Glycogenic hepatopathy is associated with type 1 diabetes mellitus in only a minority of cases in a contemporary adult population

ObjectivesThis study examines the clinical-pathological profiles of patients with glycogenic hepatopathy in a contemporary cohort of patients at an adult acute care hospital.MethodsLiver biopsies with glycogenic hepatopathy were retrieved from the departmental surgical pathology database, the histological findings were studied, and the clinical findings were reviewed.ResultsFive cases of glycogenic hepatopathy were found, including cases associated with type 1 diabetes mellitus (n = 1), type 2 diabetes mellitus (n = 1), corticosteroids (n = 2), and anorexia (n = 2, including the patient with type 1 diabetes). AST and ALT were normal to mildly elevated (13–115 U/L and 7–126 U/L, respectively). Trace ascites was present in two patients. Hepatomegaly was only present in the patient with type 1 diabetes at the time of diagnosis.ConclusionsFour of five cases were associated with etiologies other than type 1 diabetes, which is widely reported as the most common etiology of glycogenic hepatopathy. This study suggests that etiologies currently only rarely recognized may actually be more common causes of glycogenic hepatopathy than type 1 diabetes in a contemporary adult population. It is important not only to recognize that these rarely reported causes of glycogenic hepatopathy may be underrecognized, but that the clinical presentation may also be mild.     

Ultrastructural examination of skin biopsies may assist in diagnosing mitochondrial cytopathy when muscle biopsies yield negative results

Ultrastructural evaluation of skin biopsies has been utilized for diagnosis of mitochondrial disease. This study investigates how frequently skin biopsies reveal mitochondrial abnormalities, correlates skin and muscle biopsy findings, and describes clinical diagnoses rendered following the evaluation. A retrospective review of surgical pathology reports from 1990 to 2015 identified skin biopsies examined by electron microscopy for suspected metabolic disease. A total of 630 biopsies were included from 615 patients. Of these patients, 178 also underwent a muscle biopsy. Of the 630 skin biopsies, 75 (12%) showed ultrastructural abnormalities and 34 (5%) specifically showed mitochondrial abnormalities including increased size (n = 27), reduced or abnormal cristae (n = 23), dense matrices (n = 20), and increased number (n = 8). Additional findings included lysosomal abnormalities (n = 13), lipid accumulation (n = 2) or glycogen accumulation (n = 1). Of the 34 patients with mitochondrial abnormalities on skin biopsy, 20 also had muscle biopsies performed and nine showed abnormalities suggestive of a mitochondrial disorder including absent cytochrome oxidase staining (n = 2), increased subsarcolemmal NADH, SDH, or cytochrome oxidase staining (n = 1), or ultrastructural findings including large mitochondrial size (n = 5), abnormal mitochondrial structure (n = 5), and increased mitochondrial number (n = 4). The most common presenting symptoms were intellectual disability (n = 13), seizures (n = 12), encephalopathy (n = 9), and gastrointestinal disturbances (n = 9). At last known follow-up, 12 patients had a definitive diagnosis of a mitochondrial disorder. One patient each had Complex I deficiency, Complex III deficiency, Charcot-Marie-Tooth disease, pyruvate dehydrogenase deficiency, and Phelan-McDermid syndrome. Our results suggest that skin biopsy sometimes yields diagnostic clues suggestive of a mitochondrial cytopathy in cases with a negative muscle biopsy.     

Paratesticular tumors. A clinicopathological study from a single tertiary hospital in North India

ObjectiveParatesticular tumors (PTT) are rare and form a heterogenous group, ranging from benign to malignant high grade sarcomas. This study was undertaken to describe the clinicopathological spectrum of PTTs received over a 20-year period.MethodsAll primary and secondary PTTs diagnosed from 2000 to 2019 in the pathology department of a tertiary care hospital in North India were retrospectively reviewed. Gross, histopathological features and immunohistochemistry (IHC) findings were correlated with clinical details.ResultsA total of 169 intra-scrotal tumors were diagnosed during the study period, out of which there were 30 PTTs (in 27 patients) comprising 17.75%. Age range was 4 to 85 years (median 58 years). Benign PTTs were the commonest (n = 21, 70%), followed by metastasis to the paratesticular region (n = 6, 20%) and then primary malignant PTTs (n = 3, 10%). The commonest benign PTT was lipoma (n = 16, 76.19%), followed by adenomatoid tumor (n = 3, 14.28%) with one case each (4.76%) of cellular angiofibroma and hemangioma. Among primary malignant PTT, there were two cases of rhabdomyosarcoma, and one case of biphasic malignant mesothelioma. Metastatic tumors included four cases of prostatic adenocarcinoma, and one case each of pancreatic signet ring cell carcinoma and clear cell renal cell carcinoma.ConclusionPTTs show a wide clinicopathological spectrum. Benign PTTs are commoner than malignant PTTs. Meticulous grossing and histopathological examination supplemented by IHC is essential for an accurate diagnosis of this heterogenous class of tumors, which influences the role of adjuvant therapy and patient prognosis.     

Luminex screening first vs. direct single antigen bead assays: Different strategies for HLA antibody monitoring after kidney transplantation

Main problemLuminex panel and single antigen beads (SAB) are used for screening and DSA specificity determination respectively. The cost of SAB may limit its general use, so some labs perform SAB tests only after positive screening.MethodsWe compared both strategies: 1) SAB only if positive screening with kits from manufacturer A, and 2) direct SAB from manufacturer B, and correlate their sensitivity with histological findings.ResultsWe selected 118 kidney transplant recipients with a normal biopsy (n = 19), histological antibody-mediated damage (ABMR, n = 52) or interstitial fibrosis/tubular atrophy (IFTA, n = 47) following Banff 2015 and 2017 classification.Direct SAB detected DSA in 13 patients missed by screening. Strategy 1 detected DSA in 0% normal, 61.5% ABMR and 8.5% IFTA patients; percentages with strategy 2 were 5.2%, 78.8% and 14.8% (p=0.004). Strategy 2 identified DSA allowing full ABMR diagnosis in 17% cases missed by strategy 1. Thereafter, direct SAB from manufacturer A confirmed DSA in 46% DSA-positive cases with strategy 2 (55.5% ABMR cases).ConclusionsLuminex screening failed to identify clinically relevant HLA antibodies, hampering DSA detection in patients with possible ABMR. Direct SAB testing should be the chosen strategy for post-transplantation monitoring, albeit direct SAB from the two existing manufacturers may diverge in as much as 50% of cases.     

Histopathological features of systemic sclerosis-associated myopathy: A scoping review

BackgroundScleromyositis (SM) is an emerging subset of myositis associated with features of systemic sclerosis (SSc) but it is currently not recognized as a distinct histopathological subset by the European NeuroMuscular Center (ENMC). Our aim was to review studies reporting muscle biopsies from SSc patients with myositis and to identify unique histopathological features of SM.MethodsA scoping review was conducted and included all studies reporting histopathological findings in SSc patients with myositis searching the following databases: PubMed, MEDLINE, EMBASE, CINAHL and EBM-Reviews. Clinical, serological, and histopathological data were extracted using a standardized protocol.ResultsOut of 371 citations, 77 studies that included 559 muscle biopsies were extracted. Fifty-seven percent (n = 227/400) had inflammatory infiltrates, predominantly T cells, which were endomysial (49%), perimysial (42%) and perivascular (41%). Few studies (18%, n = 8/44) evaluated the presence of B-cells. Myofiber atrophy was present in 48% (n = 104/218) of biopsies, and was predominantly perifascicular in 19% (n = 6/31), with necrosis reported in 56% (n = 162/290) of cases. Sarcolemmal MHC-I upregulation was found in 72% (n = 64/89) of biopsies. Non-specified C5b-9 deposition was described in 39% of muscle biopsies (n = 28/72). Neurogenic features were present in 23% (n = 44/191); endomysial fibrosis was reported in 35% (n = 120/340); and rimmed vacuoles were observed in 32% (n = 11/34) of biopsies. Capillaropathy, such as capillary dropout and/or ultrastructural endothelial abnormalities, was reported in 33% (n = 43/129) of cases. Reported ENMC categories were mainly polymyositis (21%), non-specific myositis (19%), immune-mediated necrotizing myopathy (16%), and dermatomyositis (8%). Histopathological features were analyzed according to serological subtypes in 28 studies, including anti-PM-Scl (n = 48), -Ku (n = 23) and -U1RNP (n = 90). Most of these biopsies demonstrated inflammatory infiltrates (range 49–85%) as well as MHC-I expression (range 63–81%). Necrosis was associated with anti-Ku (85%) and anti-U1RNP (73%), while anti-Ku was also associated with neurogenic features and rimmed vacuoles in 57% and 25% of cases, respectively.ConclusionOur review suggests that SM is characterized by heterogeneous pathological features using definitions included in current histopathological criteria. Whether a distinct histopathological signature exists in SM remains to be determined. SSc-specific and SSc-associated autoantibodies may help define more homogeneous histopathological subsets.     

Emerging psychiatric disorders in Kleine‐Levin syndrome

In Kleine‐Levin syndrome (KLS), episodes of hypersomnia and cognitive, psychiatric and behavioural disturbances alternate with asymptomatic periods in adolescents. We evaluated whether psychiatric disorders would emerge during asymptomatic periods in a naturalistic, uncontrolled clinical cohort. Patients with primary KLS underwent psychiatric interviews at diagnosis and every year for 1–10 years, leading to diagnosis of former and present comorbid psychiatric disorders. Among the 115 patients (65.2% male and aged 16.1 ± 4.8 years at KLS onset), 19 (16.5%) had a history of psychiatric disorder prior to KLS onset, which persisted afterwards in 10. Twenty‐five (21%) patients developed a new, comorbid psychiatric disorder 1–6 years after KLS onset, during ‘asymptomatic’ periods, including mood disorders (n = 14; including major depressive episodes, n = 8; recurrent depressive episodes, n = 2; bipolar I disorder, n = 1; dysthymic disorder, n = 1; adjustment disorder with depressive mood, n = 1; and mood disorder not otherwise specified, n = 1), anxiety disorders (n = 7), eating disorders (n = 2), psychotic disorders not otherwise specified (n = 2), schizoaffective disorder (n = 1) and cannabis dependence (n = 1). Six patients attempted suicide: two before and two after KLS onset, and two during episodes. Female sex, longer disease course, longer time incapacitated (356 ± 223 versus 155 ± 186 days) and more frequent psychiatric symptoms during episodes (but no family or personal history of psychiatric disorders) were associated with emerging psychiatric disorders. Contrary to the alleged benignity of KLS and normality between episodes, one KLS patient in five suffers from emerging psychiatric disorders. These disorders may depend on personal vulnerability and, most probably, on psychiatric symptoms during episodes.     

Genotype-phenotype associations in a large PTEN Hamartoma Tumor Syndrome (PHTS) patient cohort

BackgroundPathogenic PTEN germline variants cause PTEN Hamartoma Tumor Syndrome (PHTS), a rare disease with a variable genotype and phenotype. Knowledge about these spectra and genotype-phenotype associations could help diagnostics and potentially lead to personalized care. Therefore, we assessed the PHTS genotype and phenotype spectrum in a large cohort study.MethodsInformation was collected of 510 index patients with pathogenic or likely pathogenic (LP/P) PTEN variants (n = 467) or variants of uncertain significance. Genotype-phenotype associations were assessed using logistic regression analyses adjusted for sex and age.ResultsAt time of genetic testing, the majority of children (n = 229) had macrocephaly (81%) or developmental delay (DD, 61%), and about half of the adults (n = 238) had cancer (51%), macrocephaly (61%), or cutaneous pathology (49%). Across PTEN, 268 LP/P variants were identified, with exon 5 as hotspot. Missense variants (n = 161) were mainly located in the phosphatase domain (PD, 90%) and truncating variants (n = 306) across all domains. A trend towards 2 times more often truncating variants was observed in adults (OR = 2.3, 95%CI = 1.5–3.4) and patients with cutaneous pathology (OR = 1.6, 95%CI = 1.1–2.5) or benign thyroid pathology (OR = 2.0, 95%CI = 1.1–3.5), with trends up to 2–4 times more variants in PD. Whereas patients with DD (OR = 0.5, 95%CI = 0.3–0.9) or macrocephaly (OR = 0.6, 95%CI = 0.4–0.9) had about 2 times less often truncating variants compared to missense variants. In DD patients these missense variants were often located in domain C2.ConclusionThe PHTS phenotypic diversity may partly be explained by the PTEN variant coding effect and the combination of coding effect and domain. PHTS patients with early-onset disease often had missense variants, and those with later-onset disease often truncating variants.     

Lobular neoplasia diagnosed on breast Core biopsy: frequency of carcinoma on excision and implications for management

The appropriate follow-up and treatment for patients with a core biopsy diagnosis of lobular neoplasia (atypical lobular hyperplasia or lobular carcinoma in situ) remains controversial. Several studies have attempted to address this issue, with recommendations ranging from close clinical follow-up or surveillance to mandatory surgical excision in all cases. We report the findings at our institution, where virtually every core needle biopsy diagnosis of lobular neoplasia results in follow-up excision. The goal of the study was to identify potential predictors of upgrade to a more significant lesion. We identified 76 patients over a 15-year period with a core biopsy diagnosis of pure lobular neoplasia and no other high-risk lesions. Subsequent surgical excision identified 10 cases (13%) that were upgraded to carcinoma. Upgrade diagnoses included invasive ductal carcinoma (n = 1), invasive lobular carcinoma (n = 4), ductal carcinoma in situ (n = 3), and pleomorphic lobular carcinoma in situ (n = 2). All 10 upgraded cases had imaging findings suspicious for malignancy including irregular masses, asymmetric densities, or pleomorphic calcifications. Of the 10 upgraded cases, 7 were diagnosed as lobular carcinoma in situ on core biopsy. The data support a role for radiologic-pathologic correlation in the evaluation of suspicious breast lesions and suggest that the extent of lobular neoplasia in core biopsy specimens may be an indicator of the likelihood of upgrade to carcinoma.     

Surgical follow-up results for apocrine adenosis and atypical apocrine adenosis diagnosed on breast core biopsy

Apocrine adenosis (AA) and atypical apocrine adenosis (AAA) are uncommon findings in breast biopsies that may be misinterpreted as carcinoma. The clinical significance and risk implications of AAA diagnosed on core biopsy are not well established. This study aimed to determine the frequency of carcinoma on follow-up excision in patients with a diagnosis of AA or AAA on core biopsy. Forty-one breast core biopsies of AA (n = 29) and AAA (n = 12) were identified during a study period of 12 years. Of the 41 core biopsies with AA or AAA, 10 biopsies showed coexisting/concurrent atypical hyperplasia or carcinoma. In the absence of coexisting/concurrent atypical hyperplasia or carcinoma in core biopsy, none of the follow-up excision specimens after a diagnosis of AA or AAA showed ductal carcinoma in situ or invasive carcinoma. In conclusion, AA or AAA by itself is an uncommon core biopsy diagnosis that may not require surgical excision.     

Diagnostic accuracy of core biopsies of renal masses: Experience in a real-life setting from a tertiary center

ObjectiveTo document and analyze diagnostic accuracy of renal core biopsy (RCB), its diagnostic correlation with resection specimens, and to question the need for immunohistochemistry (IHC) in the preoperative diagnosis of renal masses.Material and methodRCBs performed at a reference center between 2007 and 2017 were included. Pathological, clinical, and radiological data were obtained from medical records.ResultsAmong 302 biopsies included in this study, 274 (90.7%) were diagnostic. Two hundred sixty-six were neoplastic and 179 were of primary renal origin. The most common secondary neoplasms were hematolymphoid (n = 35) and metastatic (n = 17). Sixty-nine tumors were classified as small renal masses (SRMs) (≤4 cm in diameter) and 53 of them were malignant. Nephrectomy was performed in 58 patients. Overall diagnostic accuracy between resections and RCBs was 88.7%. IHC was performed in 160 (53%) cases. In 15 of those, a definite diagnosis could not be rendered. Renal cell origin and subtype were determined by histomorphology alone in 81 and 75 cases, respectively. Sixty primary neoplasms of renal cell origin required IHC for diagnosis.ConclusionRCB is a safe and highly accurate method for the diagnosis of both primary and secondary renal neoplasms. IHC is mostly required for the diagnosis of secondary tumors. Histomorphology is still the primary diagnostic tool, highly dependent on the experience of the surgical pathologist.     

Bilateral muscle atrophy after anterior cruciate ligament reconstruction in rats: Protective effects of anti-inflammatory drug celecoxib

BackgroundMuscle atrophy after anterior cruciate ligament (ACL) reconstruction occurs bilaterally and contributes to a decrease in muscle strength. However, effective treatment strategies for ACL reconstruction-induced muscle atrophy have not been established. We examined the effects of anti-inflammatory drug on muscle atrophy after ACL reconstruction.Materials and methodsRats were divided into groups according to treatment received: untreated control (n = 4), arthrotomy (n = 6), ACL transection (n = 7), ACL reconstruction (n = 8), and ACL reconstruction plus anti-inflammatory drug celecoxib (CBX; 50 mg/kg/day) administration (n = 8). At one-week post-surgery, the muscle fiber cross-sectional area (CSA) in the rectus femoris (RF) and semitendinosus (ST) was measured to assess muscle atrophy. In addition, we examined joint swelling and serum C‑reactive protein (CRP) levels to assess local and systemic inflammation, respectively.ResultsEach additional procedure (i.e., arthrotomy, ACL transection, and ACL reconstruction) gradually decreased the muscle fiber CSAs in the RF and ST on both operated and contralateral sides. The degree of muscle fiber atrophy on the operated side was larger than that detected on the contralateral side. Moreover, ACL reconstruction induced joint swelling on the operated side and tended to increase serum CRP levels. CBX lessened the RF atrophy on both sides and was associated with less joint swelling and a smaller increase CRP level; however, it did not affect ST atrophy on either side.ConclusionsAnti-inflammatory treatments after ACL reconstruction may be effective in lessening muscle atrophy in the quadriceps, but not in the hamstrings.     

CD105- and CD31-assessed microvessel density in laryngeal carcinoma biopsies as a predictor of recurrence after exclusive primary surgery

PurposeSurgery is currently indicated as a unimodal therapeutic approach with curative intent in selected laryngeal squamous cell carcinomas (LSCCs) ranging from stage I to III. The main aim of this study was to evaluate the prognostic role of CD105- and CD31-assessed microvessel density (MVD) in biopsy and in surgical specimens from a cohort of consecutive stage I-III LSCCs who had undergone exclusive primary surgery, according to current guidelines.Materials and methodsCD105- and CD31-assessed MVD were analyzed in paired biopsies and surgical specimens of 24 consecutive cases of LSCC who underwent exclusive surgery.ResultsOn biopsy specimens, CD105- and CD31-assessed MVD were positively associated with recurrence risk (hazard ratio [HR] 1.266, p = 0.0034 and HR 1.265, p = 0.0081, respectively). In surgical specimens, CD105- and CD31-assessed MVD were significantly associated with disease-free survival (DFS) (HR 1.213, p = 0.0016 and HR 1.237, p = 0.0023 respectively). Considering a stratification based on median value, recurrence risk was higher in patients with a CD105-assessed MVD>0 in both biopsies and surgical specimens (HR 11.005, p = 0.0326 and HR 34.483, p = 0.0311). No significant differences in terms of recurrence risk were found for CD31-assessed on biopsies or on surgical specimens.ConclusionsThis study supports the role of biopsy CD105-MVD as a predictor of recurrence after exclusive surgery for LSCCs. Further prospective studies are mandatory to better characterize the prognostic role of CD105-MVD evaluated on biopsies to develop novel criteria to identify patients at higher risk of recurrence for more aggressive approaches or adjuvant treatment.     

Monitoring the SARS-CoV-2 pandemic: screening algorithm with single nucleotide polymorphism detection for the rapid identification of established and emerging variants

ObjectivesTo evaluate a testing algorithm for the rapid identification of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants that includes the use of PCR-based targeted single nucleotide polymorphism (SNP) detection assays preceded by a multiplex PCR sensitive to S-Gene Target Failure (SGTF).MethodsPCR SNP assays targeting SARS-CoV-2 S-gene mutations ΔH69–V70, L452R, E484K, N501Y, H655Y and P681R using melting curve analysis were performed on 567 samples in which SARS-CoV-2 viral RNA was detected by a multiplex PCR. Viral whole-genome sequencing (WGS) was performed to confirm the presence of SNPs and to identify the Pangolin lineage. Additionally, 1133 SARS-CoV-2 positive samples with SGTF were further assessed by WGS to determine the presence of ΔH69–V70.ResultsThe N501Y-specific assay (n = 567) had an overall percentage agreement (OPA) of 98.5%. The ΔH69-V70-specific (n = 178) and E484K-specific (n = 401) assays had OPA of 96.6% and 99.7%, respectively. Assessment of H655Y (n = 139) yielded a 100.0% concordance when applied in the proposed algorithm. The L452R-specific (n = 67) and P681R-specific (n = 62) assays had an OPA of 98.2% and 98.1%, respectively. The proposed algorithm identified six variants of concern/interest (VOC/VOI)—Alpha (n = 149), Beta (n = 65), Gamma (n = 86), Delta (n = 49), Eta (n = 6), Kappa (n = 6)—and 205 non-VOC/VOI strains—including the variants under monitoring B.1.214.2 (n = 43) and B.1.1.318 (n = 18) and Epsilon (n = 1). An excellent concordance was observed for the identification of all SARS-CoV-2 lineages evaluated.ConclusionsWe present a flexible testing algorithm for the rapid detection of current and emerging SARS-CoV-2 VOC/VOIs, which can be easily adapted based on the local endemicity of specific variants.     

Remote pathology education during the COVID-19 era: Crisis converted to opportunity

ContextThe COVID-19 pandemic led to shutting of education faculties, including clinical clerkships for medical students.ObjectiveTo review a selective for a course in diagnostic pathology geared toward undergraduate medical students, including its design, technical implementation, instructor and student evaluations, and suggestions for options for further adjusting and optimizing the selective.DesignWhole slide images (WSI) were anonymized and students were given remote access to university computers, which were prepared with two freely available WSI viewers. Each topic was taught in a four-part module: Self-assigned reading, lecture via Zoom, quiz based on digital slide sets, and a frontal review of the slides via Zoom. Fifty-nine students participated in the selective. Following the course, students completed an anonymous questionnaire.ResultsOf the 59 participants, 42% (n = 25) responded. None of the respondents had any previous instruction in diagnostic pathology. Overall, the course was rated very favorably: 68% (n = 17) gave at least 3 points on a 4-point scale on questions relating to course interest, improvement in understanding of the covered diseases, and how strongly they would recommend a student take this course if given an option. The most significant disadvantage of the class, as reported by 80% (n = 20) were technical challenges in accessing the slides.ConclusionWe believe the course was a success and can be a model for future virtual pathology electives. Great effort should be done to provide technical support to the students. The selective demonstrated value for students and provided much-needed exposure to diagnostic pathology in clinical practice.     

Real-life evaluation of a rapid antigen test (DPP SARS-CoV-2 Antigen) for COVID-19 diagnosis of primary healthcare patients,in the context of the Omicron-dominant wave in Brazil

ObjectivesWe aimed to investigate the real-life performance of the rapid antigen test in the context of a primary healthcare setting, including symptomatic and asymptomatic individuals that sought diagnosis during an Omicron infection wave.MethodsWe prospectively accessed the performance of the DPP SARS-CoV-2 Antigen test in the context of an Omicron-dominant real-life setting. We evaluated 347 unselected individuals (all-comers) from a public testing centre in Brazil, performing the rapid antigen test diagnosis at point-of-care with fresh samples. The combinatory result from two distinct real-time quantitative PCR (RT-qPCR) methods was employed as a reference and 13 samples with discordant PCR results were excluded.ResultsThe assessment of the rapid test in 67 PCR-positive and 265 negative samples revealed an overall sensitivity of 80.5% (CI 95% = 69.1%–89.2%), specificity of 99.2% (CI 95% = 97.3%–99.1%) and positive/negative predictive values higher than 95%. However, we observed that the sensitivity was dependent on the viral load (sensitivity in Ct < 31 = 93.7%, CI = 82.8%–98.7%; Ct > 31 = 47.4%, CI = 24.4%–71.1%). The positive samples evaluated in the study were Omicron (BA.1/BA.1.1) by whole-genome sequencing (n = 40) and multiplex RT-qPCR (n = 17).ConclusionsAltogether, the data obtained from a real-life prospective cohort supports that the rapid antigen test sensitivity for Omicron remains high and underscores the reliability of the test for COVID-19 diagnosis in settings with high disease prevalence and limited PCR testing capability.     

Correlation of anal cytology with follow-up histology and Human Papillomavirus genotyping: A 10-year experience from an academic medical center

BackgroundAnal cytology (AC) is accepted as a practical screening modality for anal cancer. However, studies suggest that AC and anal biopsy dysplasia correlation is less robust than in cervicovaginal specimens. The current study goals were to look at our institutional experience in a subset of ACs and correlate with surgical pathology (SP), as well as evaluate their Human Papillomavirus (HPV) status.Methods377 ACs from 169 patients (151 males and 18 females) from 2008 to 2017 were included. HPV genotyping (n = 47) and SP within one year of AC (n = 58) were reviewed.ResultsAC/SP was discrepant in 22 cases (37.9%), with a tendency towards AC underestimating the degree of dysplasia. Specifically, any abnormality on AC was 93.8% sensitive for detecting high-grade dysplasia (HGD). However, when requiring a high-grade AC diagnosis, the sensitivity decreases to 12.5%. “Other high-risk HPV” was the most common genotype (57.4%). When considered with all AC with a high-grade diagnosis, co-testing with HPV improved the sensitivity for HGD to 56.3%. Sensitivity improved further to 87.5% when only considering cases with both AC and HPV testing, and were high-risk HPV positive. Furthermore, following review and consensus diagnosis, 8 cases changed from “Discrepant” to “Agreed”, reducing the discrepancy rate to 24.1%. Remaining discrepancies were explained by sampling error.ConclusionGiven the enhanced sensitivity of AC and HPV testing together, and sampling error seen with AC leading to underestimating dysplasia, we recommend AC and HPV co-testing, as well as describing confounding factors in AC reports and obtaining consensus opinion in equivocal cases.     

Current Practice in Diagnosis and Treatment of Acute Graft-versus-Host Disease: Results from a Survey among German-Austrian-Swiss Hematopoietic Stem Cell Transplant Centers

To assess current clinical practice in diagnosis and treatment of acute graft-versus-host disease (aGVHD), we performed a survey among German, Austrian, and Swiss allogeneic hematopoietic stem cell transplantation (allo-HSCT) centers. Thirty-four of 72 contacted centers (47%) completed both the diagnostic and therapeutic sections of the survey, representing 65% of allo-HSCT activity within the participating countries in 2011. Three pediatric centers answered as requested only the diagnostic part of the survey. In the presence of diarrhea and decreased oral intake after engraftment, only 4 centers (12%) do not perform any endoscopy before the start of immunosuppressive treatment. In case of a skin rash with the differential diagnosis of drug reaction, only 12 centers (35%) perform a skin biopsy up front, whereas 19 do so after failure of systemic steroids. In the presence of rapidly increasing cholestasis occurring without any other signs of aGVHD, 11 centers (32%) perform a liver biopsy up front and 14 only after failure of steroid treatment, whereas 9 centers do not perform a liver biopsy at all. Twenty centers (59%) use a percutaneous approach, 12 a transvenous approach, and 1 mini-laparoscopy for liver biopsies. First-line treatment of cutaneous aGVHD stage 1 consists of topical treatment alone in 17 of 31 responding centers (61%), whereas isolated cutaneous aGVHD stage III is treated with systemic steroids (prednisolone below 0.5 mg/kg/day n = 2, 0.5 to 1.0 mg/kg/day n = 10, above 1.0 to 2.5 mg/kg/day n = 19) without or with topical agents (steroids n = 10; calcineurin inhibitors n = 3). In gastrointestinal manifestations of aGVHD, 9 centers (29%) add topical to systemic steroids, and 3 consider topical steroids as the only treatment for mild gastrointestinal and cutaneous aGVHD. The choice of agent for second-line treatment as well as the sequence of administration are extremely heterogeneous, most likely due to a lack of convincing data published. Most frequently used are mycophenolate mofetil (n = 14) and extracorporeal photopheresis (n = 10). Our survey also demonstrates that clinicians chose salvage therapies for steroid-refractory aGVHD based on their centers' own clinical experience.     

Clinical characteristics and treatment outcomes of pulmonary invasive fungal infection among adult patients with hematological malignancy in a medical centre in Taiwan, 2008–2013

Background/purposeThis study was aimed to investigate clinical characteristics and treatment outcomes of pulmonary invasive fungal infection (IFI) among patients with hematological malignancy.MethodsAll patients with hematological malignancy who were treated at a medical centre from 2008 to 2013 were evaluated. Pulmonary IFI was classified according to the European Organization for Research and Treatment of Cancer 2008 consensus.ResultsDuring the study period, 236 (11.3%) of 2083 patients with hematological malignancy were diagnosed as pulmonary IFI, including 41 (17.4%) proven, 75 (31.8%) probable, and 120 (50.8%) possible cases. Among the 116 patients of proven and probable cases of pulmonary IFI, aspergillosis alone (n = 90, 77.6%) was predominant, followed by cryptococcosis alone (n = 9, 7.8%), and mucormycosis (n = 4, 3.4%). The overall incidence of patients with pulmonary IFI was 5.9 per 100 patient-years. The highest incidence (per 100 patient-year) was found in patients with acute myeloid leukaemia (13.7) followed by acute lymphoblastic leukaemia (11.3), and myelodysplastic syndrome/severe aplastic anaemia (6.7). Fourteen (5.9%) of the 236 patients with pulmonary IFI died within 12 weeks after diagnosis of pulmonary IFI. Univariate analysis revealed that elderly age (>65 years) (P = 0.034), lack of response to anti-fungal treatment (P < 0.001), and admission to the intensive care unit (ICU) (P < 0.001) were predictors of poor prognosis. However, only admission to the ICU was an independent predictor of poor prognosis for 12-week mortality (P = 0.022) based on multivariate analysis.ConclusionPatients with acute leukaemia and myelodysplastic syndrome/severe aplastic anaemia were at high risk of pulmonary IFI.     

HLA-G +3196 polymorphism as a risk factor for cell mediated rejection following heart transplant

BackgroundRejection is a leading cause of mortality following heart transplantation. Human leukocyte antigen-G (HLA-G) is an immune checkpoint which dampens the immune response. Reports suggest elevated HLA-G expression is associated with reduced allograft rejection. Our objective was to evaluate HLA-G polymorphisms and cell mediated rejection (CMR) development.MethodsRecipients (n = 123) were genotyped to identify relevant HLA-G polymorphisms in the 5′regulatory (−725, −201), 3′untranslated (+3197, +3187, +3142, 14-bp indel) and coding regions (haplotypes 1–6). CMR was evaluated via endomyocardial biopsy (grade ≥ 2R). Univariate/adjusted analyses were conducted via Kaplan Meier and proportional hazard models.ResultsMean recipient age was 48 (±12) years, with a median time to CMR of 4.6 years. 55 (45%) recipients had a biopsy grade ≥ 2R. Adjusted analysis revealed the +3196 G allele as a risk factor for CMR (p = 0.03). Compared to the minor GG genotype, CG had a 47.2% reduction in CMR risk (HR[95% CI] = 0.528 [0.235, 1.184]), while CC had a 66.9% reduction (0.331 [0.144, 0.761]). The recessive effect significantly increased CMR likelihood (2.388 [1.128, 5.059], p = 0.02).ConclusionThe HLA-G +3196 G allele was identified as a risk factor for CMR diagnosis. HLA-G may have a role in therapeutic/diagnostic strategies against transplant rejection.