Search results for: Chemotherapy

Authors: Aamna Tufail, Kajal Kotecha, Iordanis Toursounidis, Ravinder Pabla

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Introduction/Aims: Acute Myeloid Leukaemia (AML) is a part of leukaemic group of hematopoietic disorders with a varying range of presentations, including oro-facial manifestations. Early recognition and management are essential for favourable outcomes. Materials and Methods: We present our experience, clinical presentation, and clinical photographs of a patient with previously undiagnosed AML who presented with oral symptoms to the emergency department of our hospital. An analysis of clinical characteristics, diagnostic investigations, and management modalities was performed. Results/Statistics: A 58-year-old man presented to A&E reporting an 11-day history of right sided facial swelling, acute TMJ symptoms, and oral discomfort. A dentist ruled out acute dental causes one day post onset of symptoms. Initial assessment was anatomically inconsistent and did not reveal a routine oral or maxillofacial etiology. Detailed clinical examination demonstrated fever, generalised pallor, swelling and erythema of right nasolabial region, bilateral masseteric tenderness, intraoral palatal ecchymosis, palatal ulceration, buccal and labial petechiae, cervical lymphadenopathy, and haematoma on dorsum of right hand overlying right 2nd metacarpal joint. Suspecting a systemic medical cause, we requested haematological investigations, which revealed neutropenia, thrombocytopenia, and anaemia. Flow cytometry confirmed CD34 + AML. Oral discomfort was managed symptomatically. The patient was referred to a tertiary care centre for acute haematologic care, where he was treated with IV antibiotics and continuing cycles of chemotherapy. Conclusions/Clinical Relevance: Oro-facial manifestations may be the first clinical sign of AML. Awareness of its features is vital in early diagnosis. In this context, dentists and oral medicine specialists can play an important role in detecting clinical signs of haematological disorders such as AML.

Keywords: acute myeloid leukaemia, oral symptoms, ulceration, diagnosis, management

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Authors: Annika Stechemesser, Rachel Pounds, Emma Lucas, Chris Dawson, Julia Lipecki, Pavle Vrljicak, Jan Brosens, Sean Kehoe, Jason Yap, Lawrence Young, Sascha Ott

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Advances in technology make it now possible to retrieve the genetic information of thousands of single cancerous cells. One of the key challenges in single cell analysis of cancerous tissue is to determine the number of different cell types and their characteristic genes within the sample to better understand the tumors and their reaction to different treatments. For this analysis to be possible, it is crucial to filter out background noise as it can severely blur the downstream analysis and give misleading results. In-depth analysis of the state-of-the-art filtering methods for single cell data showed that they do, in some cases, not separate noisy and normal cells sufficiently. We introduced an algorithm that filters and clusters single cell data simultaneously without relying on certain genes or thresholds chosen by eye. It detects communities in a Shared Nearest Neighbor similarity network, which captures the similarities and dissimilarities of the cells by optimizing the modularity and then identifies and removes vertices with a weak clustering belonging. This strategy is based on the fact that noisy data instances are very likely to be similar to true cell types but do not match any of these wells. Once the clustering is complete, we apply a set of evaluation metrics on the cluster level and accept or reject clusters based on the outcome. The performance of our algorithm was tested on three datasets and led to convincing results. We were able to replicate the results on a Peripheral Blood Mononuclear Cells dataset. Furthermore, we applied the algorithm to two samples of ovarian cancer from the same patient before and after chemotherapy. Comparing the standard approach to our algorithm, we found a hidden cell type in the ovarian postchemotherapy data with interesting marker genes that are potentially relevant for medical research.

Keywords: cancer research, graph theory, machine learning, single cell analysis

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Authors: Nadia Akbarpour

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Pancreatic ductal adenocarcinoma is a forceful and obliterating illness, which is portrayed by intrusiveness, fast movement, and significant protection from treatment. Advances in neurotic arrangement and malignant growth hereditary qualities have worked on our illustrative comprehension of this infection; be that as it may, significant parts of pancreatic disease science remain ineffectively comprehended. A superior comprehension of pancreatic disease science should lead the way to more viable medicines. In the course of the most recent couple of years, there have been significant advances in the sub-atomic and organic comprehension of pancreatic malignancy. This included comprehension of the genomic intricacy of the illness, the job of pancreatic malignant growth undifferentiated organisms, the importance of the growth microenvironment, and the one-of-a-kind metabolic transformation of pancreas disease cells to acquire supplements under hypoxic climate. Endeavors have been made towards the advancement of the practical answer for its treatment with compelled achievement due to its complicated science. It is grounded that pancreatic malignancy undifferentiated cells (CSCs), yet present in a little count, contribute extraordinarily to PC inception, movement, and metastasis. Standard chemo and radiotherapeutic choices, notwithstanding, grow general endurance, the connected aftereffects are a huge concern. In the midst of the latest decade, our understanding with regards to atomic and cell pathways engaged with PC and the job of CSCs in its movement has expanded massively. By and by, the center is to target CSCs. The natural items have acquired a lot of thought as of late as they, generally, sharpen CSCs to chemotherapy and target atomic flagging engaged with different cancers, including PC. Some arranged investigations have demonstrated promising outcomes recommending that assessments in this course bring a ton to the table for the treatment of PC. Albeit preclinical investigations uncovered the significance of natural items in lessening pancreatic carcinoma, restricted examinations have been led to assess their part in centers. The current survey gives another knowledge to late advances in pancreatic malignancy science, treatment, and the current status of natural items in its expectation.

Keywords: pancreatic, genomic, organic, cancer

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Authors: Seham Samir Soliman, Ahmed A.Suliman, Khaled Fathy, Ahmed A. Sedik

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Cyclophosphamide (CP), an antineoplastic drug, has been found to induce reproductive damage. It is essential to develop approaches aimed at safeguarding ovarian tissue integrity in women experiencing reproductive toxicity as a result of chemotherapy. The current study was conducted to assess the impact of an extract derived from Moringa oleifera (M. oleifera) leaves on ovarian damage produced by CP. A total of 32 female Wistar Albino rats, which were in a healthy cycling state, were randomly separated into 4 groups, with every group contains 8 rats. The first group was administered intraperitoneal (i.p.) saline. The second group was administered a solitary intraperitoneal dosage of cyclophosphamide (200 mg/kg). The third one received M. oleifera extract (150 mg/kg orally) for 20 days, followed by i.p. of CP on the last day of the experiment. The fourth group received M. oleifera extract (250 mg/kg orally) for 20 days, followed by i.p. of CP on the last day of the experiment. Hormonal assessments, including luteinizing hormone (LH), estrogen (ES), and follicle-stimulating hormone (FSH), were performed 24 hours after CP administration. In addition, evaluating the antioxidant status and inflammatory response against CP. Moreover, conducting detailed histopathological and ultra-structural pictures of the ovary. Our findings reported that rats intoxicated with CP exhibited elevated levels of FSH, LH, malondialdehyde (MDA), tumor necrosis factor-alpha (TNF-α), and a decrease in E₂, and glutathione (GSH) levels. Pre-treatment with M. oleifera extract (250 mg/kg orally) ameliorated the disturbance in hormonal changes, oxidative stress indices, and the levels of pro-inflammatory mediators. Also, the histopathological and ultra-structural pictures of the ovaries were improved significantly in rats. In conclusion, M. oleifera extract possesses a significant protective role against CP-induced acute reproductive toxicity via modulating the values of FSH, LH, E₂ and quenching the release of reactive oxygen species and inflammatory mediators in female rats.

Keywords: cyclophosphamide, Moringa oleifera, ovarian function, oxidative stress, pro-inflammatory mediators

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Authors: Afrah Aladwani, Alexander Mullen, Mohammad AlRashidi, Omamah Alfarisi, Faisal Alterkit, Abdulwahab Aladwani, Asit Kumar, Emad Eldosouky

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Introduction: Trastuzumab is a HER-2 targeted humanized monoclonal antibody that significantly improves the therapeutic outcomes of metastatic and non-metastatic breast cancer. However, it is associated with increased risk of cardiotoxicity that ranges from mild decline in the cardiac ejection fraction to permanent cardiomyopathy. Concerns have been raised in treating eligible older patients. This study compares trastuzumab outcomes between two age cohorts in the Kuwait Cancer Control Centre (KCCC). Methods: In a prospective comparative observational study, 93 HER-2 positive breast cancer patients undergoing different chemotherapy protocols + trastuzumab were included and divided into two cohorts based on their age (˂60 and ≥60 years old). The baseline left ventricular ejection fraction (LVEF) was assessed and monitored every three months during trastuzumab treatment. Event of cardiotoxicity was defined as ≥10% decline in the LVEF from the baseline. The lower accepted normal limit of the LVEF was 50%. Results: The median baseline LVEF was 65% in both age cohorts (IQR 8% and 9% for older and younger patients respectively). Whereas, the median LVEF post-trastuzumab treatment was 51% and 55% in older and younger patients respectively (IQR 8%; p-value = 0.22), despite the fact that older patients had significantly lower exposure to anthracyclines compared to younger patients (60% and 84.1% respectively; p-value ˂0.001). 86.7% and 55.6% of older and younger patients, respectively, developed ≥10% decline in their LVEF from the baseline. Among those, only 29% of older and 27% of younger patients reached a LVEF value below 50% (p-value = 0.88). Statistically, age was the only factor that significantly correlated with trastuzumab induced cardiotoxicity (OR 4; p-value ˂0.012), but it did not increase the requirement for permanent discontinuation of treatment. A baseline LVEF value below 60% contributed to developing a post-treatment value below normal ranges (50%). Conclusion: Breast cancer patients aged 60 years and above in Kuwait were at 4-fold higher risk of developing ≥10% decline in their LVEF from the baseline than younger patients during trastuzumab treatment. Surprisingly, previous exposure to anthracyclines and multiple comorbidities were not associated with significant increased risk of cardiotoxicity.

Keywords: breast cancer, elderly, Trastuzumab, cardiotoxicity

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Authors: Mehrnaz Mostafavi

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Lung cancer is one of the most harmful forms of cancer. The long-term survival rate of lung cancer patients treated by conventional modalities such as surgical resection, radiation, and chemotherapy remains far from satisfactory. Systemic drug delivery is rarely successful because only a limited amount of the chemotherapeutic drug targets lung tumor sites, even when administered at a high dose. Targeted delivery of drug molecules to organs or special sites is one of the most challenging research areas in pharmaceutical sciences. By developing colloidal delivery systems such as liposomes, micelles and nanoparticles a new frontier was opened for improving drug delivery. Nanoparticles with their special characteristics such as small particle size, large surface area and the capability of changing their surface properties have numerous advantages compared with other delivery systems. Targeted nanoparticle delivery to the lungs is an emerging area of interest.Multimodal or combination therapy represents a promising new method to fight disease. Therefore, a combination of different therapeutic strategies may be the best alternative to improve treatment outcomes for lung cancer. Photothermal therapy was proposed as a novel approach to treatment. In this work, photothermal therapy with gold nanoparticles and near infrared laser (NIR) irradiation was investigated.Four types of small (<100nm), NIR absorbing gold nanoparticles (nanospheres, nanorods) were synthesized using wet chemical methods and characterized by transmission electron microscopy, dynamic light scattering and UV-vis spectroscopy. Their synthesis and properties were evaluated, to determine their feasibility as a photothermal agent for clinical applications. In vitro cellular uptake studies of the nanoparticles into lung cancer cell lines was measured using light scattering microscopy.Small gold nanorods had good photothermal properties and the greatest cellular uptake, and were used in photothermal studies. Under 4W laser irradiation, an increase in temperature of 10°C and decrease in cell viability of up to 80% were obtained.

Keywords: photothermal, therapy, cancer, gold nanorods

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Authors: Chueh Chang, Chia-jung Hsieh, Fu-yu Yu, Yu-Hwa Lin

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Background:The majority of women diagnosed with breast cancer undergo treatment involving surgery and radiotherapy or chemotherapy, or both. With these major advances in breast cancer management, many patients still have to deal with short or long-term side effects and psychological distress related to the disease and treatment, which have a substantial impact on their quality of life. The Laughing Qigong Program (LQP) is an interactive laughter program that combines the physical and physiological benefits of laughter with the mental benefits of Chinese qigong. Purpose: In order to improve the quality of life for breast cancer women in the community as well as echoing the WHO 2004 “Promoting Mental Health” for every one. This study focused on how to promote the positive mental health for women of breast cancer through the “laughter program” in Taiwan. During the presentation, how to practice Laughing Qigong will be demonstrated. Method: Using nonequivalent pretest-posttest design, ix-one breast cancer patients were volunteered to enroll in this study from the Taiwan Breast Cancer Alliance (TBCA). Thirty patients were assigned to the experimental group and the other 31 patients were assigned to the control group. The women who were assigned to the experimental group received laughter program one hour per session, once a week, totally 12 sessions. All subjects were tested before and after the intervention on the following: Self-Esteem scale (RSE), Face Scale (FS), Anxiety and pain experience were measured as psychological markers; saliva cortisol (CS) as an immunological marker; blood pressure (BP), heart rate (HR),and heart rate variability (HRV) as physiological markers of the body’s response to stress. Results: After comparing the experimental and control groups, the results revealed that those breast cancer women with “laughing program” their sense of humor were improved, less uncomfortable on self report physical conditions, more positive attitudes toward stress management by using laughter, and had emotional improvement according to the face scale.

Keywords: mental health promotion, breast cancer, laughing Qigong, women

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Authors: Min-Chien Su, Tzu-Hsuan Hsu, Guan-Xuan Wu, Shyh-Ming Kuo

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Lung cancer is one of the clinically challenging malignant diseases worldwide. For efficient therapeutics in cancer, combination therapy has developed to acquire a better outcome. PLK-1 was one of the major factors affecting cell mitosis in cancer cells, its inhibitor Bi6727 was proven effective in treating several different cancers namely oral cancer, colon cancer and lung cancer. Despite its low toxicity toward normal cells compared to traditional chemotherapy, it is still yet to be evaluated in detail. Livistona Chinensis (LC) is a Chinese herb that used as a traditional prescription to treat lung cancer. Due to the uncertainty of the efficacy of LC, we utilized a water extraction method to extract the Livistona Chinensis and then lyophilized into powder for further study. In this study we investigated the antiproliferation activities of Bi6727 and LC extracts (LCE) on A549 non-small lung cancer cells. The IC50 of Bi6727 and LCE on A549 are 60 nM and 0.8 mg/mL, respectively. The fluorescent staining images shown nucleolus damage in cells treated with Bi6727 and mitochondrial damage after treated with LCE. A549 cells treated with Bi6727 and LCE showed increased expression of Bax, Caspase-3 and Caspase-9 proteins from Western blot assay. LCE also inhibited A549 cells growth keeping cells at G2-M phase from cell cycle assay. Apoptosis assay results showed that LCE induced late apoptosis of A549 cells. JC-1 assay showed that the mitochondria damaged at the LCE concentration of 0.4 mg/mL. In our preliminary anti-proliferation test of combined LCE and Bi-6727 on A549 cells, we found a dramatically decrease in proliferation after treated with LCE first for 24-h and then Bi-6727 for extra 24-h. This was an important finding regarding synergistic anti-proliferation effect of these drugs, However, the usage, the application sequence of LCE and Bi-6727 on A549 cells and their related mechanisms still need to be evaluated. In summary, the drugs exerted anti-proliferation effect on A549 cells independently. We hopefully combine the usage of these two drugs will bring a different and potential outcome in treating lung cancer.

Keywords: anti-proliferation, A549, Livistona Chinensis fruit extracts, PLK-1 inhibitor

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Authors: Prasamsha Panta, Da Yeon Kim, Ja Yong Jang, Min Jae Kim, Jae Ho Kim, Moon Suk Kim

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Introduction: Among the many anticancer drugs used clinically, doxorubicin (Dox), was one of widely used drugs to treat many types of solid tumors such as liver, colon, breast, or lung. Intratumoral injection of chemotherapeutic agents is a potentially more effective alternative to systemic administration because direct delivery of the anticancer drug to the target may improve both the stability and efficacy of anticancer drugs. Injectable in situ-forming gels have attracted considerable attention because they can achieve site specific drug delivery, long term action periods, and improved patient compliance. Objective: Objective of present study is to confirm clinical benefit of intratumoral chemotherapy using injectable in situ-forming poly(ethylene glycol)-b-polycaprolactone diblock copolymer (MP) and Dox with increase in efficacy and reducing the toxicity in patients with cancer diseases. Methods and methodology: We prepared biodegradable MP hydrogel and measured viscosity for the evaluation of thermo-sensitive property. In vivo antitumor activity was performed with normal saline, MP only, single free Dox, repeat free Dox, and Dox-loaded MP gel. The remaining amount of Dox drug was measured using HPLC after the mouse was sacrified. For cytotoxicity studies WST-1 assay was performed. Histological analysis was done with H&E and TUNEL processes respectively. Results: The works in this experiment showed that Dox-loaded MP have biodegradable drug depot property. Dox-loaded MP gels showed remarkable in vitro cytotoxicity activities against cancer cells. Finally, this work indicates that injection of Dox-loaded MP allowed Dox to act effectively in the tumor and induced long-lasting supression of tumor growth. Conclusion: This work has examined the potential clinical utility of intratumorally injected Dox-loaded MP gel, which shows significant effect of higher local Dox retention compared with systemically administered Dox.

Keywords: injectable in-situ forming hydrogel, anticancer, doxorubicin, intratumoral injection

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Authors: Mohammad Hossein Habibi, Atena Sadat Hosseini

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Colorectal cancer is the third leading cause of cancer-related death in the world. Colorectal cancer screening, early detection, and treatment programs could benefit from the most up-to-date information on the disease's burden, given the present worldwide trend of increasing colorectal cancer incidence. Tumor recurrence and resistance are exacerbated by the presence of chemotherapy-resistant cancer stem cells that can generate rapidly proliferating tumor cells. In addition, tumor cells can evolve chemoresistance through adaptation mechanisms. In this work, we used in silico analysis to select suitable GEO datasets. In this study, we compared slow-growing cancer stem cells with high-growth colorectal cancer-derived cancer stem cells. We then evaluated the signal pathways, transcription factors, and kinases associated with these two types of cancer stem cells. A total of 980 upregulated genes and 870 downregulated genes were clustered. MAPK signaling pathway, AGE-RAGE signaling pathway in diabetic complications, Fc gamma R-mediated phagocytosis, and Steroid biosynthesis signaling pathways were observed in upregulated genes. Also, caffeine metabolism, amino sugar and nucleotide sugar metabolism, TNF signaling pathway, and cytosolic DNA-sensing pathway were involved in downregulated genes. In the next step, we evaluated the best transcription factors and kinases in two types of cancer stem cells. In this regard, NR2F2, ZEB2, HEY1, and HDGF as transcription factors and PRDM5, SMAD, CBP, and KDM2B as critical kinases in upregulated genes. On the other hand, IRF1, SPDEF, NCOA1, and STAT1 transcription factors and CTNNB1 and CDH7 kinases were regulated low expression genes. Using bioinformatics analysis in the present study, we conducted an in-depth study of colorectal cancer stem cells at low and high growth rates so that we could take further steps to detect and even target these cells. Naturally, more additional tests are needed in this direction.

Keywords: colorectal cancer, bioinformatics analysis, transcription factor, kinases, cancer stem cells

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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: Wadha Alqahtani

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In recent times, polymers have seen a great surge in interest in the field of medicine, particularly chemotherapeutics. One recent innovation is the conversion of polymeric materials into “polymeric nanoparticles”. These nanoparticles can be designed and modified to encapsulate and transport drugs selectively to cancer cells, minimizing collateral damage to surrounding healthy tissues, and improve patient quality of life. In this study, we have synthesized pseudo-branched polyester polymers from bio-based small molecules, including sorbitol, glutaric acid and a propargylic acid derivative to further modify the polymer to make it “click-able" with an azide-modified target ligand. Melt polymerization technique was used for this polymerization reaction, using lipase enzyme catalyst NOVO 435. This reaction was conducted between 90- 95 °C for 72 hours. The polymer samples were collected in 24-hour increments for characterization and to monitor reaction progress. The resulting polymer was purified with the help of methanol dissolving and filtering with filter paper then characterized via NMR, GPC, FTIR, DSC, TGA and MALDI-TOF. Following characterization, these polymers were converted to a polymeric nanoparticle drug delivery system using solvent diffusion method, wherein DiI optical dye and chemotherapeutic drug Taxol can be encapsulated simultaneously. The efficacy of the nanoparticle’s apoptotic effects were analyzed in-vitro by incubation with prostate cancer (LNCaP) and healthy (CHO) cells. MTT assays and fluorescence microscopy were used to assess the cellular uptake and viability of the cells after 24 hours at 37 °C and 5% CO2 atmosphere. Results of the assays and fluorescence imaging confirmed that the nanoparticles were successful in both selectively targeting and inducing apoptosis in 80% of the LNCaP cells within 24 hours without affecting the viability of the CHO cells. These results show the potential of using biodegradable polymers as a vehicle for receptor-specific drug delivery and a potential alternative for traditional systemic chemotherapy. Detailed experimental results will be discussed in the e-poster.

Keywords: chemotherapeutic drug, click chemistry, nanoparticle, prostat cancer

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Authors: Rolivhuwa Bishop Ramagoma1*, Lynn Cairncross1, , Saartjie Roux1

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According to the world health organisation, colon cancer is among the most common cancers diagnosed in both men and women. Specifically, it is the second leading cause of cancer related deaths accounting for over 860 000 deaths worldwide in 2018. Currently, chemotherapy has become an essential component of most cancer treatments. Despite progress in cancer drug development over the previous years, traditional chemotherapeutic drugs still have low selectivity for targeting tumour tissues and are frequently constrained by dose-limiting toxicity. The creation of nanoscale delivery vehicles capable of directly directing treatment into cancer cells has recently caught the interest of researchers. Herein, the development of peptide-functionalized polyethylene glycol gold nanoparticles (Peptide-PEG-AuNPs) as a cellular probe and delivery agent is described, with the higher aim to develop a specific diagnostic prototype and assess their specificity not only against cell lines but primary human cells as well. Gold nanoparticles (AuNPs) were synthesized and stabilized through chemical conjugation. The synthesized AuNPs were characterized, stability in physiological solutions was assessed, their cytotoxicity against colon carcinoma and non-carcinoma skin fibroblasts was also studied. Furthermore, genetic effect through real-time polymerase chain reaction (RT-PCR), localization and uptake, peptide specificity were also determined. In this study, different peptide-AuNPs were found to have preferential toxicity at higher concentrations, as revealed by cell viability assays, however, all AuNPs presented immaculate stability for over 3 months following the method of synthesis. The final obtained peptide-PEG-AuNP conjugates showed good biocompatibility in the presence of high ionic solutions and biological media and good cellular uptake. Formulation of colon cancer specific targeting peptide was successful, additionally, the genes/pathways affected by the treatments were determined through RT-PCR. Primary cells study is still on going with promising results thus far.

Keywords: nanotechnology, cancer, diagnosis, therapeutics, gold nanoparticles.

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Authors: Marina Shurupova, Victor Anisimov, Alexander Latanov

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Background: The cerebellar lesions inevitably provoke oculomotor impairments in patients of different age. Symptoms of subtentorial tumors, particularly medulloblastomas, include static and dynamic coordination disorders (ataxia, asynergia, imbalance), hypo-muscle tonus, disruption of the cranial nerves, and within the oculomotor system - nystagmus (fine or gross). Subtentorial tumors can also affect the areas of cerebellum that control the oculomotor system. The noninvasive eye-tracking technology allows obtaining multiple oculomotor characteristics such as the number of fixations and their duration, amplitude, latency and velocity of saccades, trajectory and scan path of gaze during the process of the visual field navigation. Eye tracking could be very useful in clinical studies serving as convenient and effective tool for diagnostics. The aim: We studied the dynamics of oculomotor system functioning in patients undergoing remission from cerebellar tumors removal surgeries and following neurocognitive rehabilitation. Methods: 38 children (23 boys, 15 girls, 9-17 years old) that have recovered from the cerebellar tumor-removal surgeries, radiation therapy and chemotherapy and were undergoing course of neurocognitive rehabilitation participated in the study. Two tests were carried out to evaluate oculomotor performance - gaze stability test and counting test. The monocular eye movements were recorded with eye tracker ArringtonResearch (60 Hz). Two experimental sessions with both tests were conducted before and after rehabilitation courses. Results: Within the final session of both tests we observed remarkable improvement in oculomotor performance: 1) in the gaze stability test the spread of gaze positions significantly declined compared to the first session, and 2) the visual path in counting test significantly shortened both compared to the first session. Thus, neurocognitive rehabilitation improved the functioning of the oculomotor system in patients following the cerebellar tumor removal surgeries and subsequent therapy. Conclusions: The experimental data support the effectiveness of the utilization of the eye tracking technique as diagnostic tool in the field of neurooncology.

Keywords: eye tracking, rehabilitation, cerebellar tumors, oculomotor system

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Authors: Mohamed Shafi Bin Mahboob Ali

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Introduction: Synchronous tumor is defined as the presence of more than one primary malignant lesion in the same patient at the indexed diagnosis. It is a rare occurrence, especially in the spectrum of colorectal cancer, which accounts for less than 4%. The underlying pathology of a synchronous tumor is thought to be due to a genomic factor, which is microsatellite instability (MIS) with the involvement of BRAF, KRAS, and the GSRM1 gene. There are no specific sites of occurrence for the synchronous colorectal tumor, but many studies have shown that a synchronous tumor has about 43% predominance in the ascending colon with rarity in the sigmoid colon. Case Report: We reported a case of a young lady in the middle of her 30's with no family history of colorectal cancer that was diagnosed with a synchronous adenocarcinoma at the descending colon and rectosigmoid region. The lady's presentation was quite perplexing as she presented to the district hospital initially with simple, uncomplicated hemorrhoids and constipation. She was then referred to our center for further management as she developed a 'football' sized right gluteal swelling with a complete intestinal obstruction and bilateral lower-limb paralysis. We performed a CT scan and biopsy of the lesion, which found that the tumor engulfed the sacrococcygeal region with more than one primary lesion in the colon as well as secondaries in the liver. The patient was operated on after a multidisciplinary meeting was held. Pelvic exenteration with tumor debulking and anterior resection were performed. Postoperatively, she was referred to the oncology team for chemotherapy. She had a tremendous recovery in eight months' time with a partial regain of her lower limb power. The patient is still under our follow-up with an improved quality of life post-intervention. Discussion: Synchronous colon cancer is rare, with an incidence of 2.4% to 12.4%. It has male predominance and is pathologically more advanced compared to a single colon lesion. Down staging the disease by means of chemoradiotherapy has shown to be effective in managing this tumor. It is seen commonly on the right colon, but in our case, we found it on the left colon and the rectosigmoid. Conclusion: Managing a synchronous colon tumor could be challenging to surgeons, especially in deciding the extent of resection and postoperative functional outcomes of the bowel; thus, individual treatment strategies are needed to tackle this pathology.

Keywords: synchronous, colon, tumor, adenocarcinoma

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Authors: Amos Sunday Onikanni, Bashir Lawal, Babatunji Emmanuel Oyinloye, Gomaa Mostafa-Hedeab, Mohammed Alorabi, Simona Cavalu, Augustine O. Olusola, Chih-Hao Wang, Gaber El-Saber Batiha

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The increasing global burden of diabetes mellitus has called for the search for a therapeutic alternative that offers better activities and safety than conventional chemotherapy. Herein, we evaluated the neuroprotective and antioxidant properties of different fractions (ethyl acetate, N-butanol and residual aqueous) of Clompanus pubescens leaves in streptozotocin (STZ)-induced diabetic rats. Our results revealed a significant elevation in the levels of blood glucose, pro-inflammatory cytokines, lipid peroxidation, neuronal activities of acetylcholinesterase, butyrylcholinesterase, nitric oxide, epinephrine, norepinephrine, and Na+/K+-ATPase in diabetic non treated rats. In addition, decreased levels of enzymatic and non-enzymatic antioxidants were observed. Treatment with different fractions of C. pubescens leaves resulted in a significant reversal of the biochemical alteration and improved the neurocognitive deficit in STZ-induced diabetic rats. However, the ethyl-acetate fraction demonstrated higher activities than the other fractions and was characterized for its phytoconstituents, revealing the presence of Gallic acid (713.00 ppm), catechin (0.91 ppm), ferulic acid (0.98 ppm), rutin (59.82 ppm), quercetin (3.22 ppm) and kaempferol (4.07 ppm). Our molecular docking analysis revealed that these compounds exhibited different binding affinities and potentials for targeting BChE/AChE/ IL-1 β/Na+-K+-ATPase. However, only Kampferol and ferulic exhibited good drug-like, ADMET, and permeability properties suitable for use as a neuronal drug target agent. Hence, the ethyl-acetate fraction of C. pubescent leaves could be considered a source of promising bioactive metabolite for the treatment and management of cognitive impairments related to type II diabetes mellitus.

Keywords: diabetes mellitus, neuroprotective, antioxidant, pro-inflammatory cytokines

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Authors: Fei Ye, Åsa Barrefelt, Manuchehr Abedi-Valugerdi, Khalid M. Abu-Salah, Salman A. Alrokayan, Mamoun Muhammed, Moustapha Hassan

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With appropriate encapsulation in functional nanoparticles drugs are more stable in physiological environment and the kinetics of the drug can be more carefully controlled and monitored. Furthermore, targeted drug delivery can be developed to improve chemotherapy in cancer treatment, not only by enhancing intracellular uptake by target cells but also by reducing the adverse effects in non-target organs. Inorganic imaging agents, delivered together with anti-cancer drugs, enhance the local imaging contrast and provide precise diagnosis as well as evaluation of therapy efficacy. We have developed biodegradable polymeric vesicles as a nanocarrier system for multimodal bio-imaging and anticancer drug delivery. The poly (lactic-co-glycolic acid) PLGA) vesicles were fabricated by encapsulating inorganic imaging agents of superparamagnetic iron oxide nanoparticles (SPION), manganese-doped zinc sulfide (MN:ZnS) quantum dots (QDs) and the anticancer drug busulfan into PLGA nanoparticles via an emulsion-evaporation method. T2-weighted magnetic resonance imaging (MRI) of PLGA-SPION-Mn:ZnS phantoms exhibited enhanced negative contrast with r2 relaxivity of approximately 523 s-1 mM-1 Fe. Murine macrophage (J774A) cellular uptake of PLGA vesicles started fluorescence imaging at 2 h and reached maximum intensity at 24 h incubation. The drug delivery ability PLGA vesicles was demonstrated in vitro by release of busulfan. PLGA vesicles degradation was studied in vitro, showing that approximately 32% was degraded into lactic and glycolic acid over a period of 5 weeks. The biodistribution of PLGA vesicles was investigated in vivo by MRI in a rat model. Change of contrast in the liver could be visualized by MRI after 7 min and maximal signal loss detected after 4 h post-injection of PLGA vesicles. Histological studies showed that the presence of PLGA vesicles in organs was shifted from the lungs to the liver and spleen over time.

Keywords: biodegradable polymers, multifunctional nanoparticles, quantum dots, anticancer drugs

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Authors: Ruqayya Naheed Khan, Awais Amjad Malik, Awais Naeem, Amina Khan, Asad Parvaiz

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Introduction: Axillary nodal status in breast cancer patients is a paramount prognosticator, next to primary tumor size and grade. It has been well established that patients with negative sentinel lymph node biopsy can safely avoid axillary lymph node dissection. A positive sentinel lymph node has traditionally required subsequent axillary dissection. According to ACOSOG Z11 trial, patients who underwent axillary dissection with 3 or more positive sentinel nodes or opted for observation in case of negative sentinel lymph node, did not find any difference in Overall Survival (OS) and Disease Free Survival (DFS). The Z11 trial included patients who underwent breast conserving surgery and excluded patients with mastectomies. The purpose of this study is to determine whether Z0011 can be applied to mastectomy patients as well in 1-3 positive sentinel lymph nodes and avoid unnecessary ALND. Methods: A retrospective review was conducted at Shaukat Khanam Memorial Cancer Hospital Pakistan from Jan 2015 to Dec 2017 including patients who were treated for invasive breast cancer and required upfront mastectomy. They were clinically node negative, so sentinel lymph node biopsy was performed. Patients underwent ALND with positive sentinel lymph node. A total of 156 breast cancer patients with mastectomies were reviewed. Results: 95% of the patients were female while 3% were male. Average age was 44 years. There was no difference in race, comorbidities, histology, T stage, N stage, and overall stage, use of adjuvant chemotherapy and radiation therapy. 64 patients underwent ALND for positive lymph node while 92 patients were spared of axillary dissection due to negative sentinel lymph node biopsy. Out of 64 patients, 38 patients (59%) had only 1 lymph node positive which was the sentinel node. 18 patients (28%) had 2 lymph nodes positive including the sentinel node while only 8 patients (13%) had 3 or more positive nodes. Conclusion: Keeping in mind the complications related to ALND, above results clearly show that ALND could have been avoided in 87% of patients in the setting of adjuvant radiation, possibly avoiding the morbidity associated with axillary lymphadenectomy although a prospective randomized trial needs to confirm these results.

Keywords: mastectomy, sentinel lymph node biopsy, axillary lymph node dissection, breast cancer

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Authors: Elizabeth Behrens, Anne Timmermann, Alexander Yerkan, Joshua Thomas, Deborah Katz, Agne Paner, Melissa Larson, Shivi Jain, Seo-Hyun Kim, Celalettin Ustun, Ankur Varma, Parameswaran Venugopal, Jamile Shammo

Abstract:

Coronavirus Disease-2019 (COVID-19) causes persistent concern for poor outcomes in vulnerable populations. Patients with hematologic malignancies (HM) have been found to have higher COVID-19 case fatality rates compared to those without malignancy. While cytopenias are common in patients with HM, especially in those undergoing chemotherapy treatment, hemoglobin (Hgb) and platelet count have not yet been studied, to our best knowledge, as potential prognostic indicators for patients with HM and COVID-19. The goal of this study is to identify factors that may increase the risk of mortality in patients with HM and COVID-19. In this single-center, retrospective, observational study, 65 patients with HM and laboratory confirmed COVID-19 were identified between March 2020 and January 2021. Information on demographics, laboratory data the day of COVID-19 diagnosis, and prognosis was extracted from the electronic medical record (EMR), chart reviewed, and analyzed using the statistical software SAS version 9.4. Chi-square testing was used for categorical variable analyses. Risk factors associated with mortality were established by logistic regression models. Non-Hodgkin lymphoma (37%), chronic lymphocytic leukemia (20%), and plasma cell dyscrasia (15%) were the most common HM. Higher Hgb level upon COVID-19 diagnosis was related to decreased mortality, odd ratio=0.704 (95% confidence interval [CI]: 0.511-0.969; P = .0263). Platelet count the day of COVID-19 diagnosis was lower in patients who ultimately died (mean 127 ± 72K/uL, n=10) compared to patients who survived (mean 197 ±92K/uL, n=55) (P=.0258). Female sex was related to decreased mortality, odd ratio=0.143 (95% confidence interval [CI]: 0.026-0.785; P = .0353). There was no mortality difference between the patients who were on treatment for HM the day of COVID-19 diagnosis compared to those who were not (P=1.000). Lower Hgb and male sex are independent risk factors associated with increased mortality of HM patients with COVID-19. Clinicians should be especially attentive to patients with HM and COVID-19 who present with cytopenias. Larger multi-center studies are urgently needed to further investigate the impact of anemia, thrombocytopenia, and demographics on outcomes of patients with hematologic malignancies diagnosed with COVID-19.

Keywords: anemia, COVID-19, hematologic malignancy, prognosis

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Authors: Ayda Youssef, Tarek Rafaat, Iman zaky

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Purpose: Langerhans’ cell histiocytosis (LCH) is not uncommon pathology that implies aberrant proliferation of a specific dendritic (Langerhans) cell. These atypical but mature cells of monoclonal origin can infiltrate many sites of the body and may occur as localized lesions or as widespread systemic disease. Liver is one of the uncommon sites of affection. The twofold objective of this study is to illustrate the radiological presentation of this disease, and to compare these results with previously reported series. Methods and Materials: Between 2007 and 2012, 150 patients with biopsy-proven LCH were treated in our hospital, a paediatric cancer tertiary care center. A retrospective review of radiographic images and reports was performed. There were 33 patients with liver affection are stratified. All patients underwent imaging studies, mostly US and CT. A chart review was performed to obtain demographic, clinical and radiological data. They were analyzed and compared to other published series. Results: Retrospective assessment of 150 patients with LCH was performed, among them 33 patients were identified who had liver involvement. All these patients developed multisystemic disease; They were 12 females and 21 males with (n= 32), seven of them had marked hepatomegaly. Diffuse hypodense liver parenchyma was encountered in five cases, the periportal location has a certain predilection in cases of focal affection where three cases has a hypodense periportal soft tissue sheets, one of them associated with dilated biliary radicals, only one case has multiple focal lesions unrelated to portal tracts. On follow up of the patients, two cases show abnormal morphology of liver with bossy outline. Conclusion: LCH is a not infrequent disease. A high-index suspicion should be raised in the context of diagnosis of liver affection. A biopsy is recommended in the presence of radiological suspicion. Chemotherapy is the preferred therapeutic modality. Liver histiocytosis are not disease specific features but should be interpreted in conjunction with the clinical history and the results of biopsy. Clinical Relevance/Application: Radiologist should be aware of different patterns of hepatobiliary histiocytosis, Thus early diagnosis and proper management of patient can be conducted.

Keywords: langerhans’ cell histiocytosis, liver, medical and health sciences, radiology

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Authors: Zahra Shokrolahi, Mohammad Reza Atashzar

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The goals of treating patients with breast cancer are to cure the disease, prolong survival, and improve quality of life. Immune cells in the tumor microenvironment have an important role in regulating tumor progression. The term of cellular immunotherapy refers to the administration of living cells to a patient; this type of immunotherapy can be active, such as a dendritic cell (DC) vaccine, in that the cells can stimulate an anti-tumour response in the patient, or the therapy can be passive, whereby the cells have intrinsic anti-tumour activity; this is known as adoptive cell transfer (ACT) and includes the use of autologous or allogeneic lymphocytes that may, or may not, be modified. The most important breast cancer cellular immunotherapies involving the use of T cells and natural killer (NK) cells in adoptive cell transfer, as well as dendritic cells vaccines. T cell-based therapies including tumour-infiltrating lymphocytes (TILs), engineered TCR-T cells, chimeric antigen receptor (CAR T cell), Gamma-delta (γδ) T cells, natural killer T (NKT) cells. NK cell-based therapies including lymphokine-activated killers (LAK), cytokine-induced killer (CIK) cells, CAR-NK cells. Adoptive cell therapy has some advantages and disadvantages some. TILs cell strictly directed against tumor-specific antigens but are inactive against tumor changes due to immunoediting. CIK cell have MHC-independent cytotoxic effect and also need concurrent high dose IL-2 administration. CAR T cell are MHC-independent; overcome tumor MHC molecule downregulation; potent in recognizing any cell surface antigen (protein, carbohydrate or glycolipid); applicable to a broad range of patients and T cell populations; production of large numbers of tumor-specific cells in a moderately short period of time. Meanwhile CAR T cells capable of targeting only cell surface antigens; lethal toxicity due to cytokine storm reported. Here we present the most popular cancer cellular immunotherapy approaches and discuss their clinical relevance referring to data acquired from clinical trials .To date, clinical experience and efficacy suggest that combining more than one immunotherapy interventions, in conjunction with other treatment options like chemotherapy, radiotherapy and targeted or epigenetic therapy, should guide the way to cancer cure.

Keywords: breast cancer , cell therapy , CAR T cell , CIK cells

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Authors: Yung-Chih Kuo, Yung-I Lou

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Cationic solid lipid nanoparticles (CSLNs) with anti-melanotransferrin (AMT) and apolipoprotein E (ApoE) were used to carry antimitotic doxorubicin (Dox) across the blood–brain barrier (BBB) for glioblastoma multiforme (GBM) treatment. Dox-loaded CSLNs were prepared in microemulsion, grafted covalently with AMT and ApoE, and applied to human brain microvascular endothelial cells (HBMECs), human astrocytes, and U87MG cells. Experimental results revealed that an increase in the weight percentage of stearyl amine (SA) from 0% to 20% increased the size of AMT-ApoE-Dox-CSLNs. In addition, an increase in the stirring rate from 150 rpm to 450 rpm decreased the size of AMT-ApoE-Dox-CSLNs. An increase in the weight percentage of SA from 0% to 20% enhanced the zeta potential of AMT-ApoE-Dox-CSLNs. Moreover, an increase in the stirring rate from 150 rpm to 450 rpm reduced the zeta potential of AMT-ApoE-Dox-CSLNs. AMT-ApoE-Dox-CSLNs exhibited a spheroid-like geometry, a minor irregular boundary deviating from spheroid, and a somewhat distorted surface with a few zigzags and sharp angles. The encapsulation efficiency of Dox in CSLNs decreased with increasing weight percentage of Dox and the order in the encapsulation efficiency of Dox was 10% SA > 20% SA > 0% SA. However, the reverse order was true for the release rate of Dox, suggesting that AMT-ApoE-Dox-CSLNs containing 10% SA had better-sustained release characteristics. An increase in the concentration of AMT from 2.5 to 7.5 μg/mL slightly decreased the grafting efficiency of AMT and an increase in that from 7.5 to 10 μg/mL significantly decreased the grafting efficiency. Furthermore, an increase in the concentration of ApoE from 2.5 to 5 μg/mL slightly reduced the grafting efficiency of ApoE and an increase in that from 5 to 10 μg/mL significantly reduced the grafting efficiency. Also, AMT-ApoE-Dox-CSLNs at 10 μg/mL of ApoE could slightly reduce the transendothelial electrical resistance (TEER) and increase the permeability of propidium iodide (PI). An incorporation of 10 μg/mL of ApoE could reduce the TEER and increase the permeability of PI. AMT-ApoE-Dox-CSLNs at 10 μg/mL of AMT and 5-10 μg/mL of ApoE could significantly enhance the permeability of Dox across the BBB. AMT-ApoE-Dox-CSLNs did not induce serious cytotoxicity to HBMECs. The viability of HBMECs was in the following order: AMT-ApoE-Dox-CSLNs = AMT-Dox-CSLNs = Dox-CSLNs > Dox. The order in the efficacy of inhibiting U87MG cells was AMT-ApoE-Dox-CSLNs > AMT-Dox-CSLNs > Dox-CSLNs > Dox. A surface modification of AMT and ApoE could promote the delivery of AMT-ApoE-Dox-CSLNs to cross the BBB via melanotransferrin and low density lipoprotein receptor. Thus, AMT-ApoE-Dox-CSLNs have appropriate physicochemical properties and can be a potential colloidal delivery system for brain tumor chemotherapy.

Keywords: anti-melanotransferrin, apolipoprotein E, cationic catanionic solid lipid nanoparticle, doxorubicin, U87MG cells

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Authors: Emma R. Arakelova, Stepan G. Grigoryan, Flora G. Arsenyan, Nelli S. Babayan, Ruzanna M. Grigoryan, Natalia K. Sarkisyan

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Novel nanosize zinc oxide composites of doxorubicin obtained by deposition of 180 nm thick zinc oxide film on the drug surface using DC-magnetron sputtering of a zinc target in the form of gels (PEO+Dox+ZnO and Starch+NaCMC+Dox+ZnO) were studied for drug delivery applications. The cancer specificity was revealed both in in vitro and in vivo models. The cytotoxicity of the test compounds was analyzed against human cancer (HeLa) and normal (MRC5) cell lines using MTT colorimetric cell viability assay. IC50 values were determined and compared to reveal the cancer specificity of the test samples. The mechanistic study of the most active compound was investigated using Flow cytometry analyzing of the DNA content after PI (propidium iodide) staining. Data were analyzed with Tree Star FlowJo software using cell cycle analysis Dean-Jett-Fox module. The in vivo anticancer activity estimation experiments were carried out on mice with inoculated ascitic Ehrlich’s carcinoma at intraperitoneal introduction of doxorubicin and its zinc oxide compositions. It was shown that the nanosize zinc oxide film deposition on the drug surface leads to the selective anticancer activity of composites at the cellular level with the range of selectivity index (SI) from 4 (Starch+NaCMC+Dox+ZnO) to 200 (PEO(gel)+Dox+ZnO) which is higher than that of free Dox (SI = 56). The significant increase in vivo antitumor activity (by a factor of 2-2.5) and decrease of general toxicity of zinc oxide compositions of doxorubicin in the form of the above mentioned gels compared to free doxorubicin were shown on the model of inoculated Ehrlich's ascitic carcinoma. Mechanistic studies of anticancer activity revealed the cytostatic effect based on the high level of DNA biosynthesis inhibition at considerable low concentrations of zinc oxide compositions of doxorubicin. The results of studies in vitro and in vivo behavior of PEO+Dox+ZnO and Starch+NaCMC+Dox+ZnO composites confirm the high potential of the nanosize zinc oxide composites as a vector delivery system for future application in cancer chemotherapy.

Keywords: anticancer activity, cancer specificity, doxorubicin, zinc oxide

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Authors: Varsha Salian, Shama Rao, N. Narendra, B. Mohana Kumar

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Evolving evidence proposes the existence of a highly tumorigenic subpopulation of undifferentiated, self-renewing cancer stem cells, responsible for exhibiting resistance to conventional anti-cancer therapy, recurrence, metastasis and heterogeneous tumor formation. Importantly, the mechanisms exploited by cancer stem cells to resist chemotherapy are very less understood. Oral squamous cell carcinoma (OSCC) is one of the most regularly diagnosed cancer types in India and is associated commonly with alcohol and tobacco use. Therefore, the isolation and in vitro characterization of cancer stem-like cells from patients with OSCC is a critical step to advance the understanding of the chemoresistance processes and for designing therapeutic strategies. With this, the present study aimed to establish and characterize cancer stem-like cells in vitro from OSCC. The primary cultures of cancer stem-like cell lines were established from the tissue biopsies of patients with clinical evidence of an ulceroproliferative lesion and histopathological confirmation of OSCC. The viability of cells assessed by trypan blue exclusion assay showed more than 95% at passage 1 (P1), P2 and P3. Replication rate was performed by plating cells in 12-well plate and counting them at various time points of culture. Cells had a more marked proliferative activity and the average doubling time was less than 20 hrs. After being cultured for 10 to 14 days, cancer stem-like cells gradually aggregated and formed sphere-like bodies. More spheroid bodies were observed when cultured in DMEM/F-12 under low serum conditions. Interestingly, cells with higher proliferative activity had a tendency to form more sphere-like bodies. Expression of specific markers, including membrane proteins or cell enzymes, such as CD24, CD29, CD44, CD133, and aldehyde dehydrogenase 1 (ALDH1) is being explored for further characterization of cancer stem-like cells. To summarize the findings, the establishment of OSCC derived cancer stem-like cells may provide scope for better understanding the cause for recurrence and metastasis in oral epithelial malignancies. Particularly, identification and characterization studies on cancer stem-like cells in Indian population seem to be lacking thus provoking the need for such studies in a population where alcohol consumption and tobacco chewing are major risk habits.

Keywords: cancer stem-like cells, characterization, in vitro, oral squamous cell carcinoma

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Authors: Ezzati Givi M., Hoveizi E., Nezhad Marani N.

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Platinum-based anticancer therapeutics are the most widely used drugs in clinical chemotherapy but have major limitations and various side effects in clinical applications. Gonadotoxicity and sterility is one of the most common complications for cancer survivors, which seem to be drug-specific and dose-related. Therefore, many efforts have been dedicated to discovering a new structure of platinum-based anticancer agents with improved therapeutic index, fewer side effects. In this regard, new Pt(II)-phosphane complexes containing heterocyclic thionate ligands (PCTL) have been synthesized, which show more potent antitumor activities in comparison to cisplatin. Cisplatin, the best leading metal-based antitumor drug in the field, induces testicular toxicity on Leydig and Sertoli cells leading to serious side effects such as azoospermia and infertility. Therefore in the present study, we aimed to investigate the cytotoxicity effect of PCTL on mice TM4 Sertoli cells with particular emphasis on the role of autophagy in comparison to cisplatin. In this study, an MTT assay was performed to evaluate the IC50 of PCTL and to analyze the TM3 Leydig cell's viability. Cells morphology was evaluated via invert microscope and Changing in morphology for nuclei swelling or autophagic vacuoles formation were assessed by DAPI and MDC staining. Testosterone production in the culture medium was measured using an ELISA kit. Finally, the expression of Autophagy-related genes, Atg5, Beclin1 and p62, were analyzed by qPCR. Based on the obtained results by MTT, the IC50 value of PCTL was 50 μM in TM3 cells and cytotoxic effects was in a dose- and time-dependent manner. Cells morphological changes investigated by inverted microscopy, DAPI, and MDC staining which showed the cytotoxic concentrations of PCTL was significantly higher than cisplatin in the treated TM3 Leydig cells. The results of PCR showed a lack of expression of the p62, Atg5 and Beclin1 gene in TM3 cells treated with PCTL in comparison to cisplatin and control groups. It should be noted that the effects of 25 μM PCTL concentration on TM3 cells have been associated with increased testosterone production and secretion, which requires further study to explain the possible causes and involved molecular mechanisms. The results of the study showed that the PCTL had less-lethal effects on TM3 cells in comparison to cisplatin and probably did not induce autophagy in TM3 cells.

Keywords: platinum-based anticancer agents, cisplatin, Leydig TM3 cells, autophagy

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Authors: Anna Rudzińska, Katarzyna Szklener, Pola Juchaniuk, Anna Rodzajweska, Katarzyna Machulska-Ciuraj, Monika Rychlik- Grabowska, Michał łOziński, Agnieszka Kolak-Bruks, SłAwomir Mańdziuk

Abstract:

Introduction: Immune checkpoint inhibition (ICI) belongs to the modern forms of anti-cancer treatment. Due to the constant development and continuous research in the field of ICI, many aspects of the treatment are yet to be discovered. One of the less researched aspects of ICI treatment is the influence of the adverse effects on the treatment success rate. It is suspected that adverse events in the course of the ICI treatment indicate a better response rate and correlate with longer progression-free- survival. Methodology: The research was conducted with the usage of the documentation of the Department of Clinical Oncology and Chemotherapy. Data of the patients with a lung cancer diagnosis who were treated between 2019-2022 and received ICI treatment were analyzed. Results: Out of over 133 patients whose data was analyzed, the vast majority were diagnosed with non-small cell lung cancer. The majority of the patients did not experience adverse effects. Most adverse effects reported were classified as grade 1 or grade 2 according to CTCAE classification. Most adverse effects involved skin, thyroid and liver toxicity. Statistical significance was found for the adverse effect incidence and overall survival (OS) and progression-free survival (PFS) (p=0,0263) and for the time of toxicity onset and OS and PFS (p<0,001). The number of toxicity sites was statistically significant for prolonged PFS (p=0.0315). The highest OS was noted in the group presenting grade 1 and grade 2 adverse effects. Conclusions: Obtained results confirm the existence of the prolonged OS and PFS in the adverse-effects-charged patients, mostly in the group presenting mild to intermediate (Grade 1 and Grade 2) adverse effects and late toxicity onset. Simultaneously our results suggest a correlation between treatment response rate and the toxicity grade of the adverse effects and the time of the toxicity onset. Similar results were obtained in several similar research conducted - with the proven tendency of better survival in mild and moderate toxicity; meanwhile, other studies in the area suggested an advantage in patients with any toxicity regardless of the grade. The contradictory results strongly suggest the need for further research on this topic, with a focus on additional factors influencing the course of the treatment.

Keywords: adverse effects, immunotherapy, lung cancer, PD-1/PD-L1 inhibitors

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Authors: Taleb Lotfi, Benarbia Maheidine, Allam Hamza, Boutira Fatima, Boukerche Abdelbaki

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Introduction and purpose of the study: This is a retrospective single-center study with an analytical aim to determine the prognostic factors for relapse in patients treated with radiotherapy after total laryngectomy with lymph node dissection for laryngeal cancer at the Emir Abdelkader cancer center in Oran (Algeria). Material and methods: During the study period from January 2014 to December 2018, eighty-nine patients (n=89) with squamous cell carcinoma of the larynx were treated with postoperative radiotherapy. Relapse-free survival was studied in the univariate analysis according to pre-treatment criteria using Kaplan-Meier survival curves. We performed a univariate analysis to identify relapse factors. Statistically significant factors have been studied in the multifactorial analysis according to the Cox model. Results and statistical analysis: The average age was 62.7 years (40-86 years). It was a squamous cell carcinoma in all cases. Postoperatively, the tumor was classified as pT3 and pT4 in 93.3% of patients. Histological lymph node involvement was found in 36 cases (40.4%), with capsule rupture in 39% of cases, while the limits of surgical excision were microscopically infiltrated in 11 patients (12.3%). Chemotherapy concomitant with radiotherapy was used in 67.4% of patients. With a median follow-up of 57 months (23 to 104 months), the probabilities of relapse-free survival and five-year overall survival are 71.2% and 72.4%, respectively. The factors correlated with a high risk of relapse were locally advanced tumor stage pT4 (p=0.001), tumor site in case of subglottic extension (p=0.0003), infiltrated surgical limits R1 (p=0.001), l lymph node involvement (p=0.002), particularly in the event of lymph node capsular rupture (p=0.0003) as well as the time between surgery and adjuvant radiotherapy (p=0.001). However, in the subgroup analysis, the major prognostic factors for disease-free survival were subglottic tumor extension (p=0.001) and time from surgery to adjuvant radiotherapy (p=0.005). Conclusion: Combined surgery and postoperative radiation therapy are effective treatment modalities in the management of laryngeal cancer. Close cooperation of the entire cervicofacial oncology team is essential, expressed during a multidisciplinary consultation meeting, with the need to respect the time between surgery and radiotherapy.

Keywords: laryngeal cancer, laryngectomy, postoperative radiotherapy, survival

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Authors: Mike Wei, Nebu Koshy, Koen van Besien, Giorgio Inghirami, Steven M. Horwitz

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T-cell prolymphocytic leukemia (T-PLL) is a rare hematologic disease characterized by a T-cell phenotype, rapid progression, and poor prognosis with median survival of less than a year. Alemtuzumab-based chemotherapy has increased the rate of complete remissions but these are often short-lived, and allogeneic transplant is considered the only curative therapy. In recent studies, JAK3 activating mutations have been identified in T-cell cancers, with T-PLL having the highest rate of JAK3 mutations (30 – 42%). As such, T-PLL is a model disease for evaluating the utility of JAK3 inhibitors. We present a case of a 64-year-old man with relapsed-refractory T-PLL. He was initially treated with alemtuzumab and obtained complete response and was consolidated with matched unrelated donor stem cell transplant. His disease stayed in remission for approximately 1.5 years before relapse, which was then treated with a clinical trial of romidepsin-lenalidomide (partial responses then progression at 6 months) and later alemtuzumab. Due to complications of myelosuppression and CMV reactivation, his treatment was interrupted leading to disease progression. The doubling time of lymphocyte count was approximately 20 days and over a span of 60 days the lymphocyte count rose from 8 x 109/L to 68 x 109/L. Exon sequencing showed a JAK3 mutation. The patient consented to and was treated with FDA-approved tofacitinib (initially 5 mg BID, increased to 10 mg BID after 15 days of treatment). An initial decrease in lymphocyte count was followed by progression. In vitro treatment of the patient’s cells showed modest effects of tofacitinib and ruxolitinib as single agents, in the range of doxorubicin, but synergy between the agents. After 40 days of treatment with tofacitinib and with a lymphocyte count of 150 x 109/L, ruxolitinib (5mg BID) was added. Over the 60 days since dual inhibition was started, the lymphocyte count has stabilized. The patient has remained completely asymptomatic during treatment with tofacitinib and ruxolitinib. Neutrophil count has remained normal. Platelet count and hemoglobin have however declined from ~50 x109/L to ~30 x109/L and from 11 g/dL to 8.1 g/dL respectively, since the introduction of ruxolitinib. The stabilization in lymphocyte count confirms the clinical activity of JAK inhibitors in T-PLL as suggested by the presence of JAK3 mutations and by in-vitro assays. It also suggests clinical synergy between ruxolitinib and tofacitinib in this setting. Prospective studies of JAK inhibitors in PLL patients with formal dose-finding studies are needed.

Keywords: tofacitinib, ruxolitinib, T-cell prolymphocytic leukemia, JAK3

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Authors: B. Petrović, M. Petrović, L. Rutonjski, I. Djan, V. Ivanović

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Objective: Cardiac pacemakers are very sensitive to radiotherapy treatment from two sources: electromagnetic influence from the medical linear accelerator producing ionizing radiation- influencing electronics within the pacemaker, and the absorption of dose to the device. On the other hand, patients with cardiac pacemakers at the place of a tumor are rather rare, and single clinic hardly has experience with the management of such patients. The widely accepted international guidelines for management of radiation oncology patients recommend that these patients should be closely monitored and examined before, during and after radiotherapy treatment by cardiologist, and their device and condition followed up. The number of patients having both cancer and pacemaker, is growing every year, as both cancer incidence, as well as cardiac diseases incidence, are inevitably growing figures. Materials and methods: Female patient, age 69, was diagnozed with valvular cardiomyopathy and got implanted a pacemaker in 2005 and prosthetic mitral valve in 1993 (cancer was diagnosed in 2012). She was stable cardiologically and came to radiation therapy department with the diagnosis of right breast cancer, with the tumor in upper lateral quadrant of the right breast. Since she had all lymph nodes positive (28 in total), she had to have irradiated the supraclavicular region, as well as the breast with the tumor bed. She previously received chemotherapy, approved by the cardiologist. The patient was estimated to be with the high risk as device was within the field of irradiation, and the patient had high dependence on her pacemaker. The radiation therapy plan was conducted as 3D conformal therapy. The delineated target was breast with supraclavicular region, where the pacemaker was actually placed, with the addition of a pacemaker as organ at risk, to estimate the dose to the device and its components as recommended, and the breast. The targets received both 50 Gy in 25 fractions (where 20% of a pacemaker received 50 Gy, and 60% of a device received 40 Gy). The electrode to the heart received between 1 Gy and 50 Gy. Verification of dose planned and delivered was performed. Results: Evaluation of the patient status according to the guidelines and especially evaluation of all associated risks to the patient during treatment was done. Patient was irradiated by prescribed dose and followed up for the whole year, with no symptoms of failure of the pacemaker device during, or after treatment in follow up period. The functionality of a device was estimated to be unchanged, according to the parameters (electrode impedance and battery energy). Conclusion: Patient was closely monitored according to published guidelines during irradiation and afterwards. Pacemaker irradiated with the full dose did not show any signs of failure despite recommendations data, but in correlation with other published data.

Keywords: cardiac pacemaker, breast cancer, radiotherapy treatment planning, complications of treatment

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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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