Normal Antigen Research Articles

Abstract 6225: Developing a novel combination therapy using engineered chimeric antigen receptor natural killer cells targeting avsialidase with avsialidase-armed oncolytic vaccinia virus in solid tumor models

Abstract Chimeric antigen receptor (CAR) - engineered natural killer (NK) cell therapy has emerged as a promising platform for adoptive immunotherapy for cancer. However, CAR-NK or CAR-T therapy so far has achieved limited efficacy in solid tumors compared with hematologic malignancies. One of the challenges is the lack of prevalent tumor-specific surface antigen target in solid tumors. Hence, we are developing a novel oncolytic vaccinia virus (VV) to deliver a dual functional glycol-immune checkpoint inhibitor and universal tumor cell marker combined with CAR-NK cell therapy to increase anti-tumor efficacy. Using the vaccinia virus deleted in both viral TK and VGF genes (vvDD) to drive the expression of a membrane-bound sialidase derived from actinomyces viscosus (avSial) under the viral late promoter, we observed efficient desialylation of both VV-infected and non-infected tumor cells, which would alleviate the suppression of sialic acid on NK and other immune cells within TME. Further, the surface bound avSial on VV-infected tumor cells can also serve as a universal target for avSial-CAR NK cells, with less concern for cross-reactivity to normal human tissues and antigen loss. We developed anti-avSial antibodies through mice immunization study. The selected single chain variable fragments (scFV) were constructed in CAR format containing CD28 CD3 ζ for co-stimulation and human IL-15 gene for better NK persistence and function. The binding affinity of anti-avSial scFv to avSialidase were further screened in CAR constructs-transfected 293T cells. The selected anti-avSial scFv CAR were packaged into gamma retroviral vectors to transduce activated and expanded NK cells derived from healthy donor peripheral blood. For proof-of-concept, target tumor cell lines A375, A549 and HT-29 expressing transmembrane sialidase and GFP were also generated. Compared with CD19 CAR NK and none transduced (NT) NK cells, avSial CAR NK had markedly increased cytotoxicity against avSial-expressing tumor cells in co-culture assays at low E:T ratios <= 1:2. Upon tumor cell rechallenge, avSial CAR NK also controlled the tumor growth significantly better than CD19 CAR NK or NT NK cells. Furthermore, avSial CAR NK completely eliminated A375 tumor spheroids expressing transmembrane sialidase whereas CD19 CAR NK or NT NK cells only transiently controlled the tumor spheroids growth. Taken together, we have developed an effective avSial targeting CAR IL15 NK that will be used to demonstrate enhanced efficacy and versatility in combination with avSial-armed VV for treatment of solid tumors. Citation Format: Xiaomei Wang, Guowei Wei, Keshav B. Karki, Winnie Chan, Mariya Viskovska, Andrew Williams, Nancy Chang, Haiyan Jiang. Developing a novel combination therapy using engineered chimeric antigen receptor natural killer cells targeting avsialidase with avsialidase-armed oncolytic vaccinia virus in solid tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6225.

Prognostic Impact of Pathology, Cytoreduction, and Tumor Markers in Pseudomyxoma Peritonei.

The pathologic classification of pseudomyxoma peritonei is controversial. This study aimed to standardize the histopathological evaluation of pseudomyxoma peritonei and identify the clinicopathological factors associated with survival. A pathologic review was performed to systematize the pathology report and verify the relationship between clinical features and survival. Terminology was based on the World Health Organization and Peritoneal Surface Oncology Group International definitions. Preoperative serum levels of carcinoembryonic antigen, CA19-9, and CA-125 were evaluated to determine their association with overall survival (OS) and ability to predict CC0-1 cytoreduction. Among 109 patients with carcinomas resulting from primary appendiceal neoplasms, 72 had pseudomyxoma peritonei of appendiceal origin and underwent debulking surgery. CC0-1 cytoreduction and CC2-3 cytoreduction were achieved in 61% and 39% of patients, respectively. Patients in the CC0-1 and CC2-3 groups had an OS of 122.80 and 32.92mo, respectively. The histologic grade was associated with CC0-1 cytoreduction; however, it did not influence OS. Patients with CC0-1 cytoreduction, acellular mucin, and low-grade lesions had better disease-free survival. Higher preoperative CA19-9 levels were associated with poor OS. Normal carcinoembryonic antigen values were associated with 100% sensitivity for predicting CC0-1. CA19-9 levels of 625 U/mL were associated with a low possibility of predicting CC0-1. Histologic grades are associated with disease-free survival when CC0-1 cytoreduction is achieved. Normal preoperative CA19-9 levels were associated with a better OS. CC0-1 cytoreduction is the main determinant of longer survival.

The time-dependent changes in serum carcinoembryonic antigen impact on posthepatectomy outcomes of colorectal liver metastasis

BackgroundOnly a few studies have examined the impact of carcinoembryonic antigen variation in patients before and after curative resection of colorectal liver metastasis . This study examined the correlation between carcinoembryonic antigen levels and patient prognosis. MethodsPatients who underwent curative resection for colorectal liver metastasis between 2000 and 2017 were enrolled. This study examined patients with high preoperative carcinoembryonic antigen levels that normalized after resection of colorectal liver metastasis and the correlation between prognosis and time-dependent changes in carcinoembryonic antigen levels. The similarity in the risk of recurrence in patients with normal preoperative carcinoembryonic antigen levels was evaluated. ResultsA total of 143 consecutive patients were included in the study cohort and classified into the normal preoperative (46 patients), normalized postoperative (57 patients), and elevated preoperative and postoperative (40 patients) carcinoembryonic antigen groups. All clinicopathologic characteristics were comparable between patients grouped according to carcinoembryonic antigen levels. The 5-year disease-free survival and overall survival rates for all patients were 30.4% and 56.0%, respectively. Multivariate analysis confirmed that elevated preoperative and postoperative carcinoembryonic antigen levels (hazard ratio = 1.73, 95% confidence interval: 1.04–2.87) were independently associated with poor disease-free survival; normalization of postoperative carcinoembryonic antigen (hazard ratio = 0.94, 95% confidence interval: 0.57–1.53) was statistically indistinguishable from normal preoperative carcinoembryonic antigen levels. The risk of recurrence was similar to that of patients with normal preoperative carcinoembryonic antigen levels ConclusionPatients with elevated preoperative carcinoembryonic antigen levels that normalized after resection of colorectal liver metastasis were not at risk of poor disease-free survival. Elevated carcinoembryonic antigen levels after surgery are independent prognostic factors for disease-free survival.

FDG PET/CT in a Case With Primary Poorly Differentiated Urothelial-Type Adenocarcinoma of the Prostate.

Primary urothelial-type adenocarcinoma of the prostate is extremely rare. We describe FDG PET/CT findings in a case with primary poorly differentiated urothelial-type adenocarcinoma of the prostate with pelvic lymph node metastases. Both the prostate tumor and its metastatic lesions showed intense FDG uptake. The patient had normal serum prostate-specific antigen and elevated carcinoembryonic antigen levels, which may be helpful for the differential diagnosis.

Criteria to make animal studies more relevant to treating human cancer.

Certain aspects of experimental tumor models in mice most accurately reflect the biology and immunology of cancer in patients. A survey of experimental cancer immunotherapy papers published in 2020 shows most do not achieve cancer shrinkage although treatment is initiated at an early time point after cancer cell injection, which does not reflect cancer immunotherapy in patients. Even then, few current experimental approaches eradicate the injected malignant cells, most only delay outgrowth. The value of targeting mutation-encoded tumor-specific antigens becomes increasingly evident while problems of finding normal gene-encoded tumor-associated antigens as safe, effective targets persist. It might be time to refocus on realistic experimental settings and truly cancer-specific targets. These antigens are associated with the least risk of side effects.

Prognostic role of preoperative carcinoembryonic antigen level in part-solid lung adenocarcinoma.

Part-solid lung adenocarcinoma appears as a heterogeneous subgroup, and its surgical management is controversial. This study aimed to elucidate whether preoperative carcinoembryonic antigen, a time-honored tumor marker, can be used as a prognostic factor that contributes to its management. We retrospectively reviewed consecutive patients with clinical-T1a-cN0M0 part-solid adenocarcinoma who underwent surgical resection between January 2011 and December 2015 at two institutions. Overall, 288 patients were identified. The median age was 69 years with 176 patients (61%) being female. The median follow-up time was 5.6 years. Lymph node metastases were found in 6 (15%) of 41 patients with elevated carcinoembryonic antigen levels, while 10 (4.0%) of 247 patients had normal carcinoembryonic antigen levels (P = 0.016). The 5-year overall survival rates in patients with normal and elevated carcinoembryonic antigen levels were 96.9% and 87.2%, respectively (P = 0.006), and the 5-year relapse-free survival rates were 91.8% and 62.8%, respectively (P < 0.001). The multivariable analysis revealed that preoperative carcinoembryonic antigen level was a significant prognostic factor for relapse-free survival (hazard ratio [HR] = 2.92, 95% confidence interval [CI] = 1.63-5.25, P < 0.001). Among the patients with elevated carcinoembryonic antigen levels, the 5-year overall survival rates in those undergoing lobar resection and segmentectomy were 87.0% and 88.9%, respectively (P = 0.59), and the 5-year relapse-free survival rates were 61.7% and 66.7%, respectively (P = 0.84). Our data suggest that preoperative carcinoembryonic antigen level appears to be an important predictor of postoperative survival outcomes in early-stage part-solid adenocarcinoma. Further studies are required to optimize management of patients with elevated preoperative carcinoembryonic antigen levels, although segmentectomy appeared acceptable in those patients.

Lymphome prostatique: une cause rare de rétention urinaire: à propos d'un cas

Prostate lymphomas (LP) are rare, fewer than 300 cases have been reported in the literature. Each time they are a diagnostic surprise as is the case with our study that is typical, didactic and reports the thirteenth case of prostatic lymphoma in the marginal zone. The study involved a 65-year-old patient, with no particular previous history who presented with signs of prostatism lasting for 4 months, aggravated by the occurrence of acute urinary retention. The diagnosis of benign prostatic hyperplasia with normal prostate-specific antigen (PSA) level was easily made and the patient underwent transurethral resection. To our surprise, the histological study revealed a massive infiltration of prostatic tissue by a non-Hodgkin lymphoma (NHL), marginal zone lymphoma (MZL) subtype. According to Steuter, it was classified as prostatic lymphoma stage IVB with leukemic transformation. The patient has experienced remission for 18 months with normalization of LDH after R-chop therapy. Although rare, these sites of occurrence should be suspected, LDH assay should be systematic in patients with prostatic signs and normal PSA levels. Prognosis is variable, according to age, histologic type and evolutionary stage, however, the median overall survival is identical for primary and secondary forms.

Dendritic Cell-Based Immunotherapies and their Potential use in Colorectal Cancer Immunotherapy.

Dendritic cells (DCs) are professional antigen-presenting cells, which are resident or proliferating in organs. Major histocompatibility complex (MHC) Class I and II on DCs in normal steady conditions process and present antigens including cancer antigens. Many approaches are used to enhance antigen presentation process of DCs and capture cancer cells. DCs are harvested from cancer patients and manipulated ex vivo in DC-based cancer immunotherapy. In addition, DCs' vaccines and other anticancer therapy combinations were discussed to optimize DCs' efficiency for cancer immunotherapy. This review addressed the use of the human conventional type-1 DCs, OX40+ plasmacytoid DCs, and DCs-derived exosomes. In addition, different combinations with DCs therapy such as combination with the monoclonal antibody, cytokine-induced killer cells, adjuvants, chemotherapy (DCs-based chemoimmunotherapy), and nanoparticles were listed and explored for their effectiveness against cancer, and mainly against colorectal cancer.

Autoimmune polyglandular syndrome type 1 and eye damage

Autoimmune polyendocrine syndrome type 1 (APS type 1) is a disease characterized by a variety of clinical manifestations resulting from the involvement of multiple endocrine and non-endocrine organs in the pathological process. APS type 1 is a rare genetically determined disease with autosomal recessive inheritance. Mutations in the autoimmune regulator gene (AIRE) lead to a disruption of the mechanism of normal antigen expression and the formation of abnormal clones of immune cells, and can cause autoimmune damage to organs. Within APS type 1, the most common disorders are primary adrenal insufficiency, hypoparathyroidism, and chronic candidiasis. Some understudied clinical manifestations of APS type 1 are autoimmune pathological processes in the eye: keratoconjunctivitis, dry eye syndrome, iridocyclitis, retinopathy, retinal detachment, and optic atrophy. This review presents the accumulated experimental and clinical data on the development of eye damage of autoimmune nature in APS type 1, as well as the laboratory and instrumental methods used for diagnosing the disease. Changes in the visual organs in combination with clinical manifestations of hypoparathyroidism, adrenal insufficiency and candidiasis should lead the clinical doctor to suspect the presence of APS type 1 and to examine the patient comprehensively. Timely genetic counselling will allow early identifi cation of the disease, timely prescription of appropriate treatment and prevention of severe complications.

Solitary lung metastasis from primary prostate cancer with normal prostate specific antigen levels: A case report and literature review

Pulmonary involvement from prostate cancer is a well‑known condition; however, solitary lung metastasis is rare, with its associated clinical characteristics not yet fully elucidated. The present study describes the case of a 77‑year‑old male, who had undergone radical prostatectomy at a previous hospital for primary prostatic carcinoma 14 years prior, who presented with a low‑grade fever. At the previous hospital, salvage radiation therapy was being considered, as the prostate‑specific antigen (PSA) level had gradually increased within the normal range. Computed tomography performed at the authors' institution revealed a solitary nodule with a spiculated morphology located on the upper lobe of the left lung, while positron emission tomography suggested malignancy without metastasis. Based on these findings, primary lung cancer was suspected and thoracoscopic left upper lobectomy with lymph node dissection was performed. The pathological diagnosis of the tumor was a solitary lung metastasis of prostate cancer. The post‑operative recovery was uneventful. In addition to reporting a case with normal PSA levels, the present study also performed a literature review. According to previous case reports, there are some pitfalls of prostate cancer leading to misdiagnosis as a primary lung tumor. However, it is considered that surgical resection is associated with an increased diagnostic accuracy and long‑term survival.

Clinical and Molecular Characterization of Qatari Patients with Inherited Dysfibrinogenemia

Background and Objectives:Inherited Dysfibrinogenemia is a rare functional fibrinogen disorder in which the fibrinogen protein is present but with a reduced function. Fibrinogen is a 340-kDa glycoprotein that is encoded by three genes namely: Fibrinogen Bb (FGB), Aa (FGA), and g (FGG). The disorder is characterized by a wide spectrum of clinical phenotypes, ranging from asymptomatic to mild- to-severe bleeding or thrombotic manifestations and recurrent miscarriages. The mode of inheritance is mostly autosomal dominant manner and frequently as a result of a point mutation in FGA (Arg35) and FGG (Arg301).The laboratory diagnosis is based on discrepancy between fibrinogen antigen (detected by immunoassay or by immuno-turbidimetric assay) and functional assay (detected by Clauss method or other clot-based assays). The disorder is often associated with prolonged activated partial thromboplastin time (APTT), prothrombin time (PT) and thrombin time (TT).Fibrinogen activity is reduced by Clauss method while the antigen assay remains normal.The management is directed towards prevention of bleeding with prophylactic fibrinogen concentrates or cryoprecipitate prior to invasive procedures, surgeries or delivery.Dysfibrinogenemia is a rare disorder yet it is very prevalent in Qatar as a result of high rate of consanguineous marriages. The aim of our study is to describe the clinical phenotype in relation to genotype in this cohort.MethodsWe conducted a retrospective analysis of 23 patients with Inherited Dysfibrinogenemia reported by our center from 2015 to 2020 . Patients with a positive family of history fibrinogen disorder and abnormal coagulation screen, low functional fibrinogen assay (by Clauss method) or normal antigen level by turbidimetry were included. Whole exome sequencing (WES) was performed on the proband case which detected a likely pathogenic mutation that was tested on subsequent cases.We diagnosed our patients with Inherited Dysfibrinogenemia based on both coagulation-based assays and molecular tests. Probable Inherited Dysfibrinogenemia was considered in patients where the molecular test or antigen assay were not performed. To assess the clinical phenotype, data was collected that included; age at diagnosis, gender, bleeding and thrombotic events as well as coagulation screening. (Table 1)Results23 patients who were described in this cohort belong to the same tribe. 74% (17 o/23) were female and only 41% (7/17) reported an obstetric bleeding (postpartum or post abortion) and one reported mild bleeding that occurred in the postmenopausal period and no previous bleeding (case#19). The median age of diagnosis was 28.8 years (5-69) for the females. All male cases in the cohort were detected either during routine screening or prior to surgery with no previous history of bleeding. No thrombotic events were observed in this cohort.Genetic AnalysisFollowing proper genetic counseling and informed consent, whole exome sequencing analysis (WES) was performed on the index case which included testing of the fibrinogen genes FGA, FGB and FGG. WES revealed a likely pathogenic mutation in the FGA gene (p. Arg35His (R35H) (CGT>CAT): c.104 G>A in exon 2)-Located within the cleavage site of fibrinopeptide A by thrombin (The UniProt Consortium, 2017), which is a mutational hotspot.This result is likely consistent with the diagnosis of Dysfibrinogenemia.ConclusionThe FGA R35H mutation is considered a probable recurrent variant in a large tribe in the Qatari population and is associated with late onset mild bleeding manifestations in minority of cases . Despite the fact that the reported tribe is highly consanguineous, the R35H mutation behaved in an autosomal dominant manner rather than recessive in this cohort.Further studies to assess phenotype - genotype correlation of Dysfibrinogenemia is warranted. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Gene Expression Profiling of Early Acute Febrile Stage of Dengue Infection and Its Comparative Analysis With Streptococcus pneumoniae Infection.

Infectious diseases are the disorders caused by organisms such as bacteria, viruses, fungi, or parasites. Although many of them are permentantly hazardous, a number of them live in and on our bodies and they are normally harmless or even helpful. Under certain circumstances, some organisms may cause diseases and these infectious diseases may be passed directly from person to person or via intermediate vectors including insects and other animals. Dengue virus and Streptococcus pneumoniae are the critical and common sources of infectious diseases. So, it is critical to understand the gene expression profiling and their inferred functions in comparison to the normal and virus infected conditions. Here, we have analyzed the gene expression profiling for dengue hemorrhagic fever, dengue fever, and normal human dataset. Similar to it, streptococcus pneumoniae infectious data were analyzed and both the outcomes were compared. Our study leads to the conclusion that the dengue hemorrhagic fever arises in result to potential change in the gene expression pattern, and the inferred functions obviously belong to the immune system, but also there are some additional potential pathways which are critical signaling pathways. In the case of pneumoniae infection, 19 pathways were enriched, almost all these pathways are associated with the immune system and 17 of the enriched pathways were common with dengue infection except platelet activation and antigen processing and presentation. In terms of the comparative study between dengue virus and Streptococcus pneumoniae infection, we conclude that cell adhesion molecules (CAMs), MAPK signaling pathway, natural killer cell mediated cytotoxicity, regulation of actin cytoskeleton, and cytokine-cytokine receptor interaction are commonly enriched in all the three cases of dengue infection and Streptococcus pneumoniae infection, focal adhesion was enriched between classical dengue fever — dengue hemorrhagic fever, dengue hemorrhagic fever—normal samples, and SP, and antigen processing and presentation and Leukocyte transendothelial migration were enriched in classical dengue fever —normal samples, dengue hemorrhagic fever—normal samples, and Streptococcus pneumoniae infection.

One to Two Cycles of Consolidation Chemotherapy With Capecitabine After Neoadjuvant Chemoradiotherapy Does Not Benefit Low-Risk Patients With Locally Advanced Middle-Low Rectal Cancer.

Background and ObjectiveOrgan preservation can enable locally advanced rectal cancer (LARC) patients with clinical complete response (cCR) after neoadjuvant treatment to maintain quality of life. In this study, we aimed to evaluate whether one or two cycles of capecitabine after neoadjuvant chemoradiotherapy (NCRT) without extending the interval between the end of NCRT and surgery could increase the complete response (CR) rate in low-risk middle-low LARC patients.Material and MethodsWe retrospectively evaluated middle-low LARC patients with low risk defined as clinical T2-3b, mesorectal fascia-clear, and extramural vascular invasion-negative by magnetic resonance imaging (MRI), treated between January 2015 and July 2019. Patients were divided into two groups according to whether consolidation chemotherapy was administered after NCRT. Patients in the consolidation chemotherapy group received one or two cycles of capecitabine (1000 mg/m2 twice daily from days 1 to 14). The main outcome was the CR rate, including pathological CR (pCR) and cCR.ResultsA total of 169 patients, 105 in the consolidation chemotherapy group and 64 in the non-consolidation chemotherapy group, were included in the study, and the median follow-up was 37.2 months (range, 0.4–71.2 months). Seventeen patients achieved cCR and the remaining 152 underwent surgery after neoadjuvant treatment. There was no significant difference in the CR rate (39.0% vs. 35.9%, p=0.686), ypT0-2N0 rate (65.2% vs. 63.3%, p=0.812), or ypN0 rate (83.7% vs. 88.3%, p=0.503) between the consolidation chemotherapy and non-consolidation chemotherapy groups. Among the patients achieved cCR, 3 (17.6%) experienced regrowth in the rectum and 2 (11.8%) experienced distant metastasis. There was also no significant difference in the 3-year disease-free survival (87.4% vs 85.9%, p=0.971) in patients who underwent surgery between the two groups. Multivariate logistic regression analysis indicated that normal Carcinoma Embryonic Antigen (CEA) levels (p = 0.001) were associated with a higher CR rate. Moreover, there were no significant differences in the incidences of grade ≥2 acute toxicities during neoadjuvant treatment.ConclusionAlthough there was no increase in treatment-related toxicities between the two groups, simply adding one or two cycles of capecitabine after NCRT might be insufficient to benefit low-risk middle-low LARC patients.

Acute Epstein‐Barr virus associated haemophagocytosis in an Asian female: What is the diagnosis?

Acute <scp>Epstein‐Barr</scp> virus associated haemophagocytosis in an Asian female: What is the diagnosis?

Prothrombin “Carmel”: Identification of a Novel Homozygous Mutation in the Prothrombin Gene Causing Coagulation Factor II Deficiency and Inherited Bleeding Disorder in an Israeli Arab Family

Congenital prothrombin deficiency, also known as hypoprothrombinemia is a rare autosomal recessive disorder characterized by severe bleeding manifestations and decreased prothrombin antigen levels below 10% activity of normal. Dysprothrombinemia, which is characterized by normal antigen levels but a dysfunctional prothrombin molecule, shows a more variable level in bleeding tendency, and there is often a good correlation between the levels of prothrombin activity and clinical severity. We have studied a large consanguineous family of thirteen members contains two patients with a prolonged protrombine time (PT) and activated partial thromboplastin time (aPTT) with prothrombin activity of 11%. DNA was isolated from leukocytes and the thrombin exons were amplified by polymerase chain reaction and sequenced. Exon 14 revealed a point mutation in the codon of Tyrosine 560 which is substituted by Histidine (Tyr560His). Mutation at this residue most probably distorts the structure of the peptidase catalytic domain. The variation segregated as expected in the family, it did not appear in dbSNP, EVS or the 1000 genome project. Further investigation is needed to determine the antigen level and to elucidate the potential effect of the mutation on the structure and the activity of the enzyme. This prothrombin is designated as Prothrombin “Carmel”. DisclosuresNo relevant conflicts of interest to declare.

How I treat dysfibrinogenemia

AbstractCongenital dysfibrinogenemia (CD) is caused by structural changes in fibrinogen that modify its function. Diagnosis is based on discrepancy between decreased fibrinogen activity and normal fibrinogen antigen levels and is confirmed by genetic testing. CD is caused by monoallelic mutations in fibrinogen genes that lead to clinically heterogenous disorders. Most patients with CD are asymptomatic at the time of diagnosis, but the clinical course may be complicated by a tendency toward bleeding and/or thrombosis. Patients with a thrombosis-related fibrinogen variant are particularly at risk, and, in such patients, long-term anticoagulation should be considered. Management of surgery and pregnancy raise important and difficult issues. The mainstay of CD treatment remains fibrinogen supplementation. Antifibrinolytic agents are part of the treatment in some specific clinical settings. In this article, we discuss 5 clinical scenarios to highlight common clinical challenges. We detail our approach to establishing a diagnosis of CD and discuss strategies for the management of bleeding, thrombosis, surgery, and pregnancy.

Sometimes You Have to Judge a Book by Its Cover: The Case of a Masquerading Pancreatic Mucinous Cyst

ABSTRACTPancreatic cystic lesions are difficult to evaluate amid acute pancreatitis. Without previous pancreatic imaging, it is challenging to discern between pancreatic acute fluid collections and cystic neoplasms. We present a 29-year-old woman with acute pancreatitis and initial cross-sectional imaging suggesting a 2.8-cm cystic lesion in the body/tail of the pancreas. Endoscopic ultrasound completed 5 weeks after index presentation revealed findings worrisome for a cystic neoplasm, but fine-needle aspiration findings suggested lesion to be a pseudocyst (normal carcinoembryonic antigen and cytology, negative mucin stain).

DEFICIENCY OF ADAMTS-13 IN SEPSIS PATIENTS AND ITS CORRELATION WITH MORBIDITY/ MORTALITY

Objective: To detect ADAMTS-13 deficiency in sepsis patients and its effect on in-hospital morbidity and mortality in adult patients of sepsis.&#x0D; Study Design: Cross sectional study.&#x0D; Place and Duration of Study: Armed Forces Institute of Pathology (AFIP) and Combined Military Hospital (CMH) Rawalpindi, from Apr 2017 to Apr 2018.&#x0D; Methodology: All indoor patients admitted at Combined Military Hospital Rawalpindi and diagnosed as suffering from sepsis at Armed Forces Institute of Pathology according to the guidelines of the Critical Care Society of Medicine Consensus Conference Committee. Forty sepsis patients were recruited for the study. Two groups were formed on the basis of ADAMTS-13 antigen levels, non-deficient and deficient. Basic haematological and clinical parameters were recorded. Levels of ADAMTS-13 antigen were analyzed by using Technozyme kit byenzyme-linked immunosorbent assay (ELISA) and level less than 0.40 IU/ml was taken deficient as defined by manufacturer. Comparison was done between ADAMTS-13 deficient and non-deficient group with regard to clinical and haematological characteristics, ICU stay, hospital admission days and in-hospital mortality. Healthy controls of same age and gender were also observed for ADAMTS-13 antigen level.&#x0D; Results: Among total 40 sepsis patients, thirty two (80%) were males and eight (20%) were females with a mean age of 61 ± 15 years (range: 30-85 years). ADAMTS-13 deficiency (&lt;0.40 IU/ml) was found in 28 (70%) of patients while 12 (30%) had normal antigen levels. In patients with ADAMTS-13 deficiency, twenty four (85.7%) had low platelet levels &lt;150 x 109/l, mean hospital stay 19.2 ± 7.6 days and in-hospital mortality was seen in eight (28.6%) patients, in comparison of non-deficient group in which platelet levels were equal or &gt;150 x 109/l, mean hospital stay was 10.2 ± 3.6 days and in-hospital mortality was in one (8.3%) patient respectively. ADAMTS-13 antigen level was found sufficient in healthy controls.&#x0D; Conclusion: Majority of the sepsis patients were found ADAMTS-13 deficient. Deficiency exhibit long term hospital admission, thrombocytopenia and increase in hospital mortality. ADAMTS-13 deficiency might play a role in sepsis induced thrombocytopenia and in hospital mortality. More studies are recommended on the subject with larger sample size to evaluate its role in sepsis.

Antibody Co-Administration Can Improve Systemic and Local Distribution of Antibody-Drug Conjugates to Increase In Vivo Efficacy.

Several antibody-drug conjugates (ADC) showing strong clinical responses in solid tumors target high expression antigens (HER2, TROP2, Nectin-4, and folate receptor alpha/FRα). Highly expressed tumor antigens often have significant low-level expression in normal tissues, resulting in the potential for target-mediated drug disposition (TMDD) and increased clearance. However, ADCs often do not cross-react with normal tissue in animal models used to test efficacy (typically mice), and the impact of ADC binding to normal tissue antigens on tumor response remains unclear. An antibody that cross-reacts with human and murine FRα was generated and tested in an animal model where the antibody/ADC bind both human tumor FRα and mouse FRα in normal tissue. Previous work has demonstrated that a "carrier" dose of unconjugated antibody can improve the tumor penetration of ADCs with high expression target-antigens. A carrier dose was employed to study the impact on cross-reactive ADC clearance, distribution, and efficacy. Co-administration of unconjugated anti-FRα antibody with the ADC-improved efficacy, even in low expression models where co-administration normally lowers efficacy. By reducing target-antigen-mediated clearance in normal tissue, the co-administered antibody increased systemic exposure, improved tumor tissue penetration, reduced target-antigen-mediated uptake in normal tissue, and increased ADC efficacy. However, payload potency and tumor antigen saturation are also critical to efficacy, as shown with reduced efficacy using too high of a carrier dose. The judicious use of higher antibody doses, either through lower DAR or carrier doses, can improve the therapeutic window by increasing efficacy while lowering target-mediated toxicity in normal tissue.

Assessment of the Diagnostic Performance of Normal and Irradiated Schistosoma mansoni Cercarial Antigens using ELISA

Assessment of the Diagnostic Performance of Normal and Irradiated Schistosoma mansoni Cercarial Antigens using ELISA