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.

Immunoengineering via Chimeric Antigen Receptor-T Cell Therapy: Reprogramming Nanodrug Delivery.

Following its therapeutic effect in hematological metastasis, chimeric antigen receptor (CAR) T cell therapy has gained a great deal of attention during the last years. However, the effectiveness of this treatment has been hampered by a number of challenges, including significant toxicities, difficult access to tumor locations, inadequate therapeutic persistence, and manufacturing problems. Developing novel techniques to produce effective CARs, administer them, and monitor their anti-tumor activity in CAR-T cell treatment is undoubtedly necessary. Exploiting the advantages of nanotechnology may possibly be a useful strategy to increase the efficacy of CAR-T cell treatment. This study outlines the current drawbacks of CAR-T immunotherapy and identifies promising developments and significant benefits of using nanotechnology in order to introduce CAR transgene motifs into primary T cells, promote T cell expansion, enhance T cell trafficking, promote intrinsic T cell activity and rewire the immunosuppressive cellular and vascular microenvironments. Therefore, the development of powerful CART cells can be made possible with genetic and functional alterations supported by nanotechnology. In this review, we discuss the innovative and possible uses of nanotechnology for clinical translation, including the delivery, engineering, execution, and modulation of immune functions to enhance and optimize the anti-tumor efficacy of CAR-T cell treatment.

Tumor cell metabolic reprogramming and hypoxic immunosuppression: driving carcinogenesis to metastatic colonization.

A significant factor in the antitumor immune response is the increased metabolic reprogramming of immunological and malignant cells. Increasing data points to the fact that cancer metabolism affects not just cancer signaling, which is essential for maintaining carcinogenesis and survival, but also the expression of immune cells and immune-related factors such as lactate, PGE2, arginine, IDO, which regulate the antitumor immune signaling mechanism. In reality, this energetic interaction between the immune system and the tumor results in metabolic competition in the tumor ecosystem, limiting the amount of nutrients available and causing microenvironmental acidosis, which impairs the ability of immune cells to operate. More intriguingly, different types of immune cells use metabolic reprogramming to keep the body and self in a state of homeostasis. The process of immune cell proliferation, differentiation, and performance of effector functions, which is crucial to the immune response, are currently being linked to metabolic reprogramming. Here, we cover the regulation of the antitumor immune response by metabolic reprogramming in cancer cells and immune cells as well as potential strategies for metabolic pathway targeting in the context of anticancer immunotherapy. We also discuss prospective immunotherapy-metabolic intervention combinations that might be utilized to maximize the effectiveness of current immunotherapy regimes.

Ultrasound detected prenatal hyperechoic lung lesions and concordance with postnatal findings: A common aspect for multiple diagnoses.

OBJECTIVE: Hyperechoic lung lesions are largely detected prenatally but their underlying etiology is still poorly defined. The aim of the study was to determine the concordance between pre and postnatal diagnosis of hyperechoic lung lesions. METHODS: Prenatal ultrasound (US) evaluation was performed by a fetal medicine specialist. Postnatal diagnosis was based on CT-scan. Pre- and postnatal features were retrieved from medical charts. RESULTS: Seventy five patients were included from January 2009 to December 2018. Main prenatal diagnoses were bronchopulmonary sequestrations (BPS) (n = 24%-32%), pulmonary cystic malformations (PCM) (n = 19%-25%), congenital lobar emphysemas (CLE) (n = 15%-20%). Mediastinal shift was observed in 18 cases (24%). The prenatal detection of a systemic arterial supply had a diagnostic accuracy of 90%, while the prenatal detection of a cystic component had a diagnostic accuracy of 76.5%. All 16 neonates with prenatal isolated mediastinal shift were asymptomatic at birth. Seven neonates showed respiratory distress that was not predicted prenatally. CONCLUSIONS: Hyperechoic lung malformations reflect a heterogeneous group of lesions with a good concordance for bronchopulmonary sequestration, but not a satisfying prediction for cystic lesions.

A Bilateral, Non-syndromic, Type III Second Branchial Arch Sinus in a Neonate: a Case Report.

The incidence of a second branchial arch sinus accounts for 26-60% of all existing congenital malformations deriving from the branchial apparatus. They are most usually detected between 14 months and 7 years of age, while their incidence during neonatal period and infancy accounts for 0.06% of all cases. The aim of this case study is to emphasize three rare characteristic features: the manifestation during neonatal period, the bilateral localization and the ultrasonographic diagnostic documentation. A 25 days old girl was admitted by her parents due to the presence of mucoid excretion from two small openings found on the neck. These openings were found bilaterally, between the mid and lower third of the anterior border of sternocleidomastoid muscle. Diagnosis was confirmed via ultrasonography. The patient underwent elective surgery during early infancy and both branchial fistulas were excised. Patient's postoperative course was uneventful. IN CONCLUSION: - in cases of a bilateral second branchial arch sinus, the branchio-oto-renal (BOR) or branchio-otic (BO) syndromes must be excluded; - ultrasound scan can be used for the thorough evaluation of the sinus anatomic course and the relationship with the adjacent anatomic structures; - rompt diagnosis and early therapeutic intervention, even during neonatal period, ensures an uneventful post-operation course.

Bronchopulmonary sequestrations in a paediatric centre: ongoing practices and debated management.

OBJECTIVES: Bronchopulmonary sequestration (BPS) is the second most common congenital lung malformation, with an estimated incidence ranging from 0.15% to 1.8%. Surgical treatment is elective in patients with symptoms, but the management of asymptomatic patients remains controversial. METHODS: We retrospectively reviewed the medical records of 99 patients treated for BPS in our institution from January 2000 to December 2015. BPS was diagnosed prenatally in 86 (87%) cases. Management throughout this 16-year period was based on 3 interventions: resection by open surgery, resection by thoracoscopy and embolization. RESULTS: Among the 86 patients with a prenatal diagnosis of BPS, 14% had symptoms at birth and 10% had delayed symptoms at a median delay of 8 months (4.5-42 months). For the other 13 patients, symptoms occurred at a median age of 34 months (range 3-96 months). Embolization of the feeding vessel was performed in 46 patients with 6 secondary surgical resections (13%). A total of 59 patients were operated on: 23 cases by open surgery and 36 cases by thoracoscopy. The mean hospitalization stay was significantly longer for open surgery: 4.8 ± 1.3 days vs 4.1 ±1.5 days, respectively (P = 0.03). Differences in hospitalization stay were also found between asymptomatic and symptomatic patients: 3.5 ± 1.2 vs 5.1 ±1.6 days, respectively (P = 0.002). Two of the operated patients died. CONCLUSIONS: When surgery is chosen, thoracoscopy appears to be a valuable procedure. A better understanding of the natural history of BPS is still needed to define the optimal management and the respective roles of surgery, embolization or non-interventional follow-up.

Acute primary mesenteroaxial gastric volvulus in a 6 years old child; the contribution of ultrasonographic findings to the prompt diagnosis (a case report and review of the literature).

The aim of the present case study is to raise concern on the proper diagnostic approach of acute gastric volvulus (AGV) cases, in which, the key issue is the timely diagnosis and the prompt therapeutic intervention. After thorough and systematic research of the current literature, it is concluded that early diagnosis remains challenging, while there is no relevant publication with emphasis on the contribution of ultrasonography to the diagnostic documentation of AGV. A 6 years old boy was admitted to our Department due to repeatedly non bilious vomiting and food refusal during the last 72 hours before admission. Physical examination revealed the presence of a spherical, painful mass in the epigastrium, which did not recede a er placement of a nasogastric tube. Abdominal radiography showed the presence of a large gastric air bubble. Ultrasonography highlighted a distended and fluid-filled stomach, which was displaced in a cephalic position compared to esophagus and a pylorus pointing downward, in a cranial caudal orientation. Following barium meal examination confirmed the diagnosis of gastric volvulus. Patient underwent an urgent exploratory laparotomy, revealing the presence of acute mesenteroaxial gastric volvulus with a serosal ecchymosis in the major arc. After restoration of the gastric volvulus, thorough intraoperative investigation on the existence of a subject cause followed. Presence of relaxation of stomach's ligaments was finally documented. Fixation of the stomach' fundus to the diaphragm and anterior gastropexy were then conducted. Postoperative period was uneventful and the patient was discharged home on the 4th postoperative day. In conclusion, we believe that ultrasonography plays a significant role in the diagnostic approach of acute gastric volvulus, as it has the potential to detect findings suggestive of the diagnosis. Once the diagnosis is suspected on ultrasonography, contrast series should be performed, without further delay, in order to con rm the diagnosis.

Transient testicular torsion: from early diagnosis to appropriate therapeutic intervention (a prospective clinical study).

Transient testicular torsion (TTT) occurs when the torsion of the spermatic cord is reversed automatically within few minutes, with subsequent restoration of the blood ow to the suffering testis. e main clinical manifestation is acute scrotal pain, which resolves within a short period of time, usually few minutes. In 25% of patients su er from nausea and vomiting, besides the scrotal discomfort. Episodes of torsion can be repeated 1-30 times, leading progressively to development of ischemic trauma of the testis, while in 30-61% of all cases they constitute a precursor of testicular torsion. From January, 2016 to December, 2016, 11 patients in total were admitted to the Emergency Department due to acute scrotal pain that lasted a few minutes (1-5 minutes in most), which had already elapsed at the time of their admission, accompanied with nausea in all patients and vomiting in 5 of them. No swelling or rubor of the scrotum was revealed during physical examination, while in 9 patients it was observed that the suffering testis had transverse orientation. Ultrasonography was negative for pseudotumor or Whirlpool sign, while transverse orientation of the testis was confirmed in 9 patients. All the patients underwent surgical investigation of the suffering hemiscrotum, while Bell Clapper Deformity was found in 9 patients. Fixation of the suffering testis to the mesoscrotal diaphragm with 3 separate sutures by using non-absorbable suture followed. By the same surgical approach, the contralateral hemiscrotum was also investigated. Bilateral high adhesion of the tunica vaginalis was found in 8 out of 9 patients, in whom preventive unilateral orchidopexy was performed. All the patients are followed-up on a 6-month basis, without report of a similar, transient episode of acute scrotal pain. TTT should always be included in differential diagnosis in cases of acute scrotal pain in the past, with transverse orientation of the suffering testis. Prompt diagnosis and early treatment of the subject anatomic deformity (Bell Clapper Deformity) prevents the ischemic consequences on testicular parenchyma due to either recurrent episode of TTT or as a consequence of intravaginal testicular torsion.

Epididymal Adenomatoid Tumor: A Very Rare Paratesticular Tumor of Childhood.

Adenomatoid tumor is an uncommon benign mesothelial neoplasm, usually localized in the epididymis. It is the most common paratesticular tumor of middle-aged patients (average age of clinical presentation: 36 years). However, these tumors in pediatric and pubertal patients are extremely rare. Due to their rarity, we present a case of adenomatoid tumor of the tail of the epididymis in a 16-year-old patient. After systematic research of the current literature, we did not find another case report of epididymal adenomatoid tumor in a male patient aged 16 years old or less. This notice and our concern, as well, about the patient's surveillance protocol during the postoperative period were the motive for this case study.

Multiple Gastric Erosion Early after a 3 V Lithium Battery (CR2025) Ingestion in an 18-Month-Old Male Patient: Consideration about the Proper Time of Intervention.

Introduction. Button battery ingestion is considered an emergency situation in pediatric patients that needs to be managed promptly; otherwise, it may lead to serious and potentially lethal complications, especially when it is impacted in the esophagus. Less attention has been given in cases where the battery passes into the stomach, with guidelines for emergency intervention being based on the presence of symptoms. Case Report. We present a case of an 18-month-old male patient who presented to our emergency department after button battery ingestion. He did not have any symptoms and no pathological findings were encountered during clinical examination. X-ray investigation revealed the presence of the battery in the stomach. The patient was admitted for observation and two hours later he had two episodes of vomiting. He underwent urgent endoscopic removal of the battery where multiple acute gastric mucosal erosion in place of direct contact of the battery's negative pole with the mucosa of the gastric antrum was found. Conclusion. In specific cases the urgent endoscopic intervention for removal of an ingested button battery that is located in the stomach even in asymptomatic patients should be suggested.

Ulcerated Scrotal Hemangioma in an 18-Month-Old Male Patient: A Case Report and Review of the Literature.

Deep scrotal hemangiomas are rare. Less than 50 case reports have been published. After systematic research of the literature, we found less than 5 cases of ulcerated scrotal hemangioma. The aim of this case report is to illustrate the challenges of scrotal hemangiomas pose and their potential therapies based on the successful surgical treatment of an ulcerated scrotal hemangioma in an 18-month-old male patient.

Clinical Study of 23 Male Patients with Congenital Ventral Penile Angulation without Hypospadias.

Congenital ventral penile angulation without hypospadias is a rare disease and causes great anxiety to the parents. The aim of our study is the presentation of this disease, especially the indications of surgical treatment and the protocol applied in our clinic. We retrospectively studied 23 male patients aged 2.5 to 7 years old (av 5.2 y) with important penile angulation (over 45°) without hypospadias, treated during the past 15 years in our department. In 9 patients the cause was the skin chordee (fibrosis of the ventral part of the prepuce), in 4 the fibrotic fascia (incomplete development of dartos and Buck's fascia) and in 10 the disproportion of the corpora cavernosa. No case of congenital short urethra was reported. In our opinion, the appliance of the algorithm suggested by Donnahoo KK et al. in uncomplicated cases, along with the experience of the surgical team, results in satisfactory treatment and avoidance of complications.

Lower esophageal sphincter relaxation by administrating hyoscine-N-butylbromide for esophageal impaction by coin - shaped foreign bodies; prospective clinical study in pediatric population.

Aim of the present study is the presentation of our experience in conservative treatment of coin-shaped, ingested foreign bodies in lower esophagus and the consideration about the indications of this method's appliance in clinical practice. From 2011 to 2014, 79 children in total (45 male - 34 female), aged from 8 months to 13 years (average 4.8 years) were admitted to our Department due to foreign body ingestion. In 21/79 patients the foreign body lodged in the esophagus, in 9 in the upper and in 12 in the lower esophagus. Cases of pre-existing esophageal stricture or of esophageal obstruction, due to sharp or linear foreign bodies or disk battery, were excluded. Finally, our study group consisted of 11 patients, aged from 10 months to 10 years (aver- age 4.6 years). The average time elapsed from the ingestion of the foreign body until the admission of the child in the Emergency Department was 4 hours. Young patients were administered suppository form of hyoscine-N-butylbromide, followed by repetition of radiograph 6 hours later. In 9 cases the ingested foreign body passed to the stomach within the first six hours, while in 2 cases no alteration of its position was noted, thus endoscopic removal followed. In these 9 cases the foreign body passed through the gastrointestinal (GI) tract and was excreted within the next 1-3 days. Smooth muscle relaxation of the lower esophageal sphincter after administration of hyoscine-N-butylbromide was successful in 82% of our patients, while the success rate in relevant publications ranges from 20 to 42%. In conclusion, it is worth noting that the pharmaceutical relaxation of the lower esophageal sphincter is a safe alternative method of treatment in cases of foreign bodies lodged in the lower esophagus, except for linear or sharp objects or coin batteries. Given that the majority of hospitals in Northern Greece lacks of pediatric gastroenterologists, while endoscopic intervention - when indicated - should be conducted early after admission, it is obvious that the proposed method becomes essential.

Increased anxiety level and high salivary and serum cortisol concentrations in patients with recurrent aphthous stomatitis.

Recurrent aphthous stomatitis (RAS) is one of the most common oral mucosal disorders. The aim of the study was to determine any association between anxiety levels and concentrations of salivary and serum cortisol in patients with RAS. It has been suggested that stress with its presumed effects on the immune system, constitutes one of the major causative agents of RAS. The concentrations of salivary and serum cortisol were measured in 38 patients with recurrent aphthous stomatitis, and 38 healthy controls. Salivary and serum cortisol levels were measured using a Luminenscent Immunoassay (LIA) method. Anxiety levels were evaluated using Spielberger's State-Trait Anxiety Inventory which measures both trait anxiety as a general aspect of personality (STAI-T) and state anxiety as a response to a specific situation (STAI-S). The salivary cortisol levels were 1.44 (+/- 0.58) microg dl(-1) in RAS patients and 0.91 (+/- 0.56) microg dl(-1) in controls (p = 0.001), while the serum cortisol levels were 3.13 (+/- 1.59) microg dl(-1) in RAS patients and 1.89 (+/- 1.11) microg dl(-1) in controls (p = 0.001). The state anxiety levels (STAI-S) were 48.85 (+/- 9.7) in RAS group and 39.45 (+/- 7.5) in control group (p = 0.001). The trait anxiety levels (STAI-T) were 49.78 (+/- 13.02) in RAS group and 38.49 (+/- 10.31) in control group (p = 0.001). Salivary and serum cortisol concentrations and state and trait anxiety levels in RAS were significantly higher than those in the control group. Our results suggest that stress may be involved in the pathogenesis of RAS.