases with lymph node involvement, decreased survival, without margin involvement and in cases that did not recur. Conclusion: While the role of eosinophils in mediating immune responses seems ambiguous as eosinophils support cell-mediated tumour immunity in early stages while inhibiting the same in advanced stages, TATE may be used as a surrogate marker for determination of prognosis in oral squamous cell carcinoma.

Keywords: tumour-associated tissue eosinophilia, oral squamous cell carcinoma, prognosticator, tumoral immunity

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