Search results for: follicular carcinoma thyroid

Authors: A. Dean, M. Pitcher, L. Storer, K. Shanahan, I. Rio, B. Mann

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Purpose: Breast cancer survivors are at risk of specific physical and psycho-social issues, such as arm swelling, fatigue, and depression. Firstly, we investigate symptoms reported by Australia breast cancer survivors upon completion of definitive treatment. Secondly, we evaluate the appropriateness and effectiveness of a multi-centre pilot program nurse-led clinic to identify these issues and make timely referrals to available services. Methods: Patients post-definitive treatment (excluding ongoing hormonal therapy) for early breast cancer or ductal carcinoma in situ were invited to participate. An hour long appointment with a breast care nurse (BCN) was scheduled. In preparation, patients completed validated quality-of-life surveys (FACT-B, Menopause Rating Scale, Distress Thermometer). During the appointment, issues identified in the surveys were addressed and referrals to appropriate services arranged. Results: 183 of 274 (67%) eligible patients attended a nurse-led clinic. Mean age 56.8 years (range 29-87 years), 181/183 women, 105/183 post-menopausal. 96 (55%) participants reported significant level of distress; 31 (18%) participants reported extreme distress or depression. Distress stemmed from a lack of energy (56/175); poor quality of sleep (50/176); inability to work or participate in household activities (35/172) and problems with sex life (28/89). 166 referrals were offered; 94% of patients accepted the referrals. 65% responded to a follow-up survey: the majority of women either strongly agreed or agreed that the BCN was overwhelmingly supportive, helpful in making referrals, and compassionate towards them. 39% reported making lifestyle changes as a result of the BCN. Conclusion: Breast cancer survivors experience a unique set of challenges, including low mood, difficulty sleeping, problems with sex life and fear of disease recurrence. The nurse-led clinic model is an appropriate and effective method to ensure physical and psycho-social issues are identified and managed in a timely manner. This model empowers breast cancer survivors with information about their diagnosis and available services.

Keywords: early breast cancer, survivorship, breast care nursing, oncology nursing and cancer care

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Authors: Tarek K. Jalouta, Jolietta R. Holliman, Kathryn R. Burke, Kathleen M. Bewley-Thomas

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Background: Chronic hepatitis C virus (HCV) infection is one of the leading causes of liver cirrhosis and hepatocellular carcinoma. In the United States, HCV screening awareness, treatment, and linkage to care are under continues ascending progress. However, still millions of people are asymptomatically infected and undiagnosed yet. Through this community mission, we sought to identify the best and the newest strategies to identify those infected people to educate them, link them to care and cure them. Methods: We have identified patients that did not have a prior HCV screening in our Electronic medical record (EMR) including all our different hospital locations (South Suburban Chicago, Northern, Western and Central Indiana). Providing education to all Primary care/Gastroenterology/Infectious diseases providers and staff in the clinic to increase awareness of the HCV screening. Health-related quality of life, chronic clinical complications, and demographics data were collected for each patient. All outcomes of HCV antibody-reactive and HCV RNA–positive results were identified and statistically analyzed. Results: From July 2016 to July 2018 we screened 35,720 individuals of birth cohort in our different Franciscan’s health medical centers. Of the screened population, 986 (2.7%) individuals were HCV AB-reactive. Of those, 319 (1%) patients were HCV RNA-positive, and 264 patients were counseled and linked to providers. 34 patients initiated anti-HCV therapy with successful treatment. Conclusions: Our HCV screening augmentation project considered the largest screening program in the Midwest. Augmenting the HCV screening process through creating a Best Practice Alert (BPA) in the EMR (Epic Sys.) and point of care testing could be helpful. Although continued work is required, our team is working on increase screening through adding HCV test to CBC-Panels in Emergency Department settings, phone calls to all birth cohort individuals through Robo-Calling System aimed to reach 75,000 individuals by 2019. However, a better linkage to care and referral monitoring system to all HCV RNA positive patients is still needed, and access to therapy, especially for uninsured patients, is challenging.

Keywords: chronic hepatitis C, chronic hepatitis C treatment, chronic hepatitis C screening, chronic hepatitis C prevention, liver cancer

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Authors: Iva Blazkova, Amitava Moulick, Vedran Milosavljevic, Pavel Kopel, Marketa Vaculovicova, Vojtech Adam, Rene Kizek

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Doxorubicin is one of the most commonly used and the most effective chemotherapeutic drugs. This antracycline drug isolated from the bacteria Streptomyces peuceticus var. caesius is sold under the trade name Adriamycin (hydroxydaunomycin, hydroxydaunorubicin). Doxorubicin is used in single therapy to treat hematological malignancies (blood cancers, leukaemia, lymphoma), many types of carcinoma (solid tumors) and soft tissue sarcomas. It has many serious side effects like nausea and vomiting, hair lost, myelosupression, oral mucositis, skin reactions and redness, but the most serious one is the cardiotoxicity. Because of the risk of heart attack and congestive heart failure, the total dose administered to patients has to be accurately monitored. With the aim to lower the side effects and to targeted delivery of doxorubicin into the tumor tissue, the different nanoparticles are studied. The drug can be bound on a surface of nanoparticle, encapsulated in the inner cavity, or incorporated into the structure of nanoparticle. Among others, carbon nanoparticles (graphene, carbon nanotubes, fullerenes) are highly studied. Besides the number of inorganic nanoparticles, a great potential exhibit also organic ones mainly lipid-based and polymeric nanoparticle. The aim of this work was to perform a toxicity study of free doxorubicin compared to doxorubicin conjugated with various nanotransporters. The effect of liposomes, fullerenes, graphene, and carbon nanotubes on the toxicity was analyzed. As a first step, the binding efficacy of between doxorubicin and the nanotransporter was determined. The highest efficacy was detected in case of liposomes (85% of applied drug was encapsulated) followed by graphene, carbon nanotubes and fullerenes. For the toxicological studies, the chicken embryos incubated under controlled conditions (37.5 °C, 45% rH, rotation every 2 hours) were used. In 7th developmental day of chicken embryos doxorubicin or doxorubicin-nanotransporter complex was applied on the chorioallantoic membrane of the eggs and the viability was analyzed every day till the 17th developmental day. Then the embryos were extracted from the shell and the distribution of doxorubicin in the body was analyzed by measurement of organs extracts using laser induce fluorescence detection. The chicken embryo mortality caused by free doxorubicin (30%) was significantly lowered by using the conjugation with nanomaterials. The highest accumulation of doxorubicin and doxorubicin nanotransporter complexes was observed in the liver tissue

Keywords: doxorubicin, chicken embryos, nanotransporters, toxicity

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Authors: Aarti Agarwal, Ajmal Khan

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Background and Objective: Breathing difficulty is most distressing symptom for the patient and their caregivers providing palliative care to individuals with advanced malignancy. It needs to be tackled effectively and sometimes preemptively to provide relief from respiratory obstruction. Interventional procedures like tracheal stenting are becoming increasingly popular as a part of palliation for respiratory symptoms. We present a case of esophageal tumor earlier stented by Gastroenterologist to maintain esophageal patency, but the tumor outgrew to produce tracheal infiltration and thereby causing airway obstruction. Method and Result: 62-year-old man presented with unresectable Carcinoma oesophagus with inability to swallow. A metallic stent was placed by the gastroenterologist, to maintain esophageal patency and enable patient to swallow. Two months later, the patient returned to hospital in emergency with respiratory distress. CT neck and thorax revealed tumor infiltration through posterior tracheal wall. Lower extent of the tumor was till 1 cm above the carina. Airway stenting with Tracheo bronchial stent with Y configuration was planned under general anaesthesia with airway blocks. Superior Laryngeal Nerve Block, Glossopharyngeal block and Trans tracheal infiltration of local anaesthetics were performed. The patient was sedated with Fentanyl, Midazolam and propofol infusion but was breathing spontaneously. Once the rigid bronchoscope was placed inside trachea, breathing was supported with oxygen and sevoflurane. Initially, the trachea was cleared of tumor by coring. After creating space, tracheal stent was positioned and deployed. After stent placement patient was awakened, suctioned and nebulized. His respiratory stridor relieved instantaneously and was shifted to recovery. Conclusion: Airway blocks help in decreasing the incidence and severity of coughing during airway instrumentation thereby help in proper stent placement. They also reduce the requirement of general anaesthetics and hasten the post stenting recovery. Airway stent provided immediate relief to patient from symptoms of respiratory difficulty. Decision for early tracheal stenting may be taken for a select group of patients with high propensity for local spread, thereby avoiding respiratory complications and providing better quality of life in patients with inoperable malignancy.

Keywords: tracheal stent, respiratory difficulty, esophageal tumor, anaesthetic management

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Authors: Alla Ovsyannikova, Oksana Rymar, Elena Shakhtshneider, Mikhail Voevoda

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In Siberia endocrinologists increasingly noted young patients with the course of diabetes mellitus differing from 1 and 2 types. Therefore we did a molecular genetic study for this group of patients to verify the monogenic forms of diabetes mellitus in them and researched the characteristics of this pathology. When confirming the monogenic form of diabetes, we performed a correction therapy for many patients (transfer from insulin to tablets), prevented specific complications, examined relatives and diagnosed their diabetes at the preclinical stage, revealed phenotypic characteristics of the pathology which led to the high significance of this work. Materials and Methods: We observed 5 patients (4 families). We diagnosed MODY (Maturity Onset Diabetes of the Young) during the molecular genetic testing (direct automatic sequencing). All patients had a full clinical examination, blood samples for biochemical research, determination of C-peptide and TSH, antibodies to b-cells, microalbuminuria, abdominal ultrasound, heart and thyroid ultrasound, examination of ophthalmologist. Results: We diagnosed 3 rare types of MODY: two women had MODY8, one man – MODY6 and man and his mother - MODY12. Patients with types 8 and 12 had clinical features. Age of onset hyperglycemia ranged from 26 to 34 years. In a patient with MODY6 fasting hyperglycemia was detected during a routine examination. Clinical symptoms, complications were not diagnosed. The patient observes a diet. In the first patient MODY8 was detected during first pregnancy, she had itchy skin and mostly postprandial hyperglycemia. Upon examination we determined glycated hemoglobin 7.5%, retinopathy, non-proliferative stage, peripheral neuropathy. She uses a basic bolus insulin therapy. The second patient with MODY8 also had clinical manifestations of hyperglycemia (pruritus, thirst), postprandial hyperglycemia and diabetic nephropathy, a stage of microalbuminuria. The patient was diagnosed autoimmune thyroiditis. She used inhibitors of DPP-4. The patient with MODY12 had an aggressive course. In the detection of hyperglycemia he had complaints of visual impairment, intense headaches, leg cramps. The patient had a history of childhood convulsive seizures of non-epileptic genesis, without organic pathology, which themselves were stopped at the age of 12 years. When we diagnosed diabetes a patient was 28 years, he had hypertriglyceridemia, atherosclerotic plaque in the carotid artery, proliferative retinopathy (lacerocoagulation). Diabetes and early myocardial infarction were observed in three cases in family. We prescribe therapy with sulfonylureas and SGLT-2 inhibitors with a positive effect. At the patient's mother diabetes began at a later age (30 years) and a less aggressive course was observed. She also has hypertriglyceridemia and uses oral hypoglycemic drugs. Conclusions: 1) When young patients with hyperglycemia have extrapancreatic pathologies and diabetic complications with a short duration of diabetes we can assume they have one of type of MODY diabetes. 2) In patients with monogenic forms of diabetes mellitus, the clinical manifestations of hyperglycemia in each succeeding generation are revealed at an earlier age. Research had increased our knowledge of the monogenic forms of diabetes. The reported study was supported by RSCF, research project No. 14-15-00496-P.

Keywords: diabetes mellitus, MODY diabetes, monogenic forms, young patients

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Authors: Vanitha Varadharaj, Vijalakshmi Krishnamurthy

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Annona squamosa Linn, commonly known as Sugar apple, belonging to the family Annonaceae, is said to show varied medicinal effects, including insecticide, antiovulatory and abortifacient. The alkaloid and flavonoids present in Annona squamosa leaf has proved to have antioxidant activity. The present work has been planned to investigate the effect of ethanolic leaf extract of Annona squamosa leaf on Den Induced wistar albino rats. The study was carried out to analyze the biochemical Parmeters like Total Proteins, Bilirubin, Enzymatic and Non –Enzymatic enzymes, Marker enzymes and Tumor markers in serum and also the histopathological studies in liver is carried out in control and DEN induced rats. Supplementation of ELAS (Ethanolic Leaf Extract Of Annona squamosa) reduced the liver weight and also reduced the tumour incidence. Chemoprevention group showed near normal values of bilirubin when compared with the control rats. Total protein was decreased in the cancer bearing group and on treatment with the extract the levels of protein were restored. Both in pre and post treatment group, the activities of enzymatic antioxidants such as superoxide dismutase, catalase, and Glutathione peroxidase were increased but in pre treated animals it was more effective than post treated animals. The non- enzymatic antioxidants such as vitamin C and vitamin E were brought back to normal level significantly in post and pre treated animals. Activities of marker enzymes such as SGOT, SGPT, ALP, γ GT were significantly elevated in the serum of cancer animals and the values returned to normal after treatment with the extract suggesting the hepato protective effect of the extract. Lipid peroxide was found to be elevated in the cancer induced group. This condition was brought back to the normal in the pre and post treated animals with ELAS. Histological examination also confirmed the anti- carcinogenic potential of ELAS, Cancer induced groups had a triple fold increase in their AFP values when compared to other groups. DEN treatment increased the level of AFP expression while ELAS partially counteracted the effect of it. So the scientific validation obtained from this study may pave way to many budding scientists to find new drugs from Annona squamosa for various ailments.

Keywords: annona squamosa, biochemical parmeters, cancer, leaf extract

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Authors: Sidra Suleman, Maliha Suleman, Stephen Brindley

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Oral rehabilitation of head and neck cancer patients plays a crucial role in the quality of life for such individuals post-treatment. Placement of dental implants or implant-retained prostheses can help restore oral function and aesthetics, which is often compromised following surgery. Conventional prosthodontic techniques can be insufficient in rehabilitating such patients due to their altered anatomy and reduced oral competence. Hence, there is a strong clinical need for the placement of dental implants. With an increasing incidence of head and neck cancer patients, the demand for such treatment is rising. Aim: The aim of the study was to determine the survival rate of dental implants in head and neck cancer patients placed at the Restorative and Maxillofacial Department, Royal Stoke University Hospital (RSUH), United Kingdom. Methodology: All patients who received dental implants between January 1, 2013 to December 31, 2020 were identified. Patients were excluded based on three criteria: 1) non-head and neck cancer patients, 2) no outpatient follow-up post-implant placement 3) provision of non-dental implants. Scanned paper notes and electronic records were extracted and analyzed. Implant survival was defined as fixtures that had remained in-situ / not required removal. Sample: Overall, 61 individuals were recruited from the 143 patients identified. The mean age was 64.9 years, with a range of 35 – 89 years. The sample included 37 (60.7%) males and 24 (39.3%) females. In total, 211 implants were placed, of which 40 (19.0%) were in the maxilla, 152 (72.0%) in the mandible and 19 (9.0%) in autogenous bone graft sites. Histologically 57 (93.4%) patients had squamous cell carcinoma, with 43 (70.5%) patients having either stage IVA or IVB disease. As part of treatment, 42 (68.9%) patients received radiotherapy, which was carried out post-operatively for 29 (69.0%) cases. Whereas 21 (34.4%) patients underwent chemotherapy, 13 (61.9%) of which were post-operative. The Median follow-up period was 21.9 months with a range from 0.9 – 91.4 months. During the study, 23 (37.7%) patients died and their data was censored beyond the date of death. Results: In total, four patients who had received radiotherapy had one implant failure each. Two mandibular implants failed secondary to osteoradionecrosis, and two maxillary implants did not survive as a result of failure to osseointegrate. The overall implant survival rates were 99.1% at three years and 98.1% at both 5 and 7 years. Conclusions: Although this data shows that implant failure rates are low, it highlights the difficulty in predicting which patients will be affected. Future studies involving larger cohorts are warranted to further analyze factors affecting outcomes.

Keywords: oncology, dental implants, survival, restorative

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Authors: Puneet Goyal, Aarti Agarwal

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Background and Objective: Nutritional support is an integral part of palliative care of advanced non-resectable abdominal malignancy patients, though is frequently neglected aspect. Non-Healing high output Entero-cutaneous fistulas sometimes require long term parenteral nutrition, to take care of catabolism and replacement of nutrients. We present a case of inoperable pancreatic malignancy with high output entero-cutaneous fistula, which was provided parenteral nutritional support with the use of Totally Implantable Venous Access Device (TIVAD). Method and Results: 55 year old man diagnosed with carcinoma pancreas had developed high entero-cutaneous fistula. His tumor was found to be inoperable and was on total parenteral nutrition through routine central line. This line was difficult to maintain as he required it for a long term TPN. He was planned to undergo Totally Implantable Venous Access Device (TIVAD) implantation. 8Fr single lumen catheter with Groshong non-return Valve (Bard Access Systems, Inc. USA) was inserted through right internal jugular vein, under fluoroscopic guidance. The catheter was tunneled subcutaneously and brought towards infraclavicular pocket, cut at appropriate length and connected to port and locked. Port was sutured in floor of pocket. Free flow of blood aspirated, flushed with heparinized saline. There was no kink observed in entire length of catheter under fluoroscopy. Skin over infraclavicular pocket was sutured. Long term catheter care and associated risks were explained to patient and relatives. Patient continued to receive total parenteral nutrition as well as other supportive therapy though TIVAD for next 6 weeks, till his demise. Conclusion: TIVADs are standard of care for long term venous access solutions in cancer patients requiring chemotherapy. In this case, we extended its use for providing parenteral nutrition and other supportive therapy. TIVADs can be implanted in advanced cancer patients for providing venous access solution required for various palliative treatments and medications. This will help in improving quality of life and satisfaction amongst terminally ill cancer patients.

Keywords: parenteral nutrition, totally implantable venous access device, long term venous access, interventions in anesthesiology

Procedia PDF Downloads 248

Authors: G. Magalhães-Mota, C. Magro, S. Sério, E. Mateus, P. A. Ribeiro, A. B. Ribeiro, M. Raposo

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Triclosan [5-chloro-2-(2,4-dichlorophenoxy) phenol], belonging to the class of Pharmaceuticals and Personal Care Products (PPCPs), is a broad-spectrum antimicrobial agent and bactericide. Because of its antimicrobial efficacy, it is widely used in personal health and skin care products, such as soaps, detergents, hand cleansers, cosmetics, toothpastes, etc. However, it has been considered to disrupt the endocrine system, for instance, thyroid hormone homeostasis and possibly the reproductive system. Considering the widespread use of triclosan, it is expected that environmental and food safety problems regarding triclosan will increase dramatically. Triclosan has been found in river water samples in both North America and Europe and is likely widely distributed wherever triclosan-containing products are used. Although significant amounts are removed in sewage plants, considerable quantities remain in the sewage effluent, initiating widespread environmental contamination. Triclosan undergoes bioconversion to methyl-triclosan, which has been demonstrated to bio accumulate in fish. In addition, triclosan has been found in human urine samples from persons with no known industrial exposure and in significant amounts in samples of mother's milk, demonstrating its presence in humans. The action of sunlight in river water is known to turn triclosan into dioxin derivatives and raises the possibility of pharmacological dangers not envisioned when the compound was originally utilized. The aim of this work is to detect low concentrations of triclosan in an aqueous complex matrix through the use of a sensor array system, following the electronic tongue concept based on impedance spectroscopy. To achieve this goal, we selected the appropriate molecules to the sensor so that there is a high affinity for triclosan and whose sensitivity ensures the detection of concentrations of at least nano-molar. Thin films of organic molecules and oxides have been produced by the layer-by-layer (LbL) technique and sputtered onto glass solid supports already covered by gold interdigitated electrodes. By submerging the films in complex aqueous solutions with different concentrations of triclosan, resistance and capacitance values were obtained at different frequencies. The preliminary results showed that an array of interdigitated electrodes sensor coated or uncoated with different LbL and films, can be used to detect TCS traces in aqueous solutions in a wide range concentration, from 10⁻¹² to 10⁻⁶ M. The PCA method was applied to the measured data, in order to differentiate the solutions with different concentrations of TCS. Moreover, was also possible to trace a curve, the plot of the logarithm of resistance versus the logarithm of concentration, which allowed us to fit the plotted data points with a decreasing straight line with a slope of 0.022 ± 0.006 which corresponds to the best sensitivity of our sensor. To find the sensor resolution near of the smallest concentration (Cs) used, 1pM, the minimum measured value which can be measured with resolution is 0.006, so the ∆logC =0.006/0.022=0.273, and, therefore, C-Cs~0.9 pM. This leads to a sensor resolution of 0.9 pM for the smallest concentration used, 1pM. This attained detection limit is lower than the values obtained in the literature.

Keywords: triclosan, layer-by-layer, impedance spectroscopy, electronic tongue

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Authors: E. Isaac, I. Jalo, Y. Alkali, A. Ajani, A. Rasaki, Y. Jibrin, K. Mustapha, A. Ayuba, S. Charanchi, H. Danlami

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Introduction: Hepatitis B infection continues to be a serious global health problem with about 2 billion people infected worldwide, many of these in sub-Saharan Africa. Nigeria is one of the countries with the highest incidence, with a prevalence of 10-15%. Methods: Records of Hepatitis B surface and envelope antigen test results in adults in Federal Teaching Hospital, Gombe between May 2000 and May 2015 were retrieved and analyzed. Findings: Adult out-patient consultations and in-patient admissions were 343,083 and 67,761 respectively, accounting for 87% of total. Hepatitis B surface antigenaemia was tested for in 23,888 adults and children. 88.9% (21240) were adults. Males constituted 56% (11902/21240) and females 44% (9211/21240). 5104 (24.0%) of tested individuals were 19-25years; 12,039 (56.7%) 26-45years; 21119 (9.0%) 46-55years; 2.8% (590/21240) and 766 (3.6%) >65years. Among adult males, 17% (2133/11902) was contributed by ages 19-25. 58% (7017/11902), 11.9% (1421/11902), 6.4% (765/11902) and 4.7% (563/11902) of males were 26-45 years old, 46-55 years old and 56-65 years and >65year old respectively. Adults aged 19-25years, 26-45 years, 46-55years, 56-65 and > 65years each constituted 32% (2966/9211); 54.4% (5009/9211); 7.4% (684/9211), 3.8% (350/9211) and 2.2% (201/9211) of females respectively. 16.2% (3431/21,240) demonstrated Hepatitis B surface antigenaemia. The sero-positivity rate was 16.9% (865//5104) between 19-25years, 21.2% (2559/12,039) among 26-45year old individuals. 17.9% (377/2111); 14.1% (83/590) and 7.3% (56/766) of 46-55year old, 56-65year old and >65year old individuals screened were seropositive. The highest sero-positivity rate was found in male young adults aged 19-25years 27.9% (398/1426) and lowest in elderly males 7.4% (28/377). HBe antigen testing rate among HbSAg seropositive individuals was 97.3% (3338/3431). Males constituted 59.7% (1992/3338) and females 40.3% (1345/3338). 25.3% (844/3338) were aged 19-25years; 61.1% (2039/3338) 26-45years; 10.2% (340/3338) 46-55years; 2.7% (90/3338) 56-65years and 0.7% >65years old. HB e antigenaemia was positive in 8.2% (275/3338) of those tested. 41% (113/275); 50.2% (138/275); 5.4% (15/275); 1.8% (5/275) and 1.1 (3/275) of HB e sero-positivity was among age groups 19-25, 26-45, 46-55, 56-65 and > 65year old individuals. Dual sero-positivity rate was highest 13% (113/844) in young adults 19-25years and lowest between 46-55years; 15/340 (4.4%). 4.2% (15/360); 13.5% (69/512); 6.7% (90/1348); 4.6% (10/214); 5% (2/40) and 6.7% (1/15) of males aged 19-25; 26-45; 46-55; 56-65; and >65years had HB e antigenaemia respectively. Among females - 27/293 (9.2%) aged 19-25; 26/500 (5.2%) 26-45; 2/84 (2.4%) 46-55; 1/12 (8.3%) 56-65 and 1/9(11.1%) >65years had dual antigenaemia. In women of childbearing age, 6.9% (53/793) had a dual carriage. Conclusion: Dual hepatitis B surface and envelope antigenaemia are highest in young adult males. This will have significant implications for the development of chronic liver disease and hepatocellular carcinoma.

Keywords: adult, Hepatitis B, Nigeria, dual carriage

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Authors: Reham H. Soliman, Noha Noufal, Howayda AbdelAal

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Calcium/calmodulin-dependent serine protein kinase (CASK) belongs to the membrane-associated guanylate kinase (MAGUK) family and has been proposed as a mediator of cell-cell adhesion and proliferation, which can contribute to tumorogenesis. CASK has been linked as a good prognostic factor with some tumor subtypes, while considered as a poor prognostic marker in others. To our knowledge, no sufficient evidence of CASK role in colorectal cancer is available. The aim of this study is to evaluate the expression of Calcium/calmodulin-dependent serine protein kinase (CASK) in non-mucinous colorectal adenocarcinoma and adenomatous polyps as precursor lesions and assess its prognostic significance. The study included 42 cases of conventional colorectal adenocarcinoma and 15 biopsies of adenomatous polyps with variable degrees of dysplasia. They were reviewed for clinicopathological prognostic factors and stained by CASK; mouse, monoclonal antibody using heat-induced antigen retrieval immunohistochemical techniques. The results showed that CASK protein was significantly overexpressed (p <0.05) in CRC compared with adenoma samples. The CASK protein was overexpressed in the majority of CRC samples with 85.7% of cases showing moderate to strong expression, while 46.7% of adenomas were positive. CASK overexpression was significantly correlated with both TNM stage and grade of differentiation (p <0.05). There was a significantly higher expression in tumor samples with early stages (I/II) rather than advanced stage (III/IV) and with low grade (59.5%) rather than high grade (40.5%). Another interesting finding was found among the adenomas group, where the stronger intensity of staining was observed in samples with high grade dysplasia (33.3%) than those of lower grades (13.3%). In conclusion, this study shows that there is significant overexpression of CASK protein in CRC as well as in adenomas with high grade dysplasia. This indicates that CASK is involved in the process of carcinogenesis and functions as a potential trigger of the adenoma-carcinoma cascade. CASK was significantly overexpressed in early stage and low-grade tumors rather than tumors with advanced stage and higher histological grades. This suggests that CASK protein is a good prognostic factor. We suggest that CASK affects CRC in two different ways derived from its physiology. CASK as part of MAGUK family can stimulate proliferation and through its cell membrane localization and as a mediator of cell-cell adhesion might contribute in tumor confinement and localization.

Keywords: CASK, colorectal cancer, overexpression, prognosis

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Authors: Angel Champion

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Chemotherapy and radiation use an acidified approach to induce apoptosis, which only kills mature cancer cells while resulting in gene and cell damage with significant levels of toxicity in tumor-affected tissues and organs. The acid approach, where the cells exterminated are not differentiated, induces the disappearance of white blood cells from the blood. This increases susceptibility to infection in severe forms of cancer spread. However, chemotherapy and radiation cannot kill cancer stem cells that metastasize, being the leading cause of 98% of cancer fatalities. With over 12 million new cancer cases symptomatic each year, including common malignancies such as Hepatocellular Carcinoma (HCC), this study aims to assess the bioactive constituents and phytochemical composition of Taraxacum Officinale (Dandelion). This analysis enables pharmaceutical quality and potency to be applied to studies on cancer cell proliferation and apoptosis. A phytochemical screening is carried out to identify the antioxidant components of Dandelion root, stem, and flower extract. The constituents tested for are phlorotannins, carbohydrates, glycosides, saponins, flavonoids, alkaloids, sterols, triterpenes, and anthraquinone glycosides. To conserve the existing phenolic compounds, a portion of the constituent tests will be examined with an acid, alcohol, or aqueous solvent. As a result, the qualitative and quantitative variations within the Dandelion extract that measure uniform effective potency are vital to the conformity for producing medicinal products. These medicines will be constructed with a consistent, uniform composition that physicians can use to control and effectively eradicate malignant diseases safely. Taraxacum Officinale's phytochemical composition comprises a highly-graded potency due to present bioactive contents that will essentially drive out malignant disease within the human body. Its high potency rate is powerful enough to eliminate both mature cancer cells and cancer stem cells without the cell and gene damage induced by chemotherapy and radiation. Correspondingly, the high margins of cancer mortality on a global scale are mitigated. This remarkable contribution to modern therapeutics will essentially optimize the margins of natural products and their derivatives, which account for 50% of pharmaceuticals in modern therapeutics, while preventing the adverse effects of radiation and chemotherapy drugs.

Keywords: antioxidant, apoptosis, metastasize, phytochemical, proliferation, potency

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Authors: Manohar Salla, Mark S. Butler, Ruby Pelingon, Geraldine Kaeslin, Daniel E. Croker, Janet C. Reid, Jong Min Baek, Paul V. Bernhardt, Elizabeth M. J. Gillam, Matthew A. Cooper, Avril A. B. Robertson

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MCC950 is a potent and selective inhibitor of the NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome that shows early promise for treatment of inflammatory diseases. The identification of major metabolites of lead molecule is an important step during drug development process. It provides an information about the metabolically labile sites in the molecule and thereby helping medicinal chemists to design metabolically stable molecules. To identify major metabolites of MCC950, the compound was incubated with human liver microsomes and subsequent analysis by (+)- and (−)-QTOF-ESI-MS/MS revealed a major metabolite formed due to hydroxylation on 1,2,3,5,6,7-hexahydro-s-indacene moiety of MCC950. This major metabolite can lose two water molecules and three possible regioisomers were synthesized. Co-elution of major metabolite with each of the synthesized compounds using HPLC-ESI-SRM-MS/MS revealed the structure of the metabolite (±) N-((1-hydroxy-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonamide. Subsequent synthesis of individual enantiomers and coelution in HPLC-ESI-SRM-MS/MS using a chiral column revealed the metabolite was R-(+)- N-((1-hydroxy-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonamide. To study the possible cytochrome P450 enzyme(s) responsible for the formation of major metabolite, MCC950 was incubated with a panel of cytochrome P450 enzymes. The result indicated that CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C18, CYP2C19, CYP2J2 and CYP3A4 are most likely responsible for the formation of the major metabolite. The biological activity of the major metabolite and the other synthesized regioisomers was also investigated by screening for for NLRP3 inflammasome inhibitory activity and cytotoxicity. The major metabolite had 170-fold less inhibitory activity (IC50-1238 nM) than MCC950 (IC50-7.5 nM). Interestingly, one regioisomer had shown nanomolar inhibitory activity (IC50-232 nM). However, no evidence of cytotoxicity was observed with any of these synthesized compounds when tested in human embryonic kidney 293 cells (HEK293) and human liver hepatocellular carcinoma G2 cells (HepG2). These key findings give an insight into the SAR of the hexahydroindacene moiety of MCC950 and reveal a metabolic soft spot which could be blocked by chemical modification.

Keywords: Cytochrome P450, inflammasome, MCC950, metabolite, microsome, NLRP3

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Authors: Danni Cheng

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Background: Preclinical and epidemiological studies have reported potential protective effects of low-density lipoprotein cholesterol (LDL-C) lowering drugs on head and neck squamous cell cancer (HNSCC) survival, but the causality was not consistent. Genetic variants associated with LDL-C lowering drug targets can predict the effects of their therapeutic inhibition on disease outcomes. Objective: We aimed to evaluate the causal association of genetically proxied cholesterol-lowering drug targets and circulating lipid traits with cancer survival in HNSCC patients stratified by human papillomavirus (HPV) status using two-sample Mendelian randomization (MR) analyses. Method: Single-nucleotide polymorphisms (SNPs) in gene region of LDL-C lowering drug targets (HMGCR, NPC1L1, CETP, PCSK9, and LDLR) associated with LDL-C levels in genome-wide association study (GWAS) from the Global Lipids Genetics Consortium (GLGC) were used to proxy LDL-C lowering drug action. SNPs proxy circulating lipids (LDL-C, HDL-C, total cholesterol, triglycerides, apoprotein A and apoprotein B) were also derived from the GLGC data. Genetic associations of these SNPs and cancer survivals were derived from 1,120 HPV-positive oropharyngeal squamous cell carcinoma (OPSCC) and 2,570 non-HPV-driven HNSCC patients in VOYAGER program. We estimated the causal associations of LDL-C lowering drugs and circulating lipids with HNSCC survival using the inverse-variance weighted method. Results: Genetically proxied HMGCR inhibition was significantly associated with worse overall survival (OS) in non-HPV-drive HNSCC patients (inverse variance-weighted hazard ratio (HR IVW), 2.64[95%CI,1.28-5.43]; P = 0.01) but better OS in HPV-positive OPSCC patients (HR IVW,0.11[95%CI,0.02-0.56]; P = 0.01). Estimates for NPC1L1 were strongly associated with worse OS in both total HNSCC (HR IVW,4.17[95%CI,1.06-16.36]; P = 0.04) and non-HPV-driven HNSCC patients (HR IVW,7.33[95%CI,1.63-32.97]; P = 0.01). A similar result was found that genetically proxied PSCK9 inhibitors were significantly associated with poor OS in non-HPV-driven HNSCC (HR IVW,1.56[95%CI,1.02 to 2.39]). Conclusion: Genetically proxied long-term HMGCR inhibition was significantly associated with decreased OS in non-HPV-driven HNSCC and increased OS in HPV-positive OPSCC. While genetically proxied NPC1L1 and PCSK9 had associations with worse OS in total and non-HPV-driven HNSCC patients. Further research is needed to understand whether these drugs have consistent associations with head and neck tumor outcomes.

Keywords: Mendelian randomization analysis, head and neck cancer, cancer survival, cholesterol, statin

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Authors: Andreea Molnar, Amalia Ardeljan, Lexi Frankel, Marissa Dallara, Brittany Nagel, Omar Rashid

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Background: Escherichia coli is a gram-negative, facultative anaerobic bacteria that belongs to the family Enterobacteriaceae and resides in the intestinal tracts of individuals. E.Coli has numerous strains grouped into serogroups and serotypes based on differences in antigens in their cell walls (somatic, or “O” antigens) and flagella (“H” antigens). More than 700 serotypes of E. coli have been identified. Although most strains of E. coli are harmless, a few strains, such as E. coli O157:H7 which produces Shiga toxin, can cause intestinal infection with symptoms of severe abdominal cramps, bloody diarrhea, and vomiting. Infection with E. Coli can lead to the development of systemic inflammation as the toxin exerts its effects. Chronic inflammation is now known to contribute to cancer development in several organs, including the prostate. The purpose of this study was to evaluate the correlation between E. Coli and the incidence of prostate cancer. Methods: Data collected in this cohort study was provided by a Health Insurance Portability and Accountability Act (HIPAA) compliant national database to evaluate patients infected with E.Coli infection and prostate cancer using the International Classification of Disease (ICD-10 and ICD-9 codes). Permission to use the database was granted by Holy Cross Health, Fort Lauderdale for the purpose of academic research. Data analysis was conducted through the use of standard statistical methods. Results: Between January 2010 and December 2019, the query was analyzed and resulted in 81, 037 patients after matching in both infected and control groups, respectively. The two groups were matched by Age Range and CCI score. The incidence of prostate cancer was 2.07% and 1,680 patients in the E. Coli group compared to 5.19% and 4,206 patients in the control group. The difference was statistically significant by a p-value p<2.2x10-16 with an Odds Ratio of 0.53 and a 95% CI. Based on the specific treatment for E.Coli, the infected group vs control group were matched again with a result of 31,696 patients in each group. 827 out of 31,696 (2.60%) patients with a prior E.coli infection and treated with antibiotics were compared to 1634 out of 31,696 (5.15%) patients with no history of E.coli infection (control) and received antibiotic treatment. Both populations subsequently developed prostate carcinoma. Results remained statistically significant (p<2.2x10-16), Odds Ratio=0.55 (95% CI 0.51-0.59). Conclusion: This retrospective study shows a statistically significant correlation between E.Coli infection and a decreased incidence of prostate cancer. Further evaluation is needed in order to identify the impact of E.Coli infection and prostate cancer development.

Keywords: E. Coli, prostate cancer, protective, microbiology

Procedia PDF Downloads 216

Authors: Ismail Bamidele Afolabi, Abdulmujeeb Babatunde Aremu, Lawal Abdurraheem Maidoki, Nnodimele Onuigbo Atulomah

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Background: Hepatitis B virus infection remains a significant global public health challenge with infectivity as well as the potential for transmission more than 50 to 100 times that of HIV. Annually, global HBV-related mortality is linked primarily to cirrhosis and liver carcinoma. The ever-increasing endemicity of HBV among children under-5-years, owing to vertical transmission and its lingering chronicity in developing countries, will hamper the global efforts concertedly endorsed towards eliminating viral hepatitis as a global public health threat by 2030. Objective: This study assessed information motivation behavioral skills model constructs as predictors of HBV infection prevention practices among consenting expectant mothers attending antenatal care in Central Uganda as a focal point of intervention towards breaking materno-foetal transmission of HBV. Methods: A cross-sectional study with a quantitative data collection approach based on the constructs of the IMB model was used to capture data on the study variables among 385 randomly selected pregnant women between September and October 2020. Data derived from the quantitative instrument were transformed into weighted aggregate scores using SPSS version 26. ANOVA and regression analysis were done to ascertain the study hypotheses with a significance level set as (p ≤ 0.05). Results: Relatively 60% of the respondents were aged between 18 and 28. Expectant mothers with secondary education (42.3%) were predominant. Furthermore, an average but inadequate knowledge (X ̅=5.97±6.61; B=0.57; p<.001), incorrect perception (X ̅=17.10±18.31; B=0.97; p=.014), and good behavioral skills (X ̅=12.39±13.37; B=0.56; p<.001) for adopting prevention practices all statistically predicted the unsatisfactory level of prevention practices (X ̅=15.03±16.20) among the study respondents as measured on rating scales of 12, 33, 21 and 30 respectively. Conclusion: Evidence from this study corroborates the imperativeness of IMB constructs in reducing the burden of HBV infection in developing countries. Therefore, the inadequate HBV knowledge and misperception among obstetric populations necessitate personalized health education during antenatal visits and subsequent health campaigns in order to inform better prevention practices and, in turn, reduce the lingering chronicity of HBV infection in developing countries.

Keywords: behavioral skills, HBV infection, knowledge, perception, pregnant women, prevention practices

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Authors: Elidrissi Laila, El Rhaoussi Fatima-Zahra, Haddad Fouad, Tahiri Mohamed, Hliwa Wafaa, Bellabah Ahmed, Badre Wafaa

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Introduction: Metabolic Dysfunction Associated with Non-Alcoholic Fatty Liver Disease (MASLD), formerly known as Non-Alcoholic Fatty Liver Disease (NAFLD), is the leading cause of chronic liver disease. The cardiometabolic risk factors associated with MASLD represent common health issues and significant public health challenges. Medical students, being active participants in the healthcare system and a young demographic, are particularly relevant for understanding this entity to prevent its occurrence on a personal and collective level. The objective of our study is to assess the level of knowledge among medical students regarding MASLD, its risk factors, and its long-term consequences. Materials and Methods: We conducted a descriptive cross-sectional study using an anonymous questionnaire distributed through social media over a period of 2 weeks. Medical students from various faculties in Morocco answered 22 questions about MASLD, its etiological factors, diagnosis, complications, and principles of treatment. All responses were analyzed using the Jamovi software. Results: A total of 124 students voluntarily provided complete responses. 59% of our participants were in their 3rd year, with a median age of 21 years. Among the respondents, 27% were overweight, obese, or diabetic. 83% correctly answered more than half of the questions, and 77% believed they knew about MASLD. However, 84% of students were unaware that MASLD is the leading cause of chronic liver disease, and 12% even considered it a rare condition. Regarding etiological factors, overweight and obesity were mentioned in 93% of responses, and type 2 diabetes in 84%. 62% of participants believed that type 1 diabetes could not be implicated in MASLD. For 83 students, MASLD was considered a diagnosis of exclusion, while 41 students believed that a biopsy was mandatory for diagnosis. 12% believed that MASLD did not lead to long-term complications, and 44% were unaware that MASLD could progress to hepatocellular carcinoma. Regarding treatment, 85% included weight loss, and 19% did not consider diabetes management as a therapeutic approach for MASLD. At the end of the questionnaire, 89% of the students expressed a desire to learn more about MASLD and were invited to access an informative sheet through a hyperlink. Conclusion: MASLD represents a significant public health concern due to the prevalence of its risk factors, notably the obesity pandemic, which is widespread among the young population. There is a need for awareness about the seriousness of this emerging and long-underestimated condition among young future physicians.

Keywords: MASLD, medical students, obesity, diabetes

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Authors: Sujatha Edla

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Introduction: New compounds and possible uses for the bioactive substances produced by freshwater cyanobacteria are constantly being discovered through research. Certain molecules are hazardous to the environment and human health, but others have potential applications in industry, biotechnology, and pharmaceuticals. These discoveries advance our knowledge of the varied functions these microbes perform in different ecosystems. Cyanobacterial silver nanoparticles (AgNPs) have special qualities and possible therapeutic advantages, which make them very promising for a range of medicinal uses. Aim: In our study; the attention was focused on the analysis and characterization of bioactive compounds extracted from freshwater cyanobacteria Planktothricoides raciorskii and its comparative study on Cyanobacteria-mediated silver nanoparticles synthesized by cell-free extract of Planktothricoides raciorskii. Material and Methods: A variety of bioactive secondary metabolites have been extracted, purified, and identified from cyanobacterial species using column chromatography, FTIR, and GC-MS/MS chromatography techniques and evaluated for antibacterial and cytotoxic studies, where the Cyanobacterial silver nanoparticles (CSNPs) were characterized by UV-Vis spectroscopy, scanning electron microscopy (SEM), transmission electron microscopy (TEM), and Fourier transform infrared (FTIR) analysis and were further tested for antibacterial and cytotoxic efficiency. Results: The synthesis of CSNPs was confirmed through visible color change and shift of peaks at 430–445 nm by UV-Vis spectroscopy. The size of CSNPs was between 22 and 34 nm and oval-shaped which were confirmed by SEM and TEM analyses. The FTIR spectra showed a new peak at the range of 3,400–3,460 cm−1 compared to the control, confirming the reduction of silver nitrate. The antibacterial activity of both crude bioactive compound extract and CSNPs showed remarkable activity with Zone of inhibition against E. coli with 9.5mm and 10.2mm, 13mm and 14.5mm against S. paratyphi, 9.2mm and 9.8mm zone of inhibition against K. pneumonia by both crude extract and CSNPs, respectively. The cytotoxicity as evaluated by extracts of Planktothricoides raciorskii against MCF7-Human Breast Adenocarcinoma cell line and HepG2- Human Hepatocellular Carcinoma cell line employing MTT assay gave IC50 value of 47.18ug/ml, 110.81ug/ml against MCF7cell line and HepG2 cell line, respectively. The cytotoxic evaluation of Planktothricoides raciorskii CSNPs against the MCF7cell line was 43.37 ug/ml and 20.88 ug/ml against the HepG2 cell line. Our ongoing research in this field aims to uncover the full therapeutic potential of cyanobacterial silver nanoparticles and address any associated challenges.

Keywords: cyanobacteria, silvernanoparticles, pharmaceuticals, bioactive compounds, cytotoxic

Procedia PDF Downloads 63

Authors: Paola Modesto, Floriana Fruscione, Isabella Martini, Simona Perga, Federica Riccardo, Mariateresa Camerino, Davide Giacobino, Cecilia Gola, Luca Licenziato, Elisabetta Razzuoli, Katia Varello, Lorella Maniscalco, Elena Bozzetta, Angelo Ferrari

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Canine and human melanoma, osteosarcoma (OSA), and mammary carcinomas are aggressive tumors with common characteristics making dogs a good model for comparative oncology. Novel therapeutic strategies against these tumors could be useful to both species. In humans, chondroitin sulphate proteoglycan 4 (CSPG4) is a marker involved in tumor progression and could be a candidate target for immunotherapy. The anti-CSPG4 DNA electrovaccination has shown to be an effective approach for canine malignant melanoma (CMM) [1]. An immunohistochemistry evaluation of CSPG4 expression in tumour tissue is generally performed prior to electrovaccination. To assess the possibility to perform a rapid molecular evaluation and in order to validate these spontaneous canine tumors as the model for human studies, we investigate the CSPG4 gene expression by RT qPCR in CMM, OSA, and canine mammary tumors (CMT). The total RNA was extracted from RNAlater stored tissue samples (CMM n=16; OSA n=13; CMT n=6; five paired normal tissues for CMM, five paired normal tissues for OSA and one paired normal tissue for CMT), retro-transcribed and then analyzed by duplex RT-qPCR using two different TaqMan assays for the target gene CSPG4 and the internal reference gene (RG) Ribosomal Protein S19 (RPS19). RPS19 was selected from a panel of 9 candidate RGs, according to NormFinder analysis following the protocol already described [2]. Relative expression was analyzed by CFX Maestro™ Software. Student t-test and ANOVA were performed (significance set at P<0.05). Results showed that gene expression of CSPG4 in OSA tissues is significantly increased by 3-4 folds when compared to controls. In CMT, gene expression of the target was increased from 1.5 to 19.9 folds. In melanoma, although an increasing trend was observed, no significant differences between the two groups were highlighted. Immunohistochemistry analysis of the two cancer types showed that the expression of CSPG4 within CMM is concentrated in isles of cells compared to OSA, where the distribution of positive cells is homogeneous. This evidence could explain the differences in gene expression results.CSPG4 immunohistochemistry evaluation in mammary carcinoma is in progress. The evidence of CSPG4 expression in a different type of canine tumors opens the way to the possibility of extending the CSPG4 immunotherapy marker in CMM, OSA, and CMT and may have an impact to translate this strategy modality to human oncology.

Keywords: canine melanoma, canine mammary carcinomas, canine osteosarcoma, CSPG4, gene expression, immunotherapy

Procedia PDF Downloads 176

Authors: Priyanka Bhowmik, Subrata Majumdar, Debprasad Chattopadhyay

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Background: Cervical cancer is the third major cause of cancer in women and the second most frequent cause of cancer related deaths causing 300,000 deaths annually worldwide. Evasion of immune response by Human Papilloma Virus (HPV), the key contributing factor behind cancer and pre-cancerous lesions of the uterine cervix, makes immunotherapy a necessity to treat this disease. Objective: A Heat killed fraction of Mycobacterium indicus pranii (MIP), a non-pathogenic Mycobacterium has been shown to exhibit cytotoxic effects on different cancer cells, including human cervical carcinoma cell line HeLa. However, the underlying mechanisms remain unknown. The aim of this study is to decipher the mechanism of MIP induced HeLa cell death. Methods: The cytotoxicity of Mycobacterium indicus pranii against HeLa cells was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Apoptosis was detected by annexin V and Propidium iodide (PI) staining. The assessment of reactive oxygen species (ROS) generation and cell cycle analysis were measured by flow cytometry. The expression of apoptosis associated genes was analyzed by real time PCR. Result: MIP could inhibit the proliferation of HeLa cell in a time and dose dependent manner but caused minor damage to normal cells. The induction of apoptosis was confirmed by the cell surface presentation of phosphatidyl serine, DNA fragmentation, and mitochondrial damage. MIP caused very early (as early as 30 minutes) transcriptional activation of p53, followed by a higher activation (32 fold) at 24 hours suggesting prime importance of p53 in MIP-induced apoptosis in HeLa cell. The up regulation of p53 dependent pro-apoptotic genes Bax, Bak, PUMA, and Noxa followed a lag phase that was required for the transcriptional p53 program. MIP also caused the transcriptional up regulation of Toll like receptor 2 and 4 after 30 minutes of MIP treatment suggesting recognition of MIP by toll like receptors. Moreover, MIP caused the inhibition of expression of HPV anti apoptotic gene E6, which is known to interfere with p53/PUMA/Bax apoptotic cascade. This inhibition might have played a role in transcriptional up regulation of PUMA and subsequently apoptosis. ROS was generated transiently which was concomitant with the highest transcription activation of p53 suggesting a plausible feedback loop network of p53 and ROS in the apoptosis of HeLa cells. Scavenger of ROS, such as N-acetyl-L-cysteine, decreased apoptosis suggesting ROS is an important effector of MIP induced apoptosis. Conclusion: Taken together, MIP possesses full potential to be a novel therapeutic agent in the clinical treatment of cervical cancer.

Keywords: cancer, mycobacterium, immunity, immunotherapy.

Procedia PDF Downloads 249

Authors: Showkat Ahmad Bhat, Iqra Reyaz, Falaque ul Afshan, Ahmad Arif Reshi, Muneeb U. Rehman, Manzoor R. Mir, Sabhiya Majid, Sonallah, Sheikh Bilal, Ishraq Hussain

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Background: Gastric cancer is the fourth most common cancer and the second leading cause of worldwide cancer-related deaths, with a wide variation in incidence rates across different geographical areas. The current view of cancer is that a malignancy arises from a transformation of the genetic material of a normal cell, followed by successive mutations and by chain of alterations in genes such as DNA repair genes, oncogenes, Tumor suppressor genes. Minerals are necessary for the functioning of several transcriptional factors, proteins that recognize certain DNA sequences and have been found to play a role in gastric cancer. Material Methods:The present work was a case control study and its aim was to ascertain the role of minerals and promoter hypermethylation of CpG islands of DAP-K gene in Gastric cancer patients among the Kashmiri population. Serum was extracted from all the samples and mineral estimation was done by AAS from serum, DNA was also extracted and was modified using bisulphite modification kit. Methylation-specific PCR was used for the analysis of the promoter hypermethylation status of DAP-K gene. The epigenetic analysis revealed that unlike other high risk regions, Kashmiri population has a different promoter hypermethylation profile of DAP-K gene and has different mineral profile. Results: In our study mean serum copper levels were significantly different for the two genders (p<0.05), while as no significant differences were observed for iron and zinc levels. In Methylation-specific PCR the methylation status of the promoter region of DAP-K gene was as 67.50% (27/40) of the gastric cancer tissues showed methylated DAP-K promoter and 32.50% (13/40) of the cases however showed unmethylated DAP-K promoter. Almost all 85% (17/20) of the histopathologically confirmed normal tissues showed unmethylated DAP-K promoter except only in 3 cases where DAP-K promoter was found to be methylated. The association of promoter hypermethylation with gastric cancer was evaluated by χ2 (Chi square) test and was found to be significant (P=0.0006). Occurrence of DAP-K methylation was found to be unequally distributed in males and females with more frequency in males than in females but the difference was not statistically significant (P =0.7635, Odds ratio=1.368 and 95% C.I=0.4197 to 4.456). When the frequency of DAP-K promoter methylation was compared with clinical staging of the disease, DAP-K promoter methylation was found to be certainly higher in Stage III/IV (85.71%) compared to Stage I/ II (57.69%) but the difference was not statistically significant (P =0.0673). These results suggest that DAP-K aberrant promoter hypermethylation in Kashmiri population contributes to the process of carcinogenesis in Gastric cancer and is reportedly one of the commonest epigenetic changes in the development of Gastric cancer.

Keywords: gastric cancer, minerals, AAS, hypermethylation, CpG islands, DAP-K gene

Procedia PDF Downloads 518

Authors: T. Ferreira, A. Kulkarni, C. Bretscher, K. Richter, M. Ehrlich, A. Marchini

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H-1 protoparvovirus (H-1PV) is a virus with inherent oncolytic and oncosuppressive activities while remaining non-pathogenic in humans. H-1PV was the first oncolytic parvovirus to undergo clinical testing. Results from trials in patients with glioblastoma or pancreatic carcinoma showed an excellent safety profile and first signs of efficacy. H-1PV infection is vastly dependent on cellular factors, from cell attachment and entry to viral replication and egress. Hence, we believe that the characterisation of the parvovirus life cycle would ultimately help further improve H-1PV clinical outcome. In the present study, we explored the entry pathway of H-1PV in cervical HeLa and glioma NCH125 cancer cell lines. Electron and confocal microscopy showed viral particles associated with clathrin-coated pits and vesicles, providing the first evidence that H-1PV cell entry occurs through clathrin-mediated endocytosis. Accordingly, we observed that by blocking clathrin-mediated endocytosis with hypertonic sucrose, chlorpromazine, or pitstop 2, H-1PV transduction was markedly decreased. Accordingly, siRNA-mediated knockdown of AP2M1, which retains a crucial role in clathrin-mediated endocytosis, verified the reliance of H-1PV on this route to enter HeLa and NCH125 cancer cells. By contrast, we found no evidence of viral entry through caveolae-mediated endocytosis. Indeed, pre-treatment of cells with nystatin or methyl-β-cyclodextrin, both inhibitors of caveolae-mediated endocytosis, did not affect viral transduction levels. Unexpectedly, siRNA-mediated knockdown of caveolin-1, the main driver of caveolae-mediated endocytosis, increased H-1PV transduction, suggesting caveolin-1 is a negative modulator of H-1PV infection. We also show that H-1PV entry is dependent on dynamin, a protein responsible for mediating the scission of vesicle neck and promoting further internalisation. Furthermore, since dynamin inhibition almost completely abolished H-1PV infection, makes it unlikely that H-1PV uses macropinocytosis as an alternative pathway to enter cells. After viral internalisation, H-1PV passes through early to late endosomes as observed by confocal microscopy. Inside these endocytic compartments, the acidic environment proved to be crucial for a productive infection. Inhibition of acidification of pH dramatically reduced H-1PV transduction. Besides, a fraction of H-1PV particles was observed inside LAMP1-positive lysosomes, most likely following a non-infectious route. To the author's best knowledge, this is the first study to characterise the cell entry pathways of H-1PV. Along these lines, this work will further contribute to understand H-1PV oncolytic properties as well as to improve its clinical potential in cancer virotherapy.

Keywords: clathrin-mediated endocytosis, H-1 parvovirus, oncolytic virus, virus entry

Procedia PDF Downloads 155

Authors: Faris Alkhalil, Rana Bitar, Amer Azaz, Hisham Natour, Noora Almeraikhi, Mohamad Miqdady

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Background: Children with liver transplantation are achieving very good survival and so there is now a need to concentrate on achieving good health in these patients and preventing disease. Immunosuppressive medications have side effects that need to be monitored and if possible avoided. Glucocorticoids and calcineurin inhibitors are detrimental to bone and mineral homeostasis in addition steroids can also affect linear growth. Steroid sparing regimes in renal transplant children has shown to improve children’s height. Aim: We aim to review the growth and bone health of children post liver transplant by measuring bone mineral density (BMD) using dual energy X-ray absorptiometry (DEXA) scan and assessing if there is a clear link between poor growth and impaired bone health and use of long term steroids. Subjects and Methods: This is a single centre retrospective Cohort study, we reviewed the medical notes of children (0-16 years) who underwent a liver transplantation between November 2000 to November 2016 and currently being followed at our centre. Results: 39 patients were identified (25 males and 14 females), the median transplant age was 2 years (range 9 months - 16 years), and the median follow up was 6 years. Four patients received a combined transplant, 2 kidney and liver transplant and 2 received a liver and small bowel transplant. The indications for transplant included, Biliary Atresia (31%), Acute Liver failure (18%), Progressive Familial Intrahepatic Cholestasis (15%), transplantable metabolic disease (10%), TPN related liver disease (8%), Primary Hyperoxaluria (5%), Hepatocellular carcinoma (3%) and other causes (10%). 36 patients (95%) were on a calcineurin inhibitor (34 patients were on Tacrolimus and 2 on Cyclosporin). The other three patients were on Sirolimus. Low dose long-term steroids was used in 21% of the patients. A considerable proportion of the patients had poor growth. 15% were below the 3rd centile for weight for age and 21% were below the 3rd centile for height for age. Most of our patients with poor growth were not on long term steroids. 49% of patients had a DEXA scan post transplantation. 21% of these children had low bone mineral density, one patient had met osteoporosis criteria with a vertebral fracture. Most of our patients with impaired bone health were not on long term steroids. 20% of the patients who did not undergo a DEXA scan developed long bone fractures and 50% of them were on long term steroid use which may suggest impaired bone health in these patients. Summary and Conclusion: The incidence of impaired bone health, although studied in limited number of patients; was high. Early recognition and treatment should be instituted to avoid fractures and improve bone health. Many of the patients were below the 3rd centile for weight and height however there was no clear relationship between steroid use and impaired bone health, reduced weight and reduced linear height.

Keywords: bone, growth, pediatric, liver, transplantation

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Authors: Markus Bredel, Sindhu Nair, Hoa Q. Trummell, Rajani Rajbhandari, Christopher D. Willey, Lewis Z. Shi, Zhuo Zhang, William J. Placzek, James A. Bonner

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Purpose: EGFR-targeted monoclonal antibodies (mAbs) provide clinical benefit in some patients with H&N squamous cell carcinoma (HNSCC), but others progress with minimal response. Missense mutations in the EGFR ectodomain (ECD) can be acquired under mAb therapy by mimicking the effect of large deletions on receptor untethering and activation. Little is known about the contribution of EGFR ECD mutations to EGFR activation and anti-EGFR response in HNSCC. Methods: We selected patient-derived HNSCC cells (UM-SCC-1) for resistance to mAb Cetuximab (CTX) by repeated, stepwise exposure to mimic what may occur clinically and identified two concurrent EGFR ECD mutations (UM-SCC-1R). We examined the competence of the mutants to bind EGF ligand or CTX. We assessed the potential impact of the mutations through visual analysis of space-filling models of the native sidechains in the original structures vs. their respective side-chain mutations. We performed CRISPR in combination with site-directed mutagenesis to test for the effect of the mutants on ligand-independent EGFR activation and sorting. We determined the effects on receptor internalization, endocytosis, downstream signaling, and radiation sensitivity. Results: UM-SCC-1R cells carried two non-synonymous missense mutations (G33S and N56K) mapping to domain I in or near the EGF binding pocket of the EGFR ECD. Structural modeling predicted that these mutants restrict the adoption of a tethered, inactive EGFR conformation while not permitting association of EGFR with the EGF ligand or CTX. Binding studies confirmed that the mutant, untethered receptor displayed a reduced affinity for both EGF and CTX but demonstrated sustained activation and presence at the cell surface with diminished internalization and sorting for endosomal degradation. Single and double-mutant models demonstrated that the G33S mutant is dominant over the N56K mutant in its effect on EGFR activation and EGF binding. CTX-resistant UM-SCC-1R cells demonstrated cross-resistance to mAb Panitumuab but, paradoxically, remained sensitive to the reversible receptor tyrosine kinase inhibitor Erlotinib. Conclusions: HNSCC cells can select for EGFR ECD mutations under EGFR mAb exposure that converge to trap the receptor in an open, constitutively activated state. These mutants impede the receptor’s competence to bind mAbs and EGF ligand and alter its endosomal trafficking, possibly explaining certain cases of clinical mAb and radiation resistance.

Keywords: head and neck cancer, EGFR mutation, resistance, cetuximab

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Authors: Jannis Kountouras, Nikolaos Kapetanakis, Stergios A. Polyzos, Apostolis Papaeftymiou, Panagiotis Katsinelos, Ioannis Venizelos, Christina Nikolaidou, Christos Zavos, Iordanis Romiopoulos, Elena Tsiaousi, Evangelos Kazakos, Michael Doulberis

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Background & Aims: Helicobacter pylori infection (Hp-I) has been recognized as a substantial risk agent involved in gastrointestinal (GI) tract oncogenesis by stimulating cancer stem cells (CSCs), oncogenes, immune surveillance processes, and triggering GI microbiota dysbiosis. We aimed to investigate the possible involvement of active Hp-I in the sequence: chronic inflammation–adenoma–colorectal cancer (CRC) development. Methods: Four pillars were investigated: (i) endoscopic and conventional histological examinations of patients with CRC, colorectal adenomas (CRA) versus controls to detect the presence of active Hp-I; (ii) immunohistochemical determination of the presence of Hp; expression of CD44, an indicator of CSCs and/or bone marrow-derived stem cells (BMDSCs); expressions of oncogene Ki67 and anti-apoptotic Bcl-2 protein; (iii) expression of CD45, indicator of immune surveillance locally (assessing mainly T and B lymphocytes locally); and (iv) correlation of the studied parameters with the presence or absence of Hp-I. Results: Among 50 patients with CRC, 25 with CRA, and 10 controls, a significantly higher presence of Hp-I in the CRA (68%) and CRC group (84%) were found compared with controls (30%). The presence of Hp-I with accompanying immunohistochemical expression of CD44 in biopsy specimens was revealed in a high proportion of patients with CRA associated with moderate/severe dysplasia (88%) and CRC patients with moderate/severe degree of malignancy (91%). Comparable results were also obtained for Ki67, Bcl-2, and CD45 immunohistochemical expressions. Concluding Remarks: Hp-I seems to be involved in the sequence: CRA – dysplasia – CRC, similarly to the upper GI tract oncogenesis, by several pathways such as the following: Beyond Hp-I associated insulin resistance, the major underlying mechanism responsible for the metabolic syndrome (MetS) that increase the risk of colorectal neoplasms, as implied by other Hp-I related MetS pathologies, such as non-alcoholic fatty liver disease and upper GI cancer, the disturbance of the normal GI microbiota (i.e., dysbiosis) and the formation of an irritative biofilm could contribute to a perpetual inflammatory upper GIT and colon mucosal damage, stimulating CSCs or recruiting BMDSCs and affecting oncogenes and immune surveillance processes. Further large-scale relative studies with a pathophysiological perspective are necessary to demonstrate in-depth this relationship.

Keywords: Helicobacter pylori, colorectal cancer, colorectal adenomas, gastrointestinal oncogenesis

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Authors: Agnes Simone

Abstract:

A 52-year-old male with unknown psychiatric and medical history was brought to the Psychiatric Emergency Room by ambulance directly from jail. He had been detained for three weeks for possession of a firearm while intoxicated. On initial evaluation, the patient was unable to provide a reliable history. He presented with odd jerking movements of his extremities and catatonic features, including mutism and stupor. His vital signs were stable. Patient was transferred to the medical emergency department for work-up of altered mental status. Due to suspicion for opioid overdose, the patient was given naloxone (Narcan) with no improvement. Laboratory work-up included complete blood count, comprehensive metabolic panel, thyroid stimulating hormone, vitamin B12, folate, magnesium, rapid plasma reagin, HIV, blood alcohol level, aspirin, and Tylenol blood levels, urine drug screen, and urinalysis, which were all negative. CT head and chest X-Ray were also negative. With this negative work-up, the medical team concluded there was no organic etiology and requested inpatient psychiatric admission. Upon re-evaluation by psychiatry, it was evident that the patient continued to have an altered mental status. Of note, the medical team did not include substance withdrawal in the differential diagnosis due to stable vital signs and a negative urine drug screen. The psychiatry team decided to check California's prescription drug monitoring program (CURES) and discovered that the patient was prescribed benzodiazepine alprazolam (Xanax) 2mg BID, a sedative-hypnotic, and hydrocodone/acetaminophen 10mg/325mg (Norco) QID, an opioid. After a thorough chart review, his daughter's contact information was found, and she confirmed his benzodiazepine and opioid use, with recent escalation and misuse. It was determined that the patient was experiencing alprazolam withdrawal, given this collateral information, his current symptoms, negative urine drug screen, and recent abrupt discontinuation of medications while incarcerated. After admission to the medical unit and two doses of alprazolam 2mg, the patient's mental status, alertness, and orientation improved, but he had no memory of the events that led to his hospitalization. He was discharged with a limited supply of alprazolam and a close follow-up to arrange a taper. Accompanying this case report, a qualitative review of presentations with alprazolam withdrawal was completed. This case and the review highlights: (1) Alprazolam withdrawal can occur at low doses and within just one week of use. (2) Alprazolam withdrawal can present without any vital sign instability. (3) Alprazolam withdrawal does not respond to short-acting benzodiazepines but does respond to certain long-acting benzodiazepines due to its unique chemical structure. (4) Alprazolam withdrawal is distinct from and more severe than other benzodiazepine withdrawals. This case highlights (1) the importance of physician utilization of drug-monitoring programs. This case, in particular, relied on California's drug monitoring program. (2) The importance of obtaining collateral information, especially in cases in which the patient is unable to provide a reliable history. (3) The importance of including substance intoxication and withdrawal in the differential diagnosis even when there is a negative urine drug screen. Toxidrome of withdrawal can be delayed. (4) The importance of discussing addiction and withdrawal risks of medications with patients.

Keywords: addiction risk of benzodiazepines, alprazolam withdrawal, altered mental status, benzodiazepines, drug monitoring programs, sedative-hypnotics, substance use disorder

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Authors: Ipsita Biswas, Arnab Sarkar, Ashikur Rahaman, Gopeswar Mukherjee, Subhrangsu Chatterjee, Shamee Bhattacharjee, Deba Prasad Mandal

Abstract:

One of the major reasons for the high mortality rate of lung cancer is the substantial delays in disease detection at late metastatic stages. It is of utmost importance to understand the detailed molecular signaling and detect the molecular markers that can be used for the early diagnosis of cancer. Several studies explored the emerging roles of long noncoding RNAs (lncRNAs) in various cancers as well as lung cancer. A long non-coding RNA LINC00273 was recently discovered to promote cancer cell migration and invasion, and its positive correlation with the pathological stages of metastasis may prove it to be a potential target for inhibiting cancer cell metastasis. Comparing real-time expression of LINC00273 in various human clinical cancer tissue samples with normal tissue samples revealed significantly higher expression in cancer tissues. This long intergenic noncoding RNA was found to be highly expressed in human liver tumor-initiating cells, human gastric adenocarcinoma AGS cell line, as well as human non-small cell lung cancer A549 cell line. SiRNA and shRNA-induced knockdown of LINC00273 in both in vitro and in vivo nude mice significantly subsided AGS and A549 cancer cell migration and invasion. LINC00273 knockdown also reduced TGF-β induced SNAIL, SLUG, VIMENTIN, ZEB1 expression, and metastasis in A549 cells. Plenty of reports have suggested the role of microRNAs of the miR200 family in reversing epithelial to mesenchymal transition (EMT) by inhibiting ZEB transcription factors. In this study, hsa-miR-200a-3p was predicted via IntaRNA-Freiburg RNA tools to be a potential target of LINC00273 with a negative free binding energy of −8.793 kcal/mol, and this interaction was verified as a confirmed target of LINC00273 by RNA pulldown, real-time PCR and luciferase assay. Mechanistically, LINC00273 accelerated TGF-β induced EMT by sponging hsa-miR-200a-3p which in turn liberated ZEB1 and promoted prometastatic functions in A549 cells in vitro as verified by real-time PCR and western blotting. The similar expression patterns of these EMT regulatory pathway molecules, viz. LINC00273, hsa-miR-200a-3p, ZEB1 and TGF-β, were also detected in various clinical samples like breast cancer tissues, oral cancer tissues, lung cancer tissues, etc. Overall, this LINC00273 mediated EMT regulatory signaling can serve as a potential therapeutic target for the prevention of lung cancer metastasis.

Keywords: epithelial to mesenchymal transition, long noncoding RNA, microRNA, non-small-cell lung carcinoma

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Authors: Andrea L. Arnett, Ann T. Packard, Yolanda I. Garces, Kenneth W. Merrell

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Objective: Pathologic response following neoadjuvant chemoradiation (CRT) has been associated with improved overall survival (OS). Conflicting results have been reported regarding the pathologic predictive value of positron emission tomography (PET) response in patients with stage III lung cancer. The aim of this study was to evaluate the correlation between post-treatment PET response and pathologic response utilizing novel FDG-PET parameters. Methods: This retrospective study included patients with non-metastatic, stage IIIA (N2) NSCLC cancer treated with CRT followed by resection. All patients underwent PET prior to and after neoadjuvant CRT. Univariate analysis was utilized to assess correlations between PET response, nodal clearance, pCR, and near-complete pathologic response (defined as the microscopic residual disease or less). Maximal standard uptake value (SUV), standard uptake ratio (SUR) [normalized independently to the liver (SUR-L) and blood pool (SUR-BP)], metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were measured pre- and post-chemoradiation. Results: A total of 44 patients were included for review. Median age was 61.9 years, and median follow-up was 2.6 years. Histologic subtypes included adenocarcinoma (72.2%) and squamous cell carcinoma (22.7%), and the majority of patients had the T2 disease (59.1%). The rate of pCR and near-complete pathologic response within the primary lesion was 28.9% and 44.4%, respectively. The average reduction in SUVmₐₓ was 9.2 units (range -1.9-32.8), and the majority of patients demonstrated some degree of favorable treatment response. SUR-BP and SUR-L showed a mean reduction of 4.7 units (range -0.1-17.3) and 3.5 units (range –1.7-12.6), respectively. Variation in PET response was not significantly associated with histologic subtype, concurrent chemotherapy type, stage, or radiation dose. No significant correlation was found between pathologic response and absolute change in MTV or TLG. Reduction in SUVmₐₓ and SUR were associated with increased rate of pathologic response (p ≤ 0.02). This correlation was not impacted by normalization of SUR to liver versus mediastinal blood pool. A threshold of > 75% decrease in SUR-L correlated with near-complete response, with a sensitivity of 57.9% and specificity of 85.7%, as well as positive and negative predictive values of 78.6% and 69.2%, respectively (diagnostic odds ratio [DOR]: 5.6, p=0.02). A threshold of >50% decrease in SUR was also significantly associated pathologic response (DOR 12.9, p=0.2), but specificity was substantially lower when utilizing this threshold value. No significant association was found between nodal PET parameters and pathologic nodal clearance. Conclusions: Our results suggest that treatment response to neoadjuvant therapy as assessed on PET imaging can be a predictor of pathologic response when evaluated via SUV and SUR. SUR parameters were associated with higher diagnostic odds ratios, suggesting improved predictive utility compared to SUVmₐₓ. MTV and TLG did not prove to be significant predictors of pathologic response but may warrant further investigation in a larger cohort of patients.

Keywords: lung cancer, positron emission tomography (PET), standard uptake ratio (SUR), standard uptake value (SUV)

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Authors: Paola Millare, Nelinda Catherine Pangilinan

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Background and Aim: Cervical cancer is the most commonly diagnosed gynecological malignancy during pregnancy. Owing to the rarity of the disease, and the complexity of all factors that have to be taken into consideration, standardization of treatment is very difficult. Cervical cancer is the second most common malignancy among women. The treatment of cancer during pregnancy is most challenging in the case of cervical cancer, since the pregnant uterus itself is affected. This report aims to present a case of cervical cancer in a pregnant woman and how to manage this case and several issues accompanied with it. Methods: This is a case of a 28 year-old, Gravida 4 Para 2 (1111), who presented with watery to mucoid, whitish, non-foul smelling and increasing in amount. Internal examination revealed normal external genitalia, parous outlet, cervix was transformed into a fungating mass measuring 5x4 cm, with left parametrial involvement, body of uterus was enlarged to 24 weeks size, no adnexal mass or tenderness. She had cervical punch biopsy, which revealed, adenocarcinoma, well-differentiated cervical tissue. Standard management for cases with stage 2B cervical carcinoma was to start radiation or radical hysterectomy. In the case of patients diagnosed with cervical cancer and currently pregnant, these kind of management will result to fetal loss. The patient still declined the said management and opted to delay the treatment and wait for her baby to reach at least term and proceed to cesarean section as route of delivery. Results: The patient underwent an elective cesarean section at 37th weeks age of gestation, with an outcome of a term, live baby boy APGAR score 7,9 birthweight 2600 grams. One month postpartum, the patient followed up and completed radiotherapy, chemotherapy and brachytherapy. She was advised to go back after 6 months for monitoring. On her last check up, an internal examination was done which revealed normal external genitalia, vagina admits 2 fingers with ease, there is a palpable fungating mass at the cervix measuring 2x2 cm. A repeat gynecologic oncologic ultrasound was done revealing cervical mass, endophytic, grade 1 color score with stromal invasion 35% post radiation reactive lymph nodes with intact paracolpium, pericervical, and parametrial involvement. The patient was then advised to undergo pelvic boost and for close monitoring of the cervical mass. Conclusion: Cervical cancer in pregnancy is rare but is a dilemma for women and their physicians. Treatment should be multidisciplinary and individualized following careful counseling. In this case, the treatment was clearly on the side of preventing the progression of cervical cancer while she is pregnant, however due to ethical reasons, the management deviates on the right of the patient to decide for her own health and her unborn child. The collaborative collection of data relating to treatment and outcome is strongly encouraged.

Keywords: cancer, cervical, ethical, pregnancy

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Authors: Sean Yao Zu Kong, Khong Yik Chew

Abstract:

Introduction: We described a case report of the successful use of advanced surgical techniques in a patient with recurrent breast cancer who underwent a wide resection including the hemi-sternum, clavicle, multiple ribs, and a lobe of the lung due to tumor involvement. This extensive resection exposed critical structures, requiring a creative approach to reconstruction. To address this complex chest wall reconstruction, a free fibula flap and a 4-zone rectus abdominis musculocutaneous flap were successfully utilized. The use of a free vascularized bone flap allowed for rapid osteointegration and resistance against osteoradionecrosis after adjuvant radiation, while a four-zone tram flap allowed for reconstruction of both the chest wall and breast mound. Although limited recipient vessels made free flaps challenging, the free fibula flap served as both a bony reconstruction and vascular conduit, supercharged with the distal peroneal artery and veins of the peroneal artery from the fibula graft. Our approach highlights the potential of advanced surgical techniques to improve outcomes in complex cases of chest wall reconstruction in patients with recurrent breast cancer, which is becoming increasingly relevant as breast cancer incidence rates increases. Case presentation: This report describes a successful reconstruction of a patient with recurrent breast cancer who required extensive resection, including the anterior chest wall, clavicle, and sternoclavicular joint. Challenges arose due to the loss of accessory muscles and the non-rigid rib cage, which could lead to compromised ventilation and instability. A free fibula osteocutaneous flap and a four-zone TRAM flap with vascular supercharging were utilized to achieve long-term stability and function. The patient has since fully recovered, and during the review, both flaps remained viable, and chest mound reconstruction was satisfactory. A planned nipple/areolar reconstruction was offered pending the patient’s decision after adjuvant radiotherapy. Conclusion: In conclusion, this case report highlights the successful use of innovative surgical techniques in addressing a complex case of recurrent breast cancer requiring extensive resection and radical reconstruction. Our approach, utilized a combination of a free fibula flap and a 4-zone rectus abdominis musculocutaneous flap, demonstrates the potential for advanced techniques in chest wall reconstruction to minimize complications and ensure long-term stability and function. As the incidence of breast cancer continues to rise, it is crucial that healthcare professionals explore and utilize innovative techniques to improve patient outcomes and quality of life.

Keywords: free fibula flap, rectus abdominis musculocutaneous flap, post-adjuvant radiotherapy, reconstructive surgery, malignancy

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