Immune Specific and Tumor-Dependent mRNA Vaccines for Cancer Immunotherapy: Reprogramming Clinical Translation into Tumor Editing Therapy.

Extensive research into mRNA vaccines for cancer therapy in preclinical and clinical trials has prepared the ground for the quick development of immune-specific mRNA vaccines during the COVID-19 pandemic. Therapeutic cancer vaccines based on mRNA are well tolerated, and are an attractive choice for future cancer immunotherapy. Ideal personalized tumor-dependent mRNA vaccines could stimulate both humoral and cellular immunity by overcoming cancer-induced immune suppression and tumor relapse. The stability, structure, and distribution strategies of mRNA-based vaccines have been improved by technological innovations, and patients with diverse tumor types are now being enrolled in numerous clinical trials investigating mRNA vaccine therapy. Despite the fact that therapeutic mRNA-based cancer vaccines have not yet received clinical approval, early clinical trials with mRNA vaccines as monotherapy and in conjunction with checkpoint inhibitors have shown promising results. In this review, we analyze the most recent clinical developments in mRNA-based cancer vaccines and discuss the optimal platforms for the creation of mRNA vaccines. We also discuss the development of the cancer vaccines' clinical research, paying particular attention to their clinical use and therapeutic efficacy, which could facilitate the design of mRNA-based vaccines in the near future.

Frequency of Thyroid Microcarcinoma in Patients Who Underwent Total Thyroidectomy with Benign Indication-A 5-Year Retrospective Review.

Background and Objectives: Incidental thyroid cancers (ITCs) are often microcarcinomas. The most frequent histologic type is a papillary microcarcinoma. Papillary thyroid microcarcinomas are defined as papillary thyroid tumours measuring less than 10 mm at their greatest diameter. They are clinically occult and frequently diagnosed incidentally in histopathology reports after a thyroidectomy. The aim of this study is to evaluate the rate of papillary thyroid microcarcinomas (PTMC) in patients who were thyroidectomised with indications of benign disease. Materials and Methods: We retrospectively evaluated the histological incidence of PTMC in 431 consecutive patients who, in a 5 year period, underwent a thyroidectomy with benign indications. Patients with benign histology and with known or suspected malignancy were excluded. Results: Histopathology reports from 540 patients who underwent a total thyroidectomy in our department between 2016 and 2021 were reviewed. A total of 431 patients were thyroidectomised for presumed benign thyroid disease. A total of 395 patients had confirmed benign thyroid disease in the final histopathology, while 36 patients had incidental malignant lesions (33 PTMC-7.67%, one multifocal PTC without microcarcinomas-0.23%, two follicular thyroid carcinoma-0.46%). Out of the PTMC patients, 29 were female and four were male (7.2:1 female-male ratio). The mean age was 54.2 years old. A total of 24 out of 33 patients had multifocal lesions, 11 of which co-existed with macro PTC. Nine patients had unifocal lesions. A total of 21 of these patients were initially operated on for multinodular goitre (64%), while 13 were operated on for Hashimoto/Lymphocytic thyroiditis (36%). Conclusions: PTMC-often multifocal-is not an uncommon, incidental finding after thyroidectomy for benign thyroid lesions (7.67% in our series) and often co-exists with other incidental malignant lesions (8.35% in our series). The possibility of an underlying papillary microcarcinoma should be taken into account in the management of patients with benign-especially nodular-thyroid disease, and total thyroidectomy should be considered.

Giant Echinococcosis of the Liver with Suppuration: A Case Report and Review of the Literature.

Purpose: Cystic echinococcosis (CE) is a common, complex parasitic disease that constitutes a major public health concern. CE demonstrates high endemicity in areas where dogs are used for herding or where animal husbandry practices involve close contact with livestock. It can clinically manifest with a variety of signs and symptoms, such as cholangitis, jaundice, pancreatitis, external biliary fistula, inferior vena cava obstruction, portal hypertension, and superinfection. The latter can notably be related to suppuration, either by rupture or bacteremia. The aim of this study is to report our 76-year-old patient who presented with a primarily infected giant-suppurated hydatid cyst of the liver and its surgical management. Methods: In this case, the diagnosis was based primarily on clinical presentation, computed tomography (CT) scan, and magnetic resonance imaging (MRI) of the patient's abdomen. The surgical procedure of choice was the partial retaining of the pericystic membrane and drainage of the cystic contents (partial pericystectomy). Results: The surgical management and meticulous long-term follow-up of our patient produced a positive outcome without any post-operative complications.

Melanoma: BRAFi Rechallenge.

Melanoma is the most aggressive type of skin cancer. Half of melanoma cases are characterized by the mutation BRAF V600. The case presented concerns a 41-year-old patient with locally advanced melanoma, being positive in mutation BRAF V600. The patient underwent surgery and received additional targeted therapy as part of a clinical study. In subsequent disease progression, immunotherapy was used. When the disease progressed again while the patient was in a good performance status, targeted therapy was administered again, and a good response was noted, making the patient reach a statistically significant overall survival, exceeding four years. Targeted therapy has proven to be an important tool in the treatment of melanoma. The use of BRAFi targeted therapy does not exclude the option of readministration at subsequent disease progression (BRAFi rechallenge). Preclinical models suggest that the resistance mechanism of cancer cells to BRAFi therapy bends, as these cell clones lose their evolutionary advantage after stopping BRAFi. Cell clones sensitive to BRAFi may then outcompete, making the treatment effective again. Therapeutical dilemmas in the management of patients with locally advanced melanoma that progresses to metastatic cancer are discussed.

A Review of the Significance in Measuring Preoperative and Postoperative Carcinoembryonic Antigen (CEA) Values in Patients with Medullary Thyroid Carcinoma (MTC).

Background and Objectives: Medullary thyroid carcinoma (MTC) accounts for 1-2% of all thyroid malignancies, and it originates from parafollicular "C" cells. Carcinoembryonic antigen (CEA) is a tumor marker, mainly for gastrointestinal malignancies. There are references in literature where elevated CEA levels may be the first finding in MTC. The aim of this study is to determine the importance of measuring preoperative and postoperative CEA values in patients with MTC and to define the clinical significance of the correlation between CEA and the origin of C cells. Materials and Methods: The existing and relevant literature was reviewed by searching for articles and specific keywords in the scientific databases of PubMedCentraland Google Scholar (till December 2020). Results: CEA has found its place, especially at the preoperative level, in the diagnostic approach of MTC. Preoperative CEA values >30 ng/mL indicate extra-thyroid disease, while CEA values >100 ng/mL are associated with lymph node involvement and distant metastases. The increase in CEA values preoperatively is associated with larger size of primary tumor, presence of lymph nodes, distant metastases and a poorer prognosis. The clinical significance of CEA values for the surgeon is the optimal planning of surgical treatment. In the recent literature, C cells seem to originate from the endoderm of the primitive anterior gut at the ultimobranchial bodies' level. Conclusions: Although CEA is not a specific biomarker of the disease in MTC, itsmeasurement is useful in assessing the progression of the disease. The embryonic origin of C cells could explain the increased CEA values in MTC.

Cardiopulmonary Arrest Caused by Large Substernal Goiter-Treatment with Combined Cervical Approach and Median Mini-Sternotomy: Report of a Case.

INTRODUCTION: Substernal goiter is usually defined as a goiter that extends below the thoracic inlet or a goiter with more than 50% of its mass lying below the thoracic inlet. Substernal goiters may compress adjacent anatomical structures causing a variety of symptoms. CASE REPORT: Here we report a rare case of a 75-year-old woman presenting with cardiac arrest caused by acute respiratory failure due to tracheal compression by a substernal goiter. DISCUSSION: Substernal goiters can be classified as primary or secondary depending on their site of origin. Symptoms are diverse and include a palpable neck mass, mild dyspnea to asphyxia, dysphagia, dysphonia, and superior vena cava syndrome. Diagnosis of substernal goiter is largely based on computed tomography imaging, which will show the location of the goiter and its extension in the thoracic cavity. Surgery is the treatment of choice for symptomatic patients with substernal goiter. The majority of substernal goiters are resected through a cervical approach. However, in approximately 5% of patients, a thoracic approach is required. The most important factor determining whether a thoracic approach should be used is the depth of the extension to the tracheal bifurcation on CT imaging. CONCLUSION: Cardiac arrest appearing as the first symptom of a substernal goiter is a very rare condition and should be treated by emergency thyroidectomy via a cervical or thoracic approach depending on the CT imaging findings.

Total Pancreatectomy with Splenectomy for Multifocal Intraductal Tubulopapillary Neoplasm (ITPN) of the Pancreas Associated with Invasive Component: Report of a Rare Case.

BACKGROUND Pancreatic intraductal tubulopapillary neoplasm (ITPN) was first described by Yamaguchi in 2009 and was recognized by World Health Organization as a distinct entity in 2010. Since then few case reports and case series have been published. Little is known about its clinicopathologic features and treatment outcomes. We present the seventh case of total pancreatectomy for ITPN reported in the English literature. CASE REPORT Our patient was an 82-year-old male with a previous history of acute evolving-to-chronic pancreatitis. After 2 years of medical consultation, an abdominal magnetic resonance imaging was suspicious for multifocal pancreatic neoplasia. A computed tomography-guided biopsy of the lesion was performed which indicated pancreatic intraductal neoplasia with intermediate dysplasia. After oncology consultation, the patient underwent pylorus-preserving total pancreatectomy with splenectomy. The pathology report showed pancreatic ITPN with intermediate to severe dysplasia and associated invasive carcinoma. All 21 resected lymph nodes were non-metastatic (pT3N0). The postoperative course of the patient was uncomplicated. He received adjuvant gemcitabine (single agent) for 6 months. At 18 months after surgery he was diagnosed with hepatic metastases; he was still alive at the time of this reporting. CONCLUSIONS ITPN has been associated with previous history of acute pancreatitis in some patients. Early diagnosis, radical surgical resection, and adjuvant chemotherapy may lead to long-term survival rates even in cases with associated invasive component. Total pancreatectomy may be a preferable procedure for ITPN in selected patients.

Treatment of a Gastrointestinal Stromal Tumor (GIST) Adherent to the Spleen and the Tail of the Pancreas: A Case Report.

BACKGROUND Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal gastrointestinal tumors (GIT). Usually, they appear in patients ages 55-65 years, with no apparent difference between males and females. Their annual incidence is about 11-14 per 106. They generally do not present with any prominent symptoms, appearing with the atypical symptoms of abdominal pain, weight loss, early satiety, and occasionally bleeding. Adequate surgical treatment involves sphenoid resection of the tumor within clear margins. If adjacent organs are involved, en bloc resection is the procedure of choice. CASE REPORT A 62-year-old male patient presented to the Emergency Department complaining of melena for 1 week. He underwent gastroscopy, colonoscopy and abdominal computed tomography scan, which revealed a large, exophytic, lobular mass (12.6×9.7×12 cm) of the greater curvature of the stomach. The patient underwent en bloc sphenoid gastrectomy, splenectomy, and caudal pancreatectomy. The histopathologic examination revealed findings compatible with a gastrointestinal stromal tumor located at the stomach, with low-grade malignancy (G1) and T4N0 according to TNM classification. He was discharged from the hospital on the 7th postoperative day. CONCLUSIONS GISTs are uncommon tumors of the gastrointestinal system that usually do not invade neighboring organs or develop distant metastases; therefore, local resection is usually the treatment of choice. However, in cases of large GISTs that are adherent to neighboring organs, en bloc resection and resection of adjacent organs may be inevitable.

A Rare Coexistence of Medullary Thyroid Cancer with Graves Disease: A Case Report and Systematic Review of the Literature.

BACKGROUND Graves disease is occasionally associated with thyroid cancer. The most common histological type of thyroid cancer in patients with Graves disease is papillary followed by follicular. Medullary thyroid cancer and Graves disease have been reported simultaneously only in a few cases in the literature. CASE REPORT A case of coexistence of Graves disease and medullary thyroid cancer is described in this report. The patient was diagnosed with Graves disease 8 years ago. Although he had an initial successful treatment with carbimazole, in the last 2 years no steady euthyroid function was achieved. Total thyroidectomy was considered as the optimal treatment. An incidental medullary microcarcinoma with maximum diameter 0.5 cm was identified by pathology report. CONCLUSIONS Medullary thyroid cancer has been reported in patients with Graves disease in 15 cases, including the current case. Medullary thyroid cancer is aggressive, and a delayed diagnosis would be harmful. Hence, patients with Graves disease should be evaluated regularly by a thyroid specialist.

Thyroid nodules as a risk factor for thyroid cancer in patients with Graves' disease: A systematic review and meta-analysis of observational studies in surgically treated patients.

OBJECTIVE: Graves' disease (GD) is an autoimmune thyroid disorder characterized by hyperthyroidism. The incidence of thyroid cancer in patients with GD varies from 0.15% to 15%. There is conflicting evidence on the role of thyroid nodules as a risk factor for thyroid cancer in patients with GD. DESIGN: Three electronic databases (PubMed, Cochrane Library, Scopus) as well as grey literature sources were searched, from inception until 25 February 2019, for observational studies about the prevalence of thyroid cancer in patients with GD. PATIENTS: Clinical and ultrasonographic examination was necessary preoperatively for all patients to be classified depending on the presence/absence of thyroid nodules. MEASUREMENTS: Primary outcome was the incidence of thyroid cancer. The latter was determined after total or near-total thyroidectomy by the histopathologic report. Statistical analysis was performed with revman 5.3 software. RESULTS: The systematic review and meta-analysis included 7 studies with 2582 patients overall. The prevalence of any thyroid cancer was 11.5%. The presence of at least one thyroid nodule in patients with GD was associated with higher risk for thyroid cancer (odds ratio [OR] 5.3, 95% confidence interval [CI] 2.4-11.6, I2 83%). A subgroup analysis showed no difference in thyroid cancer risk in patients with GD according to the number of nodules (solitary versus multiple) (OR 1.4, 95% CI 0.9-2.3, I2 0%). CONCLUSIONS: The presence of thyroid nodules is positively associated with the prevalence of thyroid cancer in surgically treated patients with GD. However, further prospective research is needed as the heterogeneity among the studies is high.

Scar tissue to lung cancer; pathways and treatment.

Lung cancer still remains diagnosed at a late stage although we have novel diagnostic techniques at our disposal. However; for metastatic disease we have novel therapies based on pharmacogenomics. Tumor heterogenity provides us different treatments. There are several reasons for carcinogenesis; fibrosis and scar tissue provides an environment that induces malignancy. In the current review we will try and elucidate the pathways involved from scar tissue to carcinogenesis.

Radial probe endobronchial ultrasound assisted conventional transbronchial needle aspiration in the diagnosis of solitary peribronchial pulmonary lesion located in the segmental bronchi.

Background: The diagnosis of peribronchial pulmonary lesions located in the tertiary bronchi, also known as segmental bronchi, as well as, the 4th order and 5th order segmental bronchi is very difficult. Histopathological specimens cannot be easily obtained by endobronchial biopsies (EBBX) due to the patent but small segmental bronchial lumen. The aim of the present study was to evaluate the diagnostic accuracy and safety of the novel technique with radial probe endobronchial ultrasound (R-EBUS) assisted conventional transbronchial needle aspiration (C-TBNA) in the diagnosis of solitary peribronchial pulmonary lesions located in segmental bronchi from 3th to 5th order. Methods: From December 2014 to December 2015, 16 patients with solitary peribronchial pulmonary lesions in the segmental bronchi from 3th to 5th order confirmed by computed tomography (CT) were enrolled. The lesions were located using radial probe endobronchial ultrasound (R-EBUS) to determine the sites of conventional transbronchial needle aspiration (C-TBNA), then, histopathological specimens were obtained using the technique of C-TBNA. The final pathological diagnosis was made based on the findings from the surgical specimens. Statistical analyses were performed for specimen results and complications. Results: On pathological evaluation, 14 of the 16 specimens were malignant, including 8 adenocarcinomas, 4 squamous cell carcinomas, and 2 small cell carcinomas, while 2 were non-malignant diseases. The diagnostic accuracy rate, sensitivity and missed diagnosis rates were 87.5%, 87.5% and 12.5%, respectively. When Combined the results of cytology with histologic samples obtained from C-TBNA the total diagnostic accuracy rate, sensitivity and missed diagnosis rate were 93.75%, 93.75% and 6.25%, respectively. There were 2 cases of bleeding complications >5 mL after C-TBNA, and both were resolved with endobronchial management. Conclusions: The combination of R-EBUS with C-TBNA was advantageous and safe for the diagnosis of solitary peribronchial pulmonary lesions located in the segmental bronchi. However, possible bleeding complications should be anticipated with needle aspiration. Further verification of this combined application should be investigated in larger clinical trials.

Transformation of ALK expression and PD-L1 0% to PD-L1 90% only after surgery: the need for rebiopsy in lung cancer patients.

Lung cancer is still diagnosed at a late stage although novel diagnostic techniques are in use. However, as pharmacogenomics have evolved novel targeted therapies either with tyrosine kinase inhibitors or immunotherapy can be currently used as daily treatment. We present the case of a woman with anaplastic lymphoma-positive expression and programmed death-ligand 1 (PD-L1) 0% score upon diagnosis who underwent therapeutic surgery and represented PD-L1 90% expression, however, without anaplastic lymphoma kinase expression. Transformation of the tumor or new tumor is a question to be answered for this patient and possibly we should try and direct rebiopsies for this group of targeted therapy patients.

Rare Co-Existence of Amyand's and Littre's Hernia Treated with Appendectomy and Bowel Resection Followed by Polypropylene Mesh Application.

BACKGROUND Amyand's and Littre's hernias are 2 rare types of inguinal hernias, which constitute less than 1% of all types of hernias. Amyand's hernia is characterized mainly by the presence of a vermiform appendix in an inguinal hernia sac, whereas Littre's hernia includes a protrusion of a Meckel's diverticulum into the hernial sac. CASE REPORT In this article, we report a case of co-existence of Amyand's and Littre's hernia in the same sac of a groin hernia. To the best of our knowledge, this is the first case report of a patient with the appendix and Meckel's diverticulum inside the hernia sac. Although there was no sign of inflammation, we performed an incidental appendectomy and partial enterectomy. We continued with the repair process with polypropylene mesh using Lichtenstein technique. The patients showed no signs of complication or recurrence of the hernia within 1 year from the day of the surgery. CONCLUSIONS The aim of this article is to present for the first time the occurrence and the repair of a combined Amyand's and Littre's hernia. Additionally, in this study, we were the first to use polypropylene mesh to repair both hernias in an elderly patient after performing appendectomy and enterectomy, avoiding any complications or recurrence of the hernia 12 months following the surgery.

The cost of hospital treatment of advanced stage lung cancer patients in a developing South East European country.

Assessing the lung cancer treatment costs is necessary in order to estimate the budget impact of new interventions and therapeutic innovations. However, there are few studies regarding the use of resources and costs associated with treatment of lung cancer patients, not only in Serbia, but internationally. The aim of this paper was to assess the hospital costs of diagnosing and treating patients with stage IIIB and IV non-small cell lung cancer. Analysis of costs of care, services, medications and medical supplies, as well as of total hospital costs, was performed. Patients diagnosed with stage IIIB or IV NSCLC in the Institute during the year 2013 were enrolled in the study. A total of 187 patients with stage IIIB or IV NSCLC were analyzed. Total hospital costs were 506.970€, of which nearly two thirds was accounted to costs of services and medications. The mean cost per patient with adenocarcinoma was 3.075€, and for squamous cell lung carcinoma patient 1.943€. Statistically significant difference was shown when comparing mean hospital costs between patients in stage IIIB and stage IV adenocarcinoma, where this cost is higher in patients with stage IIIB. Mean hospital cost per female patient was nearly double as high that of the male patients, although without statistically significant difference. The mean cost for all adenocarcinoma patients was 1.317€, and for only four patients treated with TKI therapy 21.233€. This cost analysis could provide useful information in terms of budget impact of different lung cancer treatments and innovations in Serbia and corresponding developing countries.

Lung cancer induced from chemotherapy a 20 years old case.

Lung cancer is diagnosed at a late stage although we have novel diagnostic tools. The association of smoking and other environmental factors are well known. However; there are cases where a malignancy is associated with previous radiation treatment. There is an association between radiotherapy treatment and cancer incidence. We present a case where lung cancer and laryngeal cancer was induced 20 years after radiation therapy of a hogkin lymphoma.

New hybrid method for trachea dilatation with rigid and flexible tools.

Trachea stenosis is observed either in benign or malignant situations. In cancer malignancy a tumor might obstruct the central airway in three different ways. Again granuloma tissue is usually observed after intubation or stent placement in order to manage a benign malformation of the trachea. In any case there are several tools and techniques that can be used either with surgery or endoscopically to manage such situation. We will focus on a hybrid technique in order to ventilate the patient while performing endoscopic management of granuloma tissue.

Esophagus lyomyoma diagnosed with convex endobronchial ultrasound (EBUS).

Esophageal lyomyoma are rare benign tumors of the esophagus and they remain usually undiagnosed until local compression symptoms occur in the esophagus. Gastroscopy or esophageal ultrasonography (EUS) are usually the methods of choice for diagnosis. Moreover; surgery is the solution for this entity. In our case we present diagnosis of esophageal lyomyoma using convex probe endobronchial ultrasound (EBUS) with a fine needle aspiration of 22G.

Aerosol Immunotherapy with or without Cisplatin for metastatic lung cancer non-small cell lung cancer disease: In vivo Study. A more efficient combination.

Lung cancer is the leading cause of cancer death after prostate cancer for males and breast cancer for females. There are novel therapies in the past five years such as; tyrosine kinase inhibitors and most recently in the last two years immunotherapy. Immunotherapy is currently being investigated if it can be administered alone or in combination. Previously we have investigated whether immunotherapy compounds can be produced as aerosols, and in the current study we investigated the safety and efficiency independently of the programmed death-ligand 1. The aerosol administration of both cisplatin and nivolumab is possible. The combination of the two drugs has a synergistic effect and therefore should be considered an option. Time of administration for immunotherapy is also very important.

Monitoring changes in quality of life in patients with lung cancer under treatment with chemotherapy and co administration of zoledronic acid by using specialized questionnaires.

Background: Due to the severity of the primary disease in patients with lung cancer, quality of life (QoL) is often overlooked. Factors that form QoL should be taken in consideration when planning the appropriate treatment and determining therapy targets, because of the increasing frequency of bone metastasis leading to high levels of pain. Purpose of this study is to assess quality of life in patients with lung cancer, before and after treatment combined with zoledronic acid. Methods and materials: QoL was assessed in 80 patients (49 males-31 females), of which 45 developed bone metastasis. Prior and post treatment (with co administration of zoledronic acid) seven reliable scales: Pittsburgh Sleep Quality index (PSQI), Epworth Sleeping Scale (ess), Dyspnea Scale (ds), Fatigue Severity Scale (FSS), Brief Pain Inventory (BPI), Fact-G scale for sleep quality and EQ-5D for general health condition. Results: Statistically positive correlations were verified between PSQI-DS, PSQI-FSS, BPI-ESS, DS-FSS, DS-BPI and BPI-FSS (p<0,005) prior and post treatment. Patients sleep quality was improved, pain levels decreased and betterment in quality of life was marked (p<0,001). Although significant decrease in fatigue levels was observed (p<0,001) there has been an increase in dyspnea symptoms (p<0,001). Conclusions: Significant improvement was apparent when zoledronic acid was co administered in any treatment in patients with lung cancer. Sleep quality, fatigue and pain parameters also improved, with no positive impact on the symptoms of dyspnea.