Immunoglobulin G N-glycan markers of accelerated biological aging during chronic HIV infection.

People living with HIV (PLWH) experience increased vulnerability to premature aging and inflammation-associated comorbidities, even when HIV replication is suppressed by antiretroviral therapy (ART). However, the factors associated with this vulnerability remain uncertain. In the general population, alterations in the N-glycans on IgGs trigger inflammation and precede the onset of aging-associated diseases. Here, we investigate the IgG N-glycans in cross-sectional and longitudinal samples from 1214 women and men, living with and without HIV. PLWH exhibit an accelerated accumulation of pro-aging-associated glycan alterations and heightened expression of senescence-associated glycan-degrading enzymes compared to controls. These alterations correlate with elevated markers of inflammation and the severity of comorbidities, potentially preceding the development of such comorbidities. Mechanistically, HIV-specific antibodies glycoengineered with these alterations exhibit a reduced ability to elicit anti-HIV Fc-mediated immune activities. These findings hold potential for the development of biomarkers and tools to identify and prevent premature aging and comorbidities in PLWH.

Curative Resection of T1a Inlet Patch Adenocarcinoma With Traction-Assisted Endoscopic Submucosal Dissection.

Esophageal inlet patch (EIP) adenocarcinoma is extremely rare. We present a case of a 58-year-old man who underwent a diagnostic esophagogastroduodenoscopy for dysphagia and found to have a 2 cm polypoid mass arising from an EIP. Biopsies and staging were consistent with T1aN0M0 EIP adenocarcinoma. While surgical resection was the main method of treatment of these lesions, very few case reports have shown that endoscopic resection can successfully remove these lesions. After multidisciplinary discussion, the patient underwent curative traction-assisted endoscopic submucosal dissection-which is the first known case report to highlight the success of this technique.

Plasma Glycomic Markers of Accelerated Biological Aging During Chronic HIV Infection.

People with HIV (PWH) experience an increased vulnerability to premature aging and inflammation-associated comorbidities, even when HIV replication is suppressed by antiretroviral therapy (ART). However, the factors that contribute to or are associated with this vulnerability remain uncertain. In the general population, alterations in the glycomes of circulating IgGs trigger inflammation and precede the onset of aging-associated diseases. Here, we investigate the IgG glycomes of cross-sectional and longitudinal samples from 1,216 women and men, both living with virally suppressed HIV and those without HIV. Our glycan-based machine learning models indicate that living with chronic HIV significantly accelerates the accumulation of pro-aging-associated glycomic alterations. Consistently, PWH exhibit heightened expression of senescence-associated glycan-degrading enzymes compared to their controls. These glycomic alterations correlate with elevated markers of inflammatory aging and the severity of comorbidities, potentially preceding the development of such comorbidities. Mechanistically, HIV-specific antibodies glycoengineered with these alterations exhibit reduced anti-HIV IgG-mediated innate immune functions. These findings hold significant potential for the development of glycomic-based biomarkers and tools to identify and prevent premature aging and comorbidities in people living with chronic viral infections.

The African-centric P47S Variant of TP53 Confers Immune Dysregulation and Impaired Response to Immune Checkpoint Inhibition.

The tumor suppressor TP53 is the most frequently mutated gene in cancer and is mutationally inactivated in 50% of sporadic tumors. Inactivating mutations in TP53 also occur in Li Fraumeni syndrome (LFS). In addition to germline mutations in TP53 in LFS that completely inactivate this protein, there are many more germline mutant forms of TP53 in human populations that partially inactivate this protein: we call these partially inactivating mutations "hypomorphs." One of these hypomorphs is a SNP that exists in 6%-10% of Africans and 1%-2% of African Americans, which changes proline at amino acid 47 to serine (Pro47Ser; P47S). We previously showed that the P47S variant of p53 is intrinsically impaired for tumor suppressor function, and that this SNP is associated with increased cancer risk in mice and humans. Here we show that this SNP also influences the tumor microenvironment, and the immune microenvironment profile in P47S mice is more protumorigenic. At basal levels, P47S mice show impaired memory T-cell formation and function, along with increased anti-inflammatory (so-called "M2") macrophages. We show that in tumor-bearing P47S mice, there is an increase in immunosuppressive myeloid-derived suppressor cells and decreased numbers of activated dendritic cells, macrophages, and B cells, along with evidence for increased T-cell exhaustion in the tumor microenvironment. Finally, we show that P47S mice demonstrate an incomplete response to anti-PD-L1 therapy. Our combined data suggest that the African-centric P47S variant leads to both intrinsic and extrinsic defects in tumor suppression. Significance: Findings presented here show that the P47S variant of TP53 influences the immune microenvironment, and the immune response to cancer. This is the first time that a naturally occurring genetic variant of TP53 has been shown to negatively impact the immune microenvironment and the response to immunotherapy.

An African-Specific Variant of TP53 Reveals PADI4 as a Regulator of p53-Mediated Tumor Suppression.

TP53 is the most frequently mutated gene in cancer, yet key target genes for p53-mediated tumor suppression remain unidentified. Here, we characterize a rare, African-specific germline variant of TP53 in the DNA-binding domain Tyr107His (Y107H). Nuclear magnetic resonance and crystal structures reveal that Y107H is structurally similar to wild-type p53. Consistent with this, we find that Y107H can suppress tumor colony formation and is impaired for the transactivation of only a small subset of p53 target genes; this includes the epigenetic modifier PADI4, which deiminates arginine to the nonnatural amino acid citrulline. Surprisingly, we show that Y107H mice develop spontaneous cancers and metastases and that Y107H shows impaired tumor suppression in two other models. We show that PADI4 is itself tumor suppressive and that it requires an intact immune system for tumor suppression. We identify a p53-PADI4 gene signature that is predictive of survival and the efficacy of immune-checkpoint inhibitors. SIGNIFICANCE: We analyze the African-centric Y107H hypomorphic variant and show that it confers increased cancer risk; we use Y107H in order to identify PADI4 as a key tumor-suppressive p53 target gene that contributes to an immune modulation signature and that is predictive of cancer survival and the success of immunotherapy. See related commentary by Bhatta and Cooks, p. 1518. This article is highlighted in the In This Issue feature, p. 1501.

Diversity, equity, and inclusion in the melanoma research community.

The inaugural Diversity and Inclusion in Science Session was held during the 2021 Society for Melanoma Research (SMR) congress. The goal of the session was to discuss diversity, equity, and inclusion in the melanoma research community and strategies to promote the advancement of underrepresented melanoma researchers. An international survey was conducted to assess the diversity, equity, and inclusion (DEI) climate among researchers and clinicians within the Society for Melanoma Research (SMR). The findings suggest there are feelings and experiences of inequity, bias, and harassment within the melanoma community that correlate with one's gender, ethnic/racial group, and/or geographic location. Notably, significant reports of inequity in opportunity, discrimination, and sexual harassment demonstrate there is much work remaining to ensure all scientists in our community experience an academic workplace culture built on mutual respect, fair access, inclusion, and equitable opportunity.

Convalescent Plasma for Preventing Critical Illness in COVID-19: a Phase 2 Trial and Immune Profile.

The COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an unprecedented event requiring frequent adaptation to changing clinical circumstances. Convalescent immune plasma (CIP) is a promising treatment that can be mobilized rapidly in a pandemic setting. We tested whether administration of SARS-CoV-2 CIP at hospital admission could reduce the rate of ICU transfer or 28-day mortality or alter levels of specific antibody responses before and after CIP infusion. In a single-arm phase II study, patients >18 years-old with respiratory symptoms with confirmed COVID-19 infection who were admitted to a non-ICU bed were administered two units of CIP within 72 h of admission. Levels of SARS-CoV-2 detected by PCR in the respiratory tract and circulating anti-SARS-CoV-2 antibody titers were sequentially measured before and after CIP transfusion. Twenty-nine patients were transfused high titer CIP and 48 contemporaneous comparable controls were identified. All classes of antibodies to the three SARS-CoV-2 target proteins were significantly increased at days 7 and 14 post-transfusion compared with baseline (P < 0.01). Anti-nucleocapsid IgA levels were reduced at day 28, suggesting that the initial rise may have been due to the contribution of CIP. The groups were well-balanced, without statistically significant differences in demographics or co-morbidities or use of remdesivir or dexamethasone. In participants transfused with CIP, the rate of ICU transfer was 13.8% compared to 27.1% for controls with a hazard ratio 0.506 (95% CI 0.165-1.554), and 28-day mortality was 6.9% compared to 10.4% for controls, hazard ratio 0.640 (95% CI 0.124-3.298). IMPORTANCE Transfusion of high-titer CIP to non-critically ill patients early after admission with COVID-19 respiratory disease was associated with significantly increased anti-SARS-CoV-2 specific antibodies (compared to baseline) and a non-significant reduction in ICU transfer and death (compared to controls). This prospective phase II trial provides a suggestion that the antiviral effects of CIP from early in the COVID-19 pandemic may delay progression to critical illness and death in specific patient populations. This study informs the optimal timing and potential population of use for CIP in COVID-19, particularly in settings without access to other interventions, or in planning for future coronavirus pandemics.

SMOKING, RURAL RESIDENCE AND DIABETES AS RISK FACTORS FOR PRESUMED OCULAR HISTOPLASMOSIS SYNDROME.

PURPOSE: To investigate the relationship of smoking, urbanicity, and diabetes to presumed ocular histoplasmosis syndrome (POHS) and associated choroidal neovascularization (CNV). METHODS: Medical records of 751 adult patients with POHS were reviewed, including 603 patients without CNV and 148 patients with CNV. Age-matched and gender-matched controls were randomly selected from the same practice for comparison. Statistical comparisons of smoking history, urbanicity, and diabetic history were performed using chi-square and conditional logistic regression analyses. RESULTS: Increased rates of current or former smoking, rural residence, and diabetes were found in patients with POHS compared with controls. POHS patients with CNV had increased rates of current or former smoking and rural residence as compared with controls. CONCLUSION: A history of current or past smoking is associated with an increased risk of developing both POHS alone and POHS with CNV. We did not find a significant additional risk of smoking on the development of CNV in patients with POHS. Patients living in rural locations are more likely than those in urban locations to develop both POHS and POHS with CNV. Diabetics may be more likely to develop POHS than nondiabetics.

The continual impact of the Paris System on urine cytology, a 3-year experience.

OBJECTIVE: The development of the Paris System (TPS) has provided a standard and reproducible system for reporting urine cytopathology. Our goal was to study the impact of TPS on the diagnostic accuracy of urine cytology since we began using it in 2016. METHODS: We performed a retrospective study of all urine cytology specimens received at our institution from January 2015 through July 2017. Cases were included in the study if they had corresponding surgical pathology follow up. In total, 3829 cases were identified over this time period, with 381 cases meeting inclusion criteria, comprising 87 cases from 2015, 166 from 2016 and 128 from 2017. Using the histopathology diagnosis as the gold standard, sensitivity, specificity, negative predictive value (NPV), positive predictive value (PPV) and diagnostic accuracy (DA) for the detection of carcinoma were calculated. RESULTS: Before TPS, urine cytology had a sensitivity of 100.0%, specificity of 12.5%, PPV of 83.5%, NPV of 100.0% and DA of 83.9%. After TPS, for 2016, urine cytology had sensitivity of 87.1%, specificity of 95.9%, PPV of 96.4%, NPV of 85.4% and DA of 91.0%. For 2017 after TPS, the sensitivity was 81.7%, specificity was 100.0%, PPV was 100.0%, NPV was 81.4% and DA was 89.8%. CONCLUSION: For the detection of urinary tract malignancy, after switching to TPS, we observed a marked increase in urine cytology specificity and PPV, both of which continued to gradually increase from 2016 to 2017. The DA also improved with TPS.

Procurement, Transportation, and Storage of Saliva, Buccal Swab, and Oral Wash Specimens.

Saliva and oral/buccal samples have become increasingly valuable sources of genetic material for clinical applications. The DNA obtained by these samples is of comparable quality to that from blood samples. This, coupled with the ease of collecting saliva and oral/buccal samples, has led to increased numbers of such samples being incorporated into biobanks. This chapter will detail the steps involved in procuring, transporting, and storing saliva, buccal swabs, and oral wash samples for further use in downstream applications.

Comparison of Cytopathologist-Performed Ultrasound-Guided Fine-Needle Aspiration With Cytopathologist-Performed Palpation-Guided Fine-Needle Aspiration: A Single Institutional Experience.

CONTEXT.­: Although fine-needle aspiration (FNA) practice by pathologists is now well established, it has been primarily performed by manual palpation. In recent years, pathologists have begun to venture into ultrasound-guided FNAs (UGFNAs). Reports on experiences with this relatively new technique for pathologists have shown promising results. However to date, there have been few studies in the literature comparing pathologist-performed UGFNA with the more traditional pathologist-performed palpation-guided FNA (PGFNA). OBJECTIVE.­: To compare UGFNA to PGFNA by cytopathologists at an academic medical center. DESIGN.­: A retrospective study of FNAs performed by cytopathologists within the University of California, Los Angeles (UCLA) pathology departmental FNA clinic was performed. Data collected included performance technique (UGFNA versus PGFNA), lesion site and size, adequacy status (nondiagnostic rate), and number of passes per procedure. Corresponding surgical pathology/flow cytometric/cytogenetic result follow-up was compared to FNA results. Findings between UGFNA and PGFNA cases were compared. RESULTS.­: Of 1029 FNA cases during the study period, there were 449 UGFNA cases (43.6%) and 580 PGFNA cases (56.4%). Nondiagnostic rates with UGFNA and PGFNA were 6.7% (30 of 449 cases) and 20.7% (120 of 580 cases), respectively. Nondiagnostic rate was also significantly lower with UGFNA than with PGFNA for lesions within the thyroid (6.0% versus 33.3%), head and neck (6.6% versus 21.2%), and salivary gland (6.2% versus 17.1%), and across all nodule sizes. A total of 495 of 1029 FNA cases (48.1%) had follow-up. Discordance rate was significantly lower with UGFNA than with PGFNA (5.4% versus 12.8%). CONCLUSIONS.­: This study shows improved performance characteristics of cytopathologist-performed UGFNA versus PGFNA.

Pathological and 3 Tesla Volumetric Magnetic Resonance Imaging Predictors of Biochemical Recurrence after Robotic Assisted Radical Prostatectomy: Correlation with Whole Mount Histopathology.

PURPOSE: We sought to identify the clinical and magnetic resonance imaging variables predictive of biochemical recurrence after robotic assisted radical prostatectomy in patients who underwent multiparametric 3 Tesla prostate magnetic resonance imaging. MATERIALS AND METHODS: We performed an institutional review board approved, HIPAA (Health Insurance Portability and Accountability Act) compliant, single arm observational study of 3 Tesla multiparametric magnetic resonance imaging prior to robotic assisted radical prostatectomy from December 2009 to March 2016. Clinical, magnetic resonance imaging and pathological information, and clinical outcomes were compiled. Biochemical recurrence was defined as prostate specific antigen 0.2 ng/cc or greater. Univariate and multivariate regression analysis was performed. RESULTS: Biochemical recurrence had developed in 62 of the 255 men (24.3%) included in the study at a median followup of 23.5 months. Compared to the subcohort without biochemical recurrence the subcohort with biochemical recurrence had a greater proportion of patients with a high grade biopsy Gleason score, higher preoperative prostate specific antigen (7.4 vs 5.6 ng/ml), intermediate and high D'Amico classifications, larger tumor volume on magnetic resonance imaging (0.66 vs 0.30 ml), higher PI-RADS® (Prostate Imaging-Reporting and Data System) version 2 category lesions, a greater proportion of intermediate and high grade radical prostatectomy Gleason score lesions, higher pathological T3 stage (all p <0.01) and a higher positive surgical margin rate (19.3% vs 7.8%, p = 0.016). On multivariable analysis only tumor volume on magnetic resonance imaging (adjusted OR 1.57, p = 0.016), pathological T stage (adjusted OR 2.26, p = 0.02), positive surgical margin (adjusted OR 5.0, p = 0.004) and radical prostatectomy Gleason score (adjusted OR 2.29, p = 0.004) predicted biochemical recurrence. CONCLUSIONS: In this cohort tumor volume on magnetic resonance imaging and pathological variables, including Gleason score, staging and positive surgical margins, significantly predicted biochemical recurrence. This suggests an important new imaging biomarker.

Do Nonseminomatous Germ Cell Tumors of the Testis With Lymphovascular Invasion of the Spermatic Cord Merit Staging as pT3?

The staging of testicular nonseminomatous germ cell tumors (NSGCTs) with lymphovascular invasion (LVI) of the spermatic cord in the absence of cord parenchymal involvement remains controversial. Our previous study showed that tumors with spermatic cord LVI present at a higher clinical stage than tumors with LVI confined to the testis (pT2). We compared NSGCTs with LVI of the spermatic cord without direct involvement of the spermatic cord soft tissues to pT3 tumors to help clarify the appropriate staging of this histologic finding. A retrospective, multi-institutional review was performed to identify cases of NSGCTs with LVI in the spermatic cord without soft tissue invasion of the cord. The clinical-pathologic findings were compared with NSGCTs with spermatic cord soft tissue invasion (pT3). We identified 38 pT2 NSGCTs with LVI in the spermatic cord without soft tissue invasion of the cord and 89 pT3 tumors. There were no significant differences in patient age, tumor size, or clinical stage at presentation between the 2 groups. There were no significant differences in dominant histologic subtype, rete testis invasion, hilar soft tissue invasion, or margin status. There were no significant differences in disease recurrence/progression (P=0.63), recurrence/progression after chemotherapy (P=0.35), or death (P=0.51) between patients with only spermatic cord LVI versus patients with cord soft tissue invasion. In patients with pT2 NSGCTs according to the current staging, LVI in the spermatic cord without cord soft tissue invasion is comparable with pT3 tumors in terms of clinical stage at presentation as well as disease recurrence and survival.

The Significance of Lymphovascular Invasion of the Spermatic Cord in the Absence of Cord Soft Tissue Invasion.

CONTEXT: - Testicular germ cell tumors with lymphovascular invasion (LVI) are staged pT2, and those with spermatic cord involvement are staged pT3. OBJECTIVE: - To study the clinical significance of LVI within the spermatic cord without direct involvement of the cord soft tissues. DESIGN: - A retrospective, multi-institutional review was performed on testicular GCTs with spermatic cord LVI in the absence of cord soft tissue invasion. RESULTS: - Forty-four germ cell tumors had LVI in the spermatic cord without soft tissue invasion; 37 of 44 patients (84%) had nonseminomatous germ cell tumors (NSGCT), and 7 (16%) had pure seminomas. Patients with NSGCTs and spermatic cord LVI had worse clinical outcomes compared with patients with pure seminoma and spermatic cord LVI (P = .008). We then compared patients with NSGCTs and spermatic cord LVI (n = 37) to patients with NSGCTs and LVI limited to the testis (n = 32). A significantly greater percentage of patients with LVI in the spermatic cord presented with advanced clinical stage (76% versus 50%; P = .01). There was no statistically significant difference in disease recurrence/progression or death between patients with spermatic cord LVI and patients with LVI limited to the testis (P = .40; P = .50). There was no significant difference in the presence of embryonal dominant histology (P = .30) or rete testis invasion (P = .50) between the 2 groups. More hilar soft tissue invasion was seen in patients with LVI present in the spermatic cord (P = .004). CONCLUSIONS: - In patients with NSGCTs, LVI in the spermatic cord, without soft tissue invasion, is associated with worse clinical stage at presentation compared with patients with LVI confined to the testis.

In-Bore 3-T MR-guided Transrectal Targeted Prostate Biopsy: Prostate Imaging Reporting and Data System Version 2-based Diagnostic Performance for Detection of Prostate Cancer.

Purpose To determine the diagnostic yield of in-bore 3-T magnetic resonance (MR) imaging-guided prostate biopsy and stratify performance according to Prostate Imaging Reporting and Data System (PI-RADS) versions 1 and 2. Materials and Methods This study was HIPAA compliant and institution review board approved. In-bore 3-T MR-guided prostate biopsy was performed in 134 targets in 106 men who (a) had not previously undergone prostate biopsy, (b) had prior negative biopsy findings with increased prostate-specific antigen (PSA) level, or (c) had a prior history of prostate cancer with increasing PSA level. Clinical, diagnostic 3-T MR imaging was performed with in-bore guided prostate biopsy, and pathology data were collected. The diagnostic yields of MR-guided biopsy per patient and target were analyzed, and differences between biopsy targets with negative and positive findings were determined. Results of logistic regression and areas under the curve were compared between PI-RADS versions 1 and 2. Results Prostate cancer was detected in 63 of 106 patients (59.4%) and in 72 of 134 targets (53.7%) with 3-T MR imaging. Forty-nine of 72 targets (68.0%) had clinically significant cancer (Gleason score ≥ 7). One complication occurred (urosepsis, 0.9%). Patients who had positive target findings had lower apparent diffusion coefficient values (875 × 10-6 mm2/sec vs 1111 × 10-6 mm2/sec, respectively; P < .01), smaller prostate volume (47.2 cm3 vs 75.4 cm3, respectively; P < .01), higher PSA density (0.16 vs 0.10, respectively; P < .01), and higher proportion of PI-RADS version 2 category 3-5 scores when compared with patients with negative target findings. MR targets with PI-RADS version 2 category 2, 3, 4, and 5 scores had a positive diagnostic yield of three of 23 (13.0%), six of 31 (19.4%), 39 of 50 (78.0%), and 24 of 29 (82.8%) targets, respectively. No differences were detected in areas under the curve for PI-RADS version 2 versus 1. Conclusion In-bore 3-T MR-guided biopsy is safe and effective for prostate cancer diagnosis when stratified according to PI-RADS versions 1 and 2. ©RSNA, 2016.

Adult Patient with Synchronous Gastrointestinal Stromal Tumor and Xp11 Translocation-Associated Renal Cell Carcinoma: A Unique Case Presentation with Discussion and Review of Literature.

Gastrointestinal stromal tumor (GIST) is the most common primary mesenchymal tumor of the gastrointestinal tract. This entity comprises a wide spectrum of tumors that vary from benign to overtly malignant, with the majority of these tumors harboring oncogenic mutations of the KIT receptor tyrosine kinase that can aid in diagnosis as well as in targeted therapy. Although the majority of GISTs are sporadic, there are forms that are associated with a variety of syndromes including Carney-Stratakis syndrome and neurofibromatosis type 1, as well as a subset of familial GIST syndromes that are caused by germline mutations in KIT or PDGFRA. Here, we describe an unusual case of a patient who was found to have a large abdominal GIST with an incidentally found Xp11 translocation-associated renal carcinoma. The karyotype of the renal carcinoma revealed an unbalanced rearrangement involving an (X;22) translocation at Xp11.2 and 22p11.2, which has not been reported in the literature. Although GISTs have shown an association with other primary malignant neoplasms, including simultaneous presence with unilateral clear cell renal cell carcinoma and bilateral papillary renal cell carcinomas, we describe the first reported case of synchronous GIST and Xp11 translocation-associated renal cell carcinoma.