A Lassa virus mRNA vaccine confers protection but does not require neutralizing antibody in a guinea pig model of infection.

Lassa virus is a member of the Arenaviridae family, which causes human infections ranging from asymptomatic to severe hemorrhagic disease with a high case fatality rate. We have designed and generated lipid nanoparticle encapsulated, modified mRNA vaccines that encode for the wild-type Lassa virus strain Josiah glycoprotein complex or the prefusion stabilized conformation of the Lassa virus glycoprotein complex. Hartley guinea pigs were vaccinated with two 10 µg doses, 28 days apart, of either construct. Vaccination induced strong binding antibody responses, specific to the prefusion conformation of glycoprotein complex, which were significantly higher in the prefusion stabilized glycoprotein complex construct group and displayed strong Fc-mediated effects. However, Lassa virus-neutralizing antibody activity was detected in some but not all animals. Following the challenge with a lethal dose of the Lassa virus, all vaccinated animals were protected from death and severe disease. Although the definitive mechanism of protection is still unknown, and assessment of the cell-mediated immune response was not investigated in this study, these data demonstrate the promise of mRNA as a vaccine platform against the Lassa virus and that protection against Lassa virus can be achieved in the absence of virus-neutralizing antibodies.

p16 Immunohistochemical Expression in Nephrogenic Adenoma.

Nephrogenic adenoma (NA) is a rare metaplastic entity commonly associated with a prior urothelial injury. Most are seen in the urinary bladder and a minority involve the urethra. In this study, we evaluated the expression of p16 as a surrogate marker of this entity and correlated it with clinical pathological parameters. A total of 17 cases of NA were retrospectively studied to assess the immunohistochemical expression of p16 and its value for the diagnosis of this entity.

Laryngeal Sarcomatoid Carcinoma With Rhabdomyoblastic Differentiation: A Potential Pitfall for Misdiagnosis As Rhabdomyosarcoma.

Sarcomatoid carcinoma (SC) of the larynx is an uncommon subtype of squamous cell carcinoma which shows both squamous carcinoma and a sarcomatous component, including heterologous elements. The presence of rhabdomyosarcomatous elements in the larynx is extremely rare. Diagnosis of SC can be particularly challenging when the malignant epithelial component is not evident. We present a case of SC in a 72-year-old man with a superficial exophytic mass in the vocal cord initially misdiagnosed as rhabdomyosarcoma due to a predominant spindle cell component with rhabdomyoblastic features by morphology and immunohistochemistry. This case report aims to increase awareness that a rhabdomyoblastic heterologous component can be present in SC of the larynx and to consider this diagnosis in a mucosal exophytic malignant spindle cell neoplasm, even in the absence of epithelial differentiation.

Invasive Breast Carcinoma With Sebaceous Morphologic Pattern Showing Lymph Node Macrometastasis: A Case Report.

Invasive ductal carcinoma of no special type can present with various patterns. It is not possible to diagnose them through imaging alone. Microscopic examination is necessary to accurately identify and characterize them. The sebaceous pattern was historically considered a distinct subtype of breast carcinoma. However, the number of cases is relatively small and the prognosis has not been fully established. In this paper, we present a case of invasive ductal carcinoma with focal sebaceous features, which had a macrometastasis to the axillary lymph nodes showing the sebaceous morphology.

Nephrogenic Adenoma Arising From a Female Urethral Diverticulum: A Case Report and Potential Diagnostic Pitfalls.

Nephrogenic adenoma is a benign lesion of the urothelial tract characterized by tubules surrounded by thick, hyalinized basement membranes. There is a great variety of architectural patterns within nephrogenic adenomas, including patterns that mimic malignancy, such as focal clear or hobnail cells, areas of significant nuclear atypia, mitosis, and isolated cystic changes. This represents a diagnostic pitfall, where a malignant lesion can be mistaken for a nephrogenic adenoma, leading to a delay in diagnosis and treatment that adversely affects the outcome. In this case report, we describe a nephrogenic adenoma arising in a female urethral diverticulum and discuss the differential diagnosis, which includes clear cell carcinomas, microcystic variant urothelial carcinomas, and Skene's gland cysts.

Overcoming Drug Resistance in Advanced Prostate Cancer by Drug Repurposing.

Prostate cancer (PCa) is the second most common cancer in men. Common treatments include active surveillance, surgery, or radiation. Androgen deprivation therapy and chemotherapy are usually reserved for advanced disease or biochemical recurrence, such as castration-resistant prostate cancer (CRPC), but they are not considered curative because PCa cells eventually develop drug resistance. The latter is achieved through various cellular mechanisms that ultimately circumvent the pharmaceutical's mode of action. The need for novel therapeutic approaches is necessary under these circumstances. An alternative way to treat PCa is by repurposing of existing drugs that were initially intended for other conditions. By extrapolating the effects of previously approved drugs to the intracellular processes of PCa, treatment options will expand. In addition, drug repurposing is cost-effective and efficient because it utilizes drugs that have already demonstrated safety and efficacy. This review catalogues the drugs that can be repurposed for PCa in preclinical studies as well as clinical trials.

Repurposing of Anticancer Stem Cell Drugs in Brain Tumors.

Brain tumors in adults may be infrequent when compared with other cancer etiologies, but they remain one of the deadliest with bleak survival rates. Current treatment modalities encompass surgical resection, chemotherapy, and radiotherapy. However, increasing resistance rates are being witnessed, and this has been attributed, in part, to cancer stem cells (CSCs). CSCs are a subpopulation of cancer cells that reside within the tumor bulk and have the capacity for self-renewal and can differentiate and proliferate into multiple cell lineages. Studying those CSCs enables an increasing understanding of carcinogenesis, and targeting CSCs may overcome existing treatment resistance. One approach to weaponize new drugs is to target these CSCs through drug repurposing which entails using drugs, which are Food and Drug Administration-approved and safe for one defined disease, for a new indication. This approach serves to save both time and money that would otherwise be spent in designing a totally new therapy. In this review, we will illustrate drug repurposing strategies that have been used in brain tumors and then further elaborate on how these approaches, specifically those that target the resident CSCs, can help take the field of drug repurposing to a new level.

Rising incidence of appendiceal neoplasms over time: Does pathological handling of appendectomy specimens play a role?

BACKGROUND: Appendectomy is the most common emergent surgical procedure. Primary appendiceal neoplasms are rare entities that are usually detected incidentally in less than 2% of all appendectomies. The increase in the incidence rates of appendiceal neoplasms over time raises the question whether there is an actual change in the disease occurrence or is it a matter of increased recognition and reporting of what would have been previously missed and undiagnosed. OBJECTIVES: In our study, we aimed to review the archived tissue specimens of patients who were diagnosed with appendiceal neoplasms during the past decade at our institution and compare our clinical experience with published data to identify possible reasons that contribute to the increase in incidence rates of such neoplasms over the past few years. METHODS: Using a pathological database of surgical specimens from patients who underwent appendectomies between January 01, 2010 and September 30, 2020 at a large academic medical center, a single-center retrospective cohort analysis was performed, and medical charts of patients were reviewed. RESULTS: Of the total 1568 patients included, 102 (6.5%) had appendiceal neoplasms divided between primary (79.4%) and secondary/metastatic (20.6%) neoplasms. Annual incidence of appendiceal neoplasms over the past 10 years in our institution demonstrated an increasing trend from 5.6% in 2010 to 12.7% in 2020, which we hypothesize might be attributed to submitting more representative sections of the appendix for pathological examination than we had previously. Our results also showed that 2.8% of patients initially presenting with a typical clinical picture of acute appendicitis had appendiceal neoplasms as a truly incidental finding, while 20.3% of patients who underwent elective appendectomies for a suspicious appendiceal mass were found to be neoplastic. Interestingly, among the 80 cases of epithelial neoplasms, more non-carcinoid neoplasms were detected than carcinoid tumors. CONCLUSION: Based on our results and what has been published recently, we confirm an additional increase in incidental appendiceal neoplasms found in appendectomies performed for a clinical picture of acute appendicitis, which may be related to more thorough specimen assessment. Whether this is clinically impactful remains to be determined. However, these data support a modification in the way appendectomy specimens are handled in pathology labs post-operatively.

Correlation between spread through air spaces (STAS) and other clinicopathological parameters in lung cancer.

BACKGROUND: "Spread through airspace" (STAS) is defined as micropapillary clusters, solid nests or single cells of tumor extending beyond the edge of the tumor into the air spaces of the surrounding lung parenchyma. It is associated with reduced overall survival and disease-free survival. Assessment of STAS in lung cancer appears to be necessary to guide clinical interventions. However, data on the correlation between the status of STAS and other lung cancer clinicopathological parameters are scarce. METHODS: We reviewed 240 resected lung cancers and investigated the clinical significance of STAS in relation to other relevant lung cancer clinicopathological variables. We performed univariate and multivariate logistic regression analyses with STAS as a dependent variable. RESULTS: Of the total 240 patients, STAS was observed in 67 (27.9 %) of them. STAS is highly prevalent in adenocarcinoma with a micropapillary growth pattern (70.0 %) than in other lung cancer growth patterns. STAS was frequently reported in wedge resections (31.0%) than in lobectomy specimens (26.7 %). STAS was significantly associated with advanced pN stage (p < 0.001) and lymphovascular invasion (p = 0.005). In multivariate models, we found that lung cancers in the right lower lobe (RLL) (OR, 2.674; 95 % CI = 1.313-5.448, p = 0.007), micropapillary lung cancer growth pattern (OR = 5.199, 95 % CI = 1.220-22.162, p = 0.026), and pN2 stage (OR = 3.683, 95 % CI = 1.324-10.245, p = 0.013) serve as independent predictors for STAS. CONCLUSION: Our findings suggest that the presence of STAS is associated with right lower lobe tumors, micropapillary adenocarcinoma, and pN2 tumor stage. Hence, it could serve as one of the prognostically significant histologic findings in lung cancer. It is thus valid to mandate reporting STAS status in CAP surgical pathology lung cancer case summaries.

Rhabdoid collecting duct carcinoma with lymphangitic carcinomatosis causing acute lethal chylopericardium.

Collecting duct carcinoma is a rare neoplasm of the kidney, accounting for only 1-2% of renal tumors. These tumors arise from the principal cells of the renal collecting ducts of Bellini. The majority of patients have lymph node involvement and metastases to lungs, liver, bone, adrenal glands, and brain. We present a case of a 48 year old woman who came to the hospital with a clinical presentation suspicious for pneumonia. One week later her symptoms aggravated. A CT chest and abdominal imaging showed bilateral pulmonary infiltrates, retroperitoneal lymphadenopathy, and left hydroureteronephrosis. She expired after developing acute respiratory failure. An autopsy was performed which revealed chylopericadium of 150 cc; bilateral reticular pattern on the surfaces of the lungs; neck, mediastinal and retroperitoneal lymphadenopathy, and a 5.1 cm left kidney mass located in the mid portion medulla. The kidney tumor was a rhabdoid collecting duct carcinoma. The lungs showed diffuse subpleural lymphangitic spread of the carcinoma. We report a rare case of chylopericardium due to lymphangitic carcinomatosis from a 5.1 cm rhabdoid collecting duct carcinoma not suspected clinically or radiologically. This case highlights the importance of performing autopsies in an era when clinicians heavily rely on high-tech imaging diagnostic modalities.