Pathology Review Research Articles

Genome Instability and DNA Repair in Somatic and Reproductive Aging.

Genetic material is constantly subjected to genotoxic insults and is critically dependent on DNA repair. Genome maintenance mechanisms differ in somatic and germ cells as the soma only requires maintenance during an individual's lifespan, while the germline indefinitely perpetuates its genetic information. DNA lesions are recognized and repaired by mechanistically highly diverse repair machineries. The DNA damage response impinges on a vast array of homeostatic processes and can ultimately result in cell fate changes such as apoptosis or cellular senescence. DNA damage causally contributes to the aging process and aging-associated diseases, most prominently cancer. By causing mutations, DNA damage in germ cells can lead to genetic diseases and impact the evolutionary trajectory of a species. The mechanisms ensuring tight control of germline DNA repair could be highly instructive in defining strategies for improved somatic DNA repair. They may provide future interventions to maintain health and prevent disease during aging.

Epigenomic Characterization of Lymphoid Neoplasms.

Lymphoid neoplasms represent a heterogeneous group of disease entities and subtypes with markedly different molecular and clinical features. Beyond genetic alterations, lymphoid tumors also show widespread epigenomic changes. These severely affect the levels and distribution of DNA methylation, histone modifications, chromatin accessibility, and three-dimensional genome interactions. DNA methylation stands out as a tracer of cell identity and memory, as B cell neoplasms show epigenetic imprints of their cellular origin and proliferative history, which can be quantified by an epigenetic mitotic clock. Chromatin-associated marks are informative to uncover altered regulatory regions and transcription factor networks contributing to the development of distinct lymphoid tumors. Tumor-intrinsic epigenetic and genetic aberrations cooperate and interact with microenvironmental cells to shape the transcriptome at different phases of lymphoma evolution, and intraclonal heterogeneity can now be characterized by single-cell profiling. Finally, epigenetics offers multiple clinical applications, including powerful diagnostic and prognostic biomarkers as well as therapeutic targets.

Comparative Pathogenesis of Severe Acute Respiratory Syndrome Coronaviruses.

Over the last two decades the world has witnessed the global spread of two genetically related highly pathogenic coronaviruses, severe acute respiratory syndrome coronavirus (SARS-CoV) and SARS-CoV-2. However, the impact of these outbreaks differed significantly with respect to the hospitalizations and fatalities seen worldwide. While many studies have been performed recently on SARS-CoV-2, a comparative pathogenesis analysis with SARS-CoV may further provide critical insights into the mechanisms of disease that drive coronavirus-induced respiratory disease. In this review, we comprehensively describe clinical and experimental observations related to transmission and pathogenesis of SARS-CoV-2 in comparison with SARS-CoV, focusing on human, animal, and in vitro studies. By deciphering the similarities and disparities of SARS-CoV and SARS-CoV-2, in terms of transmission and pathogenesis mechanisms, we offer insights into the divergent characteristics of these two viruses. This information may also be relevant to assessing potential novel introductions of genetically related highly pathogenic coronaviruses.

Within-Host Evolution of Bacterial Pathogens in Acute and Chronic Infection.

Bacterial pathogens undergo remarkable adaptive change in response to the selective forces they encounter during host colonization and infection. Studies performed over the past few decades have demonstrated that many general evolutionary processes can be discerned during the course of host adaptation, including genetic diversification of lineages, clonal succession events, convergent evolution, and balanced fitness trade-offs. In some cases, elevated mutation rates resulting from mismatch repair or proofreading deficiencies accelerate evolution, and active mobile genetic elements or phages may facilitate genome plasticity. The host immune response provides another critical component of the fitness landscapes guiding adaptation, and selection operating on pathogens at this level may lead to immune evasion and the establishment of chronic infection. This review summarizes recent advances in this field, with a special focus on different forms of bacterial genome plasticity in the context of infection, and considers clinical consequences of adaptive changes for the host.

Hypoxia-Induced Signaling in Gut and Liver Pathobiology.

Oxygen (O2) is essential for cellular metabolism and biochemical reactions. When the demand for O2 exceeds the supply, hypoxia occurs. Hypoxia-inducible factors (HIFs) are essential to activate adaptive and survival responses following hypoxic stress. In the gut (intestines) and liver, the presence of oxygen gradients or physiologic hypoxia is necessary to maintain normal homeostasis. While physiologic hypoxia is beneficial and aids in normal functions, pathological hypoxia is harmful as it exacerbates inflammatory responses and tissue dysfunction and is a hallmark of many cancers. In this review, we discuss the role of gut and liver hypoxia-induced signaling, primarily focusing on HIFs, in the physiology and pathobiology of gut and liver diseases. Additionally, we examine the function of HIFs in various cell types during gut and liver diseases, beyond intestinal epithelial and hepatocyte HIFs. This review highlights the importance of understanding hypoxia-induced signaling in the pathogenesis of gut and liver diseases and emphasizes the potential of HIFs as therapeutic targets.

Clonal Hematopoiesis, Inflammation, and Hematologic Malignancy.

Somatic or acquired mutations are postzygotic genetic variations that can occur within any tissue. These mutations accumulate during aging and have classically been linked to malignant processes. Tremendous advancements over the past years have led to a deeper understanding of the role of somatic mutations in benign and malignant age-related diseases. Here, we review the somatic mutations that accumulate in the blood and their connection to disease states, with a particular focus on inflammatory diseases and myelodysplastic syndrome. We include a definition of clonal hematopoiesis (CH) and an overview of the origins and implications of these mutations. In addition, we emphasize somatic disorders with overlapping inflammation and hematologic disease beyond CH, including paroxysmal nocturnal hemoglobinuria and aplastic anemia, focusing on VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. Finally, we provide a practical view of the implications of somatic mutations in clinical hematology, pathology, and beyond.

THU104 An Atypical Case Of A Suprasellar Cyst: A Diagnostic Challenge

Abstract Disclosure: A. Chen: None. S. Zachariah: None. B. Wong: None. E. Owusu: None. A. Levitt: None. R. Todor: None. P. Kishore: None. Background: Cystic sellar masses may be challenging to diagnose on a clinical, imaging, and histopathological basis due to overlapping features. We report a case of a cystic sellar mass in which traditional imaging findings did not correspond to its histopathological findings. Clinical Case: A 37-year-old female presented with headaches and bilateral blurry vision for two months with acute worsening of left peripheral vision for one week. She denied irregular periods, hirsutism, or breast discharge. Ophthalmology evaluation found left temporal field vision loss but normal maculae/optic nerves. MRI pituitary exhibited 2.3 x 1.5 x 1.7 cm complex cystic suprasellar mass with partial rim enhancement, thought to represent a cystic macroadenoma. Initial tests were notable for negative HCG, prolactin 96.32 mIU/mL (n < 23.3 mIU/mL), TSH 9.440 uIU/mL (0.270-4.2 uIU/mL), normalized to 0.855 uIU/mL on repeat testing, FT4 0.748 ng/dL (n = 0.75 – 2.0 ng/dL). IGF-1, ACTH, AM cortisol, FSH, and LH were within normal limits. She was started on cabergoline prior to trans-nasal-sphenoid resection with cyst drainage of white and thick content. Histopathology exhibited a squamous epithelium-lined cyst with no columnar epithelium or mucin-containing cells, consistent with an epidermoid cyst (EC), although the differential included a Rathke’s cleft cyst (RCC). No pituitary tumor was noted. A re-evaluation of MRI in multidisciplinary rounds deemed epidermoid cyst unlikely, given that these present with restricted diffusion. Our patient had overall T2 hyperintensity with an associated T2 hypointense nodule and did not restrict diffusion [1]. After interdisciplinary discussion, including imaging and pathology review, it was felt that the most likely diagnosis was RCC with squamous metaplasia. After surgery, the patient's symptoms and visual function completely recovered, and follow-up imaging is scheduled. Conclusion: Differentiating RCC with squamous metaplasia from EC can be challenging since both may present with a squamous epithelial lining [2]. Rates of progression and recurrence vary amongst cysts; therefore, making an accurate diagnosis is essential for selecting management, predicting the likelihood of recurrence, and guiding postoperative surveillance. This case is unique in that radiologic features were more helpful than histopathology in determining the diagnosis and highlights the importance of collectively considering clinical, imaging, and histopathological features in making a final diagnosis.

FRI250 Dual Aldosterone And Cortisol Secreting Adrenal Cortical Carcinoma: Pre- And Perioperative Evaluation And Management

Abstract Disclosure: R. Rosenberg: None. M.R. Clay: None. C. Raeburn: None. M.E. Wierman: None. Representing 0.3% of all adrenal tumors, adrenal cortical carcinoma (ACC) is a rare and understudied disease. It is estimated that 60% of patients with ACC present with hormone excess syndromes, while the remainder present incidentally or with compressive symptoms from tumor invasion. ACC presentation with a combination of hormonal excess syndromes from different adrenal zones is rare and only described previously in four case reports. We present a case of dual-secreting ACC with hyperaldosteronism and cortisol excess. The previously healthy patient was noted to have new onset hypertension and hypokalemia during a primary care visit. On hormonal evaluation, he was found to have evidence of hyperaldosteronism and ACTH-independent cortisol excess (aldosterone 28.2ng/dL, plasma renin activity 0.1ng/mL/hr, and overnight 1mg dexamethasone suppression test cortisol of 13ug/dL). Imaging revealed a 2.7 x 3.1 x 3.5cm left adrenal mass suggestive of an adenoma. He underwent laparoscopic adrenalectomy and required glucocorticoid replacement for adrenal insufficiency post-operatively. Pathologic review of the gross specimen showed a sizable neoplasm measuring 6.5 x 3.0 x 2.5 cm, much larger than on CT imaging. Microscopic review showed stage T2N0M0 ACC with modified Weiss score of 6 and 68 mitoses per 50 hpf, indicative of aggressive disease. The patient’s hypokalemia resolved post-operatively, and glucocorticoids were tapered within a month. The mechanism of dual aldosterone/cortisol secretion is hypothesized to be due to overlap between genes coding for 11β-hydroxylase and aldosterone synthase, resulting in a chimeric gene with increased secretion of both enzymes, and, therefore, both hormones. Though dual secretion is rare, this case report stresses the importance of screening for cortisol excess, and hyperaldosteronism in the correct clinical setting, in patients with adrenal masses detected on imaging. A complete biochemical hormone evaluation should be performed regardless of the discovery of other hormone secreting syndromes, ideally preoperatively with a multidisciplinary team including endocrinology. The medical team should continue to bear in mind that the existence of one hypersecretory syndrome does not rule out the presence of a second or third, and hormonal excess syndromes may affect patient outcomes peri- and postoperatively. Presentation: Friday, June 16, 2023

Long-term behavior and functional outcomes of ileal-pouch anal anastomosis in inflammatory bowel disease with changing phenotype

BackgroundIleal-pouch-anal anastomosis is the operation of choice after proctocolectomy for ulcerative colitis; some patients will develop Crohn’s disease. We aim to determine long-term behavior and outcomes of inflammatory bowel disease–ileal-pouch-anal anastomosis after colectomy, where a specialist gastrointestinal pathologist re-evaluated the initial colectomy specimen. MethodsPatients with inflammatory bowel disease–ileal-pouch-anal anastomosis were identified from a single-surgeon prospective database containing 1,165 patients accrued from 1991 to 2017 and invited to complete pouch-function and quality-of-life assessments. Medical records were used to obtain clinical outcomes and subjective functional assessments for those unable to be contacted. Data were compared between patients with and without histological assessment disagreement and subsequent inflammatory bowel disease behavior subgroups. ResultsFor 138 patients included in the analysis, the median follow-up was 22.5 (range: 5–39) years. A total of 39.1% of patients had histologic diagnostic change after gastrointestinal pathologist review, and 19% and 39% developed Crohn’s disease-like disease behavior at 10- and 20-year follow-ups. Pouch function and quality-of-life scores were similar across diagnostic change subgroups. Pouch failure was higher in Crohn’s-like disease (31.1 vs 13.0%, P < .05). Intestinal continuity was maintained in 68.9% of Crohn’s disease-like patients, 57.9% required biologics. Gastrointestinal pathologist review did not alter the time to new diagnosis (P = .419) or time to pouch failure (P = .320), mean: 11.0 and 11.41 years, respectively. ConclusionWe describe equivocal patient-reported outcomes in patients with ileal-pouch-anal anastomosis and changing histologic and clinical diagnosis. Although pouch excision and biologic use rates are higher, many Crohn’s disease-like patients maintain their pouch. Diagnostic change and pouch failure often occur >10 years after ileal-pouch-anal anastomosis creation. This supports the consideration of ileal-pouch-anal anastomosis after colectomy in carefully selected patients with inflammatory bowel disease, even those with ambiguous histology and the need for close long-term follow-up.

Control of Cell Death in Health and Disease.

Apoptosis, necroptosis, and pyroptosis are genetically programmed cell death mechanisms that eliminate obsolete, damaged, infected, and self-reactive cells. Apoptosis fragments cells in a manner that limits immune cell activation, whereas the lytic death programs of necroptosis and pyroptosis release proinflammatory intracellular contents. Apoptosis fine-tunes tissue architecture during mammalian development, promotes tissue homeostasis, and is crucial for averting cancer and autoimmunity. All three cell death mechanisms are deployed to thwart the spread of pathogens. Disabling regulators of cell death signaling in mice has revealed how excessive cell death can fuel acute or chronic inflammation. Here we review strategies for modulating cell death in the context of disease. For example, BCL-2 inhibitor venetoclax, an inducer of apoptosis, is approved for the treatment of certain hematologic malignancies. By contrast, inhibition of RIPK1, NLRP3, GSDMD, or NINJ1 to limit proinflammatory cell death and/or the release of large proinflammatory molecules from dying cells may benefit patients with inflammatory diseases.

Clinical Behavior and Molecular Landscape of Stage I p53-Abnormal Low-Grade Endometrioid Endometrial Carcinomas.

The clinical significance of the p53-abnormal (p53abn) molecular subtype in stage I low-grade endometrioid endometrial carcinoma (EEC) is debated. We aimed to review pathologic and molecular characteristics, and outcomes of stage I low-grade p53abn EEC in a large international cohort. Previously diagnosed stage I p53abn EC (POLE-wild-type, mismatch repair-proficient) low-grade EEC from Canadian retrospective cohorts and PORTEC-1&2 trials were included. Pathology review was performed by six expert gynecologic pathologists blinded to p53 status. IHC profiling, next-generation sequencing, and shallow whole-genome sequencing was performed. Kaplan-Meier method was used for survival analysis. We identified 55 stage I p53abn low-grade EEC among 3,387 cases (2.5%). On pathology review, 17 cases (31%) were not diagnosed as low-grade EEC by any pathologists, whereas 26 cases (47%) were diagnosed as low-grade EEC by at least three pathologists. The IHC and molecular profile of the latter cases were consistent with low-grade EEC morphology (ER/PR positivity, patchy p16 expression, PIK3CA and PTEN mutations) but they also showed features of p53abn EC (TP53 mutations, many copy-number alterations). These cases had a clinically relevant risk of disease recurrence (5-year recurrence-free survival 77%), with pelvic and/or distant recurrences observed in 12% of the patients. A subset of p53abn EC is morphologically low-grade EEC and exhibit genomic instability. Even for stage I disease, p53abn low-grade EEC are at substantial risk of disease recurrence. These findings highlight the clinical relevance of universal p53-testing, even in low-grade EEC, to identify women at increased risk of recurrence.

Outcomes of Patients with Oral Cavity Squamous Cell Carcinomas Treated with Adjuvant IMRT with Perineural Invasion

Patients with advanced oral cavity squamous cell carcinoma (OCSCC) have high rates of recurrence and dismal outcomes. Treatment consists of definitive surgery followed by risk-adapted adjuvant radiation therapy based on pathologic review. Perineural invasion (PNI) is thought to be an intermediate risk factor, leading to clinical uncertainty as to adjuvant therapy in the setting of PNI. We performed a single institution retrospective review of patients with OCSCC treated with adjuvant radiation with or without PNI and examined relapse-free survival (RFS) and overall survival (OS). We performed a single-institutional retrospective review of patients with OCSCC treated with adjuvant IMRT +/- chemotherapy after surgical resection from July 2002- August 2021 using our institution's Head and Neck SPORE database. Time to recurrence or death was calculated from end of RT. OCSCC within 5 years of RT was considered a recurrence, beyond this timeframe any OCSCC was considered a new primary. Univariate analysis of predictors for RFS and OS were performed using the Kaplan-Meier method with log-rank test. Factors significant on univariable analysis were entered into parsimonious cox multivariable analysis using forward selection methodology. A p-value <0.05 was considered significant in both analyses. In total, 494 patients with OCSCC were identified that received surgery and adjuvant IMRT. In this cohort, 48.8% of patients had pT4 tumors, 62.2% of patients had nodal involvement, and 40.3% of patients had extranodal extension. PNI was present in 63.6% of patients (n = 314). With regards to tumor subsite, 40.9% originated from the oral tongue, 21.5% originated from the gums, 18% originated from the floor of mouth, and 19.6% from the other sites. Median age was 59 years, and median adjuvant RT dose was 63 Gy (Interquartile range [IQR]) 60-66 Gy). The majority of patient received platinum-based chemotherapy (51.8%), and 44.1% of patients did not receive adjuvant chemotherapy. The 3-year RFS and OS with a median follow-up of 32 months (IQR 12-69 months) is presented in Table 1. On univariable analysis for OS, T stage (p = 0.003), N stage (p<0.001), PNI (p = 0.005), extranodal extension (ENE) (p<0.001), margin status (p = 0.038), and chemotherapy (p<0.001) were significant. On multivariable analysis, T stage (p<0.001), N stage (p = 0.010), PNI (p = 0.017), and ENE (p = 0.007) remained significant. Similar results were seen in the RFS analysis. In this large single institution study, PNI was a significant and independent negative predictive factor for RFS and OS in patients with OCSCC that had received definitive surgery followed by adjuvant IMRT. To our knowledge this is the largest study of its kind, and these findings can help guide clinical decision making for these patients.

The Early and Late Effects of High-Dose Irradiation on Cardiac Injury in a Rat Model

Radiation-induced heart disease is a critical concern after radiotherapy (RT) for thoracic and chest wall tumors; however, the biological effects and mechanisms are still unknown. In this study, we investigated dose-responsive functional and pathological changes in rat hearts at 1, 3, and 5 months after high-dose irradiation. Then, we sought to elucidate the underlying mechanisms of myocardial changes induced by high-dose irradiation. Whole hearts of rats (N = 72) were irradiated with a single fraction of 0 (control), 10, 20, or 30 Gy and allocated into three groups according to the follow-up period after RT: baseline, one, three, and five months. During follow-up periods, rats underwent functional evaluation by electrocardiogram and echocardiography at 4-week intervals. If a rat's body weight decreased by 20% or more, it was considered premature death, and the heart was explanted immediately. Otherwise, all hearts were explanted when each group's follow-up period was completed. Pathological changes of cardiac structures were evaluated using a light microscope after staining with hematoxylin-eosin, Masson's trichrome, α-smooth muscle actin, desmin, and connexin-43. All rats irradiated with 0 or 10 Gy completed their follow-up periods with continuously increasing body weight. However, among rats irradiated with 20 or 30 Gy, half of the rats died prematurely at 8-10 weeks after RT, and the remainder survived until 20 weeks. In echocardiography, increased wall thickness and E/E' ratio, and decreased end-diastolic volume were observed in 20-30 Gy groups compared to 0-10 Gy groups from 8 weeks after RT. Ejection fraction was preserved in all groups. In pathological review, 20-30 Gy groups demonstrated diffuse inflammation and vacuolization at 4 weeks. Then, at 8 weeks, prominent fibrotic changes and intercalated disc disruptions were observed. Notably, fibrotic changes were somewhat resolved at 20 weeks, but intercalated disc disruptions were not repaired until 20 weeks. The 0 and 10 Gy groups showed no significant changes in both functional and pathological analyses. Rats irradiated with 20 or 30 Gy showed diastolic dysfunction in functional analysis and time-dependent myocardial changes in pathological analysis. Radiation-induced fibrosis might be a "reactive" fibrosis, which could proceed to either a profibrotic course (progressive fibrosis) or an anti-fibrotic course (recovery phase). Further studies are needed to identify whether high-dose irradiation-induced cardiac fibrosis could be reversible.

Can We Improve the Quality of Care Delivered to Cervical Cancer Patients? Development of Quality Metrics and Quality Improvement Program at a Single Institution

Cervical cancer patients often face significant barriers to receiving high quality, multi-disciplinary standard of care therapy due to socio-economic factors and failures in the health care system. Other cancers, such as rectal cancer, requiring complex multi-disciplinary care, have shown improved outcomes with the use of standardized quality metrics. We hypothesized that developing evidence-based quality metrics for cervical cancer and tracking adherence in a large tertiary care medical system would allow identification of systemic issues that can then be addressed to improve quality of care and patient outcomes. We also implemented a weekly cervical cancer huddle in September 2021 attended by a physician, nurse practitioner, social workers, and other caregivers to discuss all newly diagnosed patients prior to treatment with a focus on improving quality in real time. Here we report our initial results. AnIRB-approved retrospective review of cervical cancer patients treated at our institution from January 2019 to December 2022 was performed using a data collection web application. We assessed quality metrics in newly diagnosed patients including: tumor board presentation, outside pathology review, receipt of PET-CT/MRI prior to treatment start, use of radiology and pathology synoptic reports, receipt of external beam radiation and brachytherapy, completion of chemotherapy and radiation within 56 days, receipt of post-treatment PET-CT, referral to social work, and laparotomy for radical hysterectomy. In addition, we tracked the impact of the "huddle" on pre-treatment quality metrics before and after implementation. One hundred seventy-three patients were identified with newly diagnosed cervical cancer; most were squamous cell carcinoma (61%). 44% were stage I, 39% stage II or III, and 16% stage IV. Over the entire study period, 65% of patients completed imaging prior to treatment start, 73% had a radiology synoptic report on MRI, 71% of hysterectomy patients had pathology synoptic reports, 90% of eligible patients had receipt of both external beam radiation and brachytherapy, 91% of eligible patients had completion of chemotherapy and radiation within 56 days, and 96% had a post-treatment PET-CT within 3-6 months. The impact of the huddle on pre-treatment quality metrics was evident: tumor board presentation increased from 38% to 73%, social work referral increased from 42% to 59%, outside pathology review increased from 64% to 83%, and use of laparotomy increased from 67% to 81%. Definingquality metrics in cervical cancer and tracking adherence can help identify areas of improvement in the continuum of care in a large healthcare system. A dedicated weekly huddle can help reduce barriers to diagnosis and initiation of treatment with earlier and increased referral to social work and increased multi-disciplinary review and discussion that can affect patient treatment and subsequent outcomes. Future work will focus on implementation of systemic processes to improve adherence to metrics.

Update on Epithelial-Mesenchymal Plasticity in Cancer Progression.

Epithelial-mesenchymal transition (EMT) is a cellular process by which epithelial cells lose their characteristics and acquire mesenchymal traits to promote cell movement. This program is aberrantly activated in human cancers and endows tumor cells with increased abilities in tumor initiation, cell migration, invasion, metastasis, and therapy resistance. The EMT program in tumors is rarely binary and often leads to a series of gradual or intermediate epithelial-mesenchymal states. Functionally, epithelial-mesenchymal plasticity (EMP) improves the fitness of cancer cells during tumor progression and in response to therapies. Here, we discuss the most recent advances in our understanding of the diverse roles of EMP in tumor initiation, progression, metastasis, and therapy resistance and address major clinical challenges due to EMP-driven phenotypic heterogeneity in cancer. Uncovering novel molecular markers and key regulators of EMP in cancer will aid the development of new therapeutic strategies to prevent cancer recurrence and overcome therapy resistance.

Tertiary lymphoid structure and neutrophil-lymphocyte ratio coordinately predict outcome of pembrolizumab.

Emerging evidence suggests that the presence of tertiary lymphoid structures (TLS) and neutrophil-lymphocyte ratio (NLR) in peripheral blood is associated with the treatment response to checkpoint inhibitors (CPIs), whereas there is limited knowledge regarding whether these factors reciprocally impact the treatment outcomes of CPIs in metastatic urothelial carcinoma (mUC). Herein, we investigated treatment outcomes of platinum-refractory mUC patients (50 cases with whole-exome and transcriptome sequencing) treated with pembrolizumab. The pathological review identified 24% of cases of TLS in the specimens. There was no significant difference in the NLR between the TLS- and TLS+ groups (p = 0.153). In the lower NLR group, both overall survival and progression-free survival were significantly longer in patients with TLS than in those without TLS, whereas the favorable outcomes associated with TLS were not observed in patients in the higher NLR group. We explored transcriptomic differences in UC with TLS. The TLS was comparably observed between luminal (20%) and basal (25%) tumor subtypes (p = 0.736). Exploring putative immune-checkpoint genes revealed that ICOSLG (B7-H2) was significantly increased in tumors with lower NLR. KRT expression levels exhibited higher basal cell markers (KRT5 and KRT17) in the higher NLR group and lower differentiated cell markers (KRT8 and KRT18) in patients with TLS. In conclusion, the improved outcomes of pembrolizumab treatment in mUC are restricted to patients with lower NLR. Our findings begin to elucidate a distinct molecular pattern for the presence of TLS according to the NLR in peripheral blood.

Antibody and B Cell Responses to SARS-CoV-2 Infection and Vaccination: The End of the Beginning.

As the COVID-19 pandemic has evolved during the past years, interactions between human immune systems, rapidly mutating and selected SARS-CoV-2 viral variants, and effective vaccines have complicated the landscape of individual immunological histories. Here, we review some key findings for antibody and B cell-mediated immunity, including responses to the highly mutated omicron variants; immunological imprinting and other impacts of successive viral antigenic variant exposures on antibody and B cell memory; responses in secondary lymphoid and mucosal tissues and non-neutralizing antibody-mediated immunity; responses in populations vulnerable to severe disease such as those with cancer, immunodeficiencies, and other comorbidities, as well as populations showing apparent resistance to severe disease such as many African populations; and evidence of antibody involvement in postacute sequelae of infection or long COVID. Despite the initial phase of the pandemic ending, human populations will continue to face challenges presented by this unpredictable virus.

Genetics and Pathogenesis of Dystonia.

Dystonia is a clinically and genetically highly heterogeneous neurological disorder characterized by abnormal movements and postures caused by involuntary sustained or intermittent muscle contractions. A number of groundbreaking genetic and molecular insights have recently been gained. While they enable genetic testing and counseling, their translation into new therapies is still limited. However, we are beginning to understand shared pathophysiological pathways and molecular mechanisms. It has become clear that dystonia results from a dysfunctional network involving the basal ganglia, cerebellum, thalamus, and cortex. On the molecular level, more than a handful of, often intertwined, pathways have been linked to pathogenic variants in dystonia genes, including gene transcription during neurodevelopment (e.g., KMT2B, THAP1), calcium homeostasis (e.g., ANO3, HPCA), striatal dopamine signaling (e.g., GNAL), endoplasmic reticulum stress response (e.g., EIF2AK2, PRKRA, TOR1A), autophagy (e.g., VPS16), and others. Thus, different forms of dystonia can be molecularly grouped, which may facilitate treatment development in the future.

Hysteroscopic management of infected and partially discharged desidual cast in an adolescent: A case report and review of the literature in adolescents

Objective: Decidual cast in other words membranous dysmenorrhea is a rare entity. Hereby, we report the first infected case caused by drospirenon containing contraceptive use and managed successfully by hysteroscopy.&#x0D; Case presentation: A13 year-old girl started on drospirenon containing contraceptive theraphy since her menarche resulted in menorrhagia and anemia that requires transfusion. On follow up, she developed a partially discharged infected mass revealed to be a decidual cast on pathological review.&#x0D; Discussion: Membranous dysmenorrhea occurs more frequently in the adolescent and young adult population. All cases in this review were on hormonal theraphy except one occured spontaneously. Cast formation of the immature uterus after menarche is an exaggerated response to dose-independent increased progestin levels.&#x0D; Conclusion: We conclude that diagnosis of decidual cast/membranous dysmenorrhea should be kept in mind for colicky pain with bleeding of adolescents under hormonal contraceptive therapy and partially discharged cases may be managed successfully by hysteroscopy.

Dynamic Multiplex Tissue Imaging in Inflammation Research.

Inflammation is a highly dynamic process with immune cells that continuously interact with each other and parenchymal components as they migrate through tissue. The dynamic cellular responses and interaction patterns are a function of the complex tissue environment that cannot be fully reconstructed ex vivo, making it necessary to assess cell dynamics and changing spatial patterning in vivo. These dynamics often play out deep within tissues, requiring the optical focus to be placed far below the surface of an opaque organ. With the emergence of commercially available two-photon excitation lasers that can be combined with existing imaging systems, new avenues for imaging deep tissues over long periods of time have become available. We discuss a selected subset of studies illustrating how two-photon microscopy (2PM) has helped to relate the dynamics of immune cells to their in situ function and to understand the molecular patterns that govern their behavior in vivo. We also review some key practical aspects of 2PM methods and point out issues that can confound the results, so that readers can better evaluate the reliability of conclusions drawn using this technology.