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.

Preoperative Assessment of Perianal Fistulas with Combined Magnetic Resonance and Tridimensional Endoanal Ultrasound: A Prospective Study.

BACKGROUND: we designed a prospective study of diagnostic accuracy that compared pelvic MRI and 3D-EAUS with pelvic MRI alone in the preoperative evaluation and postoperative outcomes of patients with perianal fistulas. METHODS: the sample size was 72 patients and this was divided into two imaging groups. MRI alone was performed on the first group. Both MRI and 3D-EAUS were performed in parallel on the second group. Surgical exploration took place after two weeks and was the standard reference. Park's classification, the presence of a concomitant abscess or a secondary tract, and the location of the internal opening were recorded. All patients were re-evaluated for complete fistula healing and fecal incontinence six months postoperatively. All of the collected data were subjected to statistical analysis. RESULTS: the MRI group included 36 patients with 42 fistulas. The MRI + 3D-EAUS group included 36 patients with 46 fistulas. The adjusted sensitivity and negative predictive value were 1.00 for most fistula types in the group that underwent combined imaging. The adjusted specificity improved for intersphincteric fistulas in the same group. The adjusted balanced accuracy improved for all fistula types except rectovaginal. The combination of imaging methods showed improved diagnostic accuracy only in the detection of a secondary tract. The healing rate at six months was 100%. Fecal incontinence at six months did not present a statistically significant difference between the two groups (Fisher's exact test p-value > 0.9). Patients with complex perianal fistulas had a statistically significant higher probability of undergoing a second surgery (x2 test p-value = 0.019). CONCLUSIONS: the combination of pelvic MRI and 3D-EAUS showed improved metrics of diagnostic accuracy and should be used in the preoperative evaluation of all patients with perianal fistulas, especially those with complex types.

Phytobezoar-Induced Mechanical Ileus and Incipient Intussusception: A Case Report.

Phytobezoars constitute conglomerates of indigested plant fibers and are a rare cause of acute mechanical ileus. They exhibit an increased prevalence in the elderly population and people with specific predisposing conditions. Radiological imaging can often set a definitive diagnosis and dictate the optimal therapeutic approach, combined with the patient's clinical status. An 81-year-old male presented with deteriorating clinical symptoms of intestinal obstruction, and an exploratory laparotomy was performed following inconclusive radiological findings; multiple phytobezoars and incipient intussusception were revealed intraoperatively. A patient's medical history can often raise clinical suspicion of phytobezoars. However, a careful etiological investigation is imperative in all cases of mechanical ileus in advanced ages; early detection and dissolution of phytobezoars, when applicable, can reduce the need for surgical interventions.

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.

An Easily Missed But Life-Threatening Diagnosis: A Case Report of Gorlin Syndrome.

BACKGROUND Gorlin syndrome, also known as basal cell nevus syndrome (BCNS), nevoid basal cell carcinoma syndrome (NBCCS), and Jaw cyst-Basal cell nevus-Bifid rib syndrome, is a rare multisystemic syndrome that can affect a remarkable number of tissues and organs in the human body. Patients with this syndrome are in jeopardy of developing basal cell skin cancer during puberty or early adulthood. CASE REPORT Herein, we report a case of a 58-year-old woman who had multiple pigmented skin lesions and a palpable tumor of the left scapula. The patient underwent surgical excision of the above-mentioned lesions. The histopathological examination revealed that 10 of them were basal cell skin carcinomas (BCCs); therefore, the patient was proven to have the syndrome. She had a history of similar skin lesions, which were removed before the age of 20. CONCLUSIONS This case highlights that rare phenomena, such as the presence of multiple BCCs, require additional investigations and a multidisciplinary approach since a rare and potentially life-threating condition might be the underlying cause. Early diagnosis of Gorlin syndrome is of paramount importance to facilitate the appropriate therapeutic approach, as directed by a multidisciplinary team. Patients with multiple skin lesions need to have regular assessments by their general practitioner or dermatologist, with dermoscopy serving as an important preventive measure. Furthermore, because pathogenesis of the syndrome is characterized by development of basal cell carcinomas, consecutive follow-up is of a great significance.

HPV-Induced Anal and Peri-Anal Neoplasia, a Surgeon's Experience: 5-Year Case Series.

Purpose: One of the most known sexually transmitted diseases is Condylomata acuminata (CA), a skin lesion occurring due to infection from Human Papilloma Virus (HPV). CA has a typical appearance of raised, skin-colored papules ranging in size from 1 mm to 5 mm. These lesions often form cauliflower-like plaques. Depending on the involved HPV-subtype (either high-risk or low-risk) and its malignant potential, these lesions are likely to lead to malignant transformation when specific HPV subtypes and other risk factors are present. Therefore, high clinical suspicion is required when examining the anal and perianal area. Methods: In this article, the authors aim to present the results of a five-year case series (2016-2021) of anal and perianal cases of CA. Results: A total of 35 patients were included in this study. Patients were categorized based on specific criteria, which included gender, sex preferences, and human immunodeficiency virus infection. All patients underwent proctoscopy and excision biopsies were obtained. Based on dysplasia grade patients were further categorized. The group of patients where high-dysplasia squamous cell carcinoma was present was initially treated with chemoradiotherapy. Abdominoperineal resection was necessary in five cases after local recurrence. Conclusions: CA remains a serious condition where several treatment options are available if detected early. Delay in diagnosis can lead to malignant transformation, often leaving abdominoperineal resection as the only option. Vaccination against HPV poses a key role in eliminating the transmission of the virus, and thus the prevalence of CA.

The Associations of Dietary Vitamin K Intake and Circulating Vitamin 25(OH)D with Serum Lipoprotein Levels: The Vitamin Deficiency Matters.

A synergistic interplay between vitamins K and D appears to exist. We aimed to investigate for the first time whether the associations of dietary vitamin K intake and circulating 25(OH)D with serum lipoprotein levels are influenced by the existence of deficiency of either or both vitamins K and D. Sixty individuals [24 males, 36(18-79) years old] were examined. Vitamin deficiency of K1 and D were defined as vitamin K1 intake/body weight (BW)<1.00 µg/kg/day and circulating 25(OH)D<20 ng/ml, respectively. In individuals with vitamin K1 deficiency, the vitamin K1 intake/BW correlated positively with high density lipoprotein-cholesterol (HDL-C) (r=0.509, p=0.008) and negatively with serum triglycerides (TG) (r=-0.638, p=0.001), whereas circulating 25(OH)D correlated negatively with TG (r=-0.609, p=0.001). In individuals with vitamin D deficiency, the vitamin K1 intake/BW correlated positively with HDL-C (r=0.533, p=0.001) and negatively with TG (r=-0.421, p=0.009), while circulating 25(OH)D correlated negatively with TG (r=-0.458, p=0.004). The above-mentioned associations of vitamin K1 intake/BW and circulating 25(OH)D with serum lipoproteins were not detected in individuals without vitamin K1 deficiency or the ones without vitamin D deficiency. The vitamin K2 intake/BW correlated negatively with low density lipoprotein-cholesterol (LDL-C) (r=-0.404, p=0.001). In conclusion, the associations of vitamin K1 intake with TG and HDL-C and of circulating 25(OH)D with TG were more pronounced in individuals with deficiency of either or both vitamins K1 and D. Increased dietary vitamin K2 intake was associated with decreased LDL-C.

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.

Idiopathic Multicentric Castleman Disease with Cutaneous Manifestation: Case Report.

Castleman disease constitutes a rare class of lymphoproliferative disorders, with an estimated incidence of 21 to 25 per million patient years. The idiopathic subtype exhibits a significantly diverse clinical presentation, which can imitate many autoimmune, malignant, and infectious diseases. Cutaneous manifestations are uncommon and require in-depth investigation, especially when concurrent lymphadenopathy is present. A 79-year-old female, with a chronic, complicated erysipelas-like lesion, presented with bilaterally enlarged inguinal lymph nodes; after surgical excision, their histopathological examination revealed Castleman disease. Even though it is a benign condition, patients are often predisposed to developing certain types of malignancies, which can deteriorate their prognosis. An accurate and early diagnosis, along with effective treatment and prevention of recurrence, is of utmost importance in order to increase the patients' overall survival and quality of life.

Perianal fistulas: A review with emphasis on preoperative imaging.

PURPOSE: We aim to present a comprehensive literature review which focuses on the preoperative imaging of perianal fistulas. MATERIAL/METHODS: Pelvic magnetic resonance imaging (MRI) and endoanal ultrasound (EAUS) are the two first-line imaging modalities for the preoperative evaluation of patients with perianal fistulas. We conducted a search in PubMed, Scopus and Google Scholar concerning articles comparing pelvic MRI with EAUS, which were published from 1994 until 2019. RESULTS: In most articles, pelvic MRI is superior to EAUS for the evaluation of perianal fistulas (especially for supralevator and extrasphincteric ones). Preoperative pelvic MRI is associated with statistically significant better results and prognosis after surgical treatment of the disease. Preoperative EAUS poses high sensitivity and specificity in identifying intersphincteric and transsphincteric perianal fistulas, as well as the internal opening of a fistula-in-ano. There is only one meta-analysis which compares the diagnostic accuracy of the two mentioned imaging modalities in preoperative fistula detection. Sensitivity of both - pelvic MRI and EAUS, is acceptably high (0.87). Specificity of pelvic MRI is 0.69 in comparison to EAUS (0.43), but both values are considered low. CONCLUSIONS: Future well-designed prospective studies are needed to investigate the diagnostic accuracy of pelvic MRI and EAUS in the preoperative assessment of patients with perianal fistulas. Moreover, the combination of pelvic MRI and EAUS should also be studied, since several published articles suggest that it could lead to improved diagnostic accuracy. A novel treatment algorithm for perianal fistulas could arise from this study.

Extramammary Paget's Disease of the Vulva: Report of Two Cases.

Extramammary Paget's disease is a rare condition, affecting 6.5% of all patients with Paget's disease. The most common extramammary site is the vulvar area. Although diagnosis in some patients is difficult to set, early diagnosis is of high importance in order to detect the irreversible progression of the lesion early and prevent distant metastasis. An 89-year-old female and a 69-year-old female presented within three months with an eczematous lesion with leukoplakia in the vulva. The incisional biopsy of the skin revealed extramammary Paget's disease. Both patients underwent a surgical wide local excision of the lesion and the specimens were sent for histopathological examination. Extramammary Paget's disease has a high potential for distant malignancies and local recurrence, dictating that surgical excision is the most efficient treatment. The rareness of the condition and the diagnostic difficulties underline the need for early skin biopsy, which is the most efficient diagnostic tool.

A critical review of the effects of vitamin K on glucose and lipid homeostasis: its potential role in the prevention and management of type 2 diabetes.

In recent years, our knowledge regarding the physiological role of vitamin K has expanded beyond regulation of coagulation to include many other aspects of human health. In the present review, we aimed to evaluate the existing evidence for beneficial effects of vitamin K on type 2 diabetes and components of the metabolic syndrome as risk factors for cardiovascular disease. Increased dietary intake of vitamin K has been linked to lower incidence of type 2 diabetes mellitus (T2DM), possibly through its enhancement of insulin production and sensitivity. Additionally, higher plasma levels of vitamin K1 have been associated with lower T2DM risk and decreased insulin resistance, and supplementation trials also suggest a positive influence of vitamin K on glucose regulation. Vitamin K might also beneficially affect serum lipids and lipid metabolism. However, the available data remain controversial. Additionally, different studies use different approaches to assess vitamin K status owing to the absence of a generally accepted marker, which further complicates data evaluation. In conclusion, vitamin K possibly improves glucose and lipid metabolism and could be an emerging target in the context of prevention and control of T2DM, insulin resistance, and dyslipidemia.

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.

Management of low rectal gastrointestinal stromal tumor with neoadjuvant therapy and transanal excision: a rare case report and review of the literature.

BACKGROUND: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. However, rectal GISTs represent only 5% of this category. We report a case of a rectal GIST treated with local excision after neoadjuvant therapy. CASE PRESENTATION: A 41-year-old male patient presented with anal bleeding. Colonoscopy revealed a mass located 5 cm from the anal verge. Histological examination showed a GIST with immunohistochemical positivity for CD117 and CD34. Transanal local excision was performed after neoadjuvant therapy. CONCLUSION: Neoadjuvant immunotherapy for GISTs with unfavorable localization may facilitate local excision and avoid complications of more demanding operations.

Primary hepatocellular carcinoma in a patient with history of treated breast cancer: a case report with challenging diagnosis and treatment.

INTRODUCTION: Breast cancer is the most common malignancy in women worldwide. Long-term survivors among patients treated for breast cancer are at a high risk for developing a second primary malignancy. Hepatocellular carcinoma is the most frequent primary hepatic malignancy and should be ruled out in breast cancer patients who are diagnosed with solitary hepatic lesions. False diagnosis may lead to inappropriate oncologic staging and treatment of the disease. CASE PRESENTATION: We present the case of a 73-year-old female patient who had been treated for invasive ductal breast cancer 7 years ago and was diagnosed with a solid hepatic lesion at segments VI and VII and a small, calcified lesion at the tail of the pancreas on follow-up with an abdominal computed tomography. Oncology council decided that both lesions could be resected after determining whether they were metastatic or second primary malignancies. The patient underwent laparotomy and rapid biopsy which showed primary hepatocellular carcinoma and fibrosis of the pancreas. We performed hepatic segmentectomy (VI-VII) and cholecystectomy, while the pancreatic lesion was left intact. The postoperative course of the patient was uncomplicated and she remains disease free 2 years after the operation without any adjuvant therapy. CONCLUSION: All hepatic lesions detected in breast cancer patients should be evaluated with open mind and liver biopsy should be performed to get a definitive diagnosis and implement the proper treatment strategy.

Endoscopically Assisted Laparoscopic Gastric Resection for Benign and Malignant Lesions: A Report of Two Cases.

BACKGROUND The first gastric resection for stomach cancer was performed in 1879, and the first gastric resection for gastric ulcer disease was performed in 1882. During the 1990s, the first laparoscopic gastrostomies were reported. During the past decade, laparoscopic techniques have developed rapidly, gaining wide clinical acceptance. Minimally invasive surgery is now shifting the balance away from traditional open methods. We report 2 cases of endoscopically assisted laparoscopic local gastric resections for both gastric cancer and gastric ulcer disease. CASE REPORT The first case involves a 67-year-old male patient who suffered from recurrent bleeding from a gastric ulcer located 4-5 cm from the gastroesophageal junction. The patient was subjected to endoscopically assisted laparoscopic wedge resection of the affected part of the stomach, had an uneventful recovery and was discharged on the third postoperative day. The second case involves a 60-year-old female patient who was diagnosed with intramucosal gastric adenocarcinoma and was also subjected to endoscopically assisted laparoscopic wedge gastrectomy. This patient also had an uneventful recovery and was discharged on the second postoperative day. CONCLUSIONS Endoscopically assisted laparoscopic local gastric resection is a minimally invasive procedure which allows the surgeon to operate under direct visualization of the internal part of the stomach. Thus, it enables the surgeon to safely remove the affected part within healthy margins, providing the patient with all the advantages of laparoscopic surgery.

Interferon-γ and Colorectal Cancer: an up-to date.

Colorectal cancer still remains the third cause of cancer death among cancer patients. Early diagnosis is crucial and they can be either endoscopic or with blood biomarkers. Endoscopic methods consist of gastroscopy and colonoscopy, however; in recent years, endoscopic ultrasound is being used. The microenvironment is very important for the successful delivery of the treatment. Several proteins and hormones play a crucial role in the efficiency of the treatment. In the current mini review we will focus on interferon-γ.

Episode of Familial Mediterranean Fever-Related Peritonitis in the Second Trimester of Pregnancy Followed by Acute Cholecystitis: Dilemmas and Pitfalls.

BACKGROUND: Differential diagnosis of acute abdomen in pregnant patients is one of the greatest challenges for the clinician. Occurrence of Familial Mediterranean Fever (FMF) paroxysm of peritonitis and acute cholecystitis during pregnancy is a unique clinical entity that leads to serious diagnostic and therapeutic dilemmas. CASE REPORT: We present the case of a 33-year-old Armenian patient at 16 weeks' gestational age with a history of FMF, who was admitted twice within 1 month with acute abdomen. The first episode was attributed to FMF and successfully treated conservatively with colchicine. The second episode was diagnosed as acute cholecystitis and led to emergent laparoscopic cholecystectomy and lysis of peritoneal adhesions from previous FMF attacks. The patient presented an uneventful postoperative clinical course and had a normal delivery of a healthy infant at the 39th week of gestation. CONCLUSIONS: Pregnant patients with acute abdomen should be evaluated with open mind. To the best of our knowledge, this is the first published report of the coexistence of 2 different causes of acute abdomen during pregnancy. Meticulous history and thorough physical, laboratory, and radiologic examination are the keys to reach a correct diagnosis. Treatment of pregnant patients with acute abdomen should be individualized. Administration of colchicine should be continued during conception, pregnancy, and lactation in patients with FMF history. Laparoscopic intervention in pregnant patients with surgical abdomen such as acute cholecystitis is the optimal method of treatment.