Histologic Categories Research Articles

209: Obstetric and neonatal outcomes in pregnancies complicated by fetal lung masses: does final histology matter?

The predicted etiology of prenatally diagnosed fetal lung masses is not always consistent with lung mass histology at the time of neonatal resection. Most data to date describe outcomes based on prenatal imaging characteristics. Our aim was to assess obstetric and neonatal outcomes by fetal lung mass histology. We reviewed all pregnancies complicated by fetal lung mass from a single academic center from 2009-2017. For the current analysis, only those with prenatal and neonatal data, including final histology data, were included. Maternal demographics, prenatal imaging, obstetric and neonatal outcomes were analyzed and compared between lung mass histologic categories: bronchopulmonary sequestration (BPS) and congenital pulmonary airway malformation (CPAM) subtypes. The primary composite outcome was neonatal respiratory distress defined as any of: continuous positive airway pressure; intubation and mechanical ventilation; extracorporeal membrane oxygenation; or resection of the lung mass before neonatal discharge. Of 60 pregnancies complicated by fetal lung mass during the study period, 43 had prenatal, postnatal, and final histology data. Of those, there were 10 cases of CPAM type 1, 9 cases of CPAM type 2, and 16 cases of BPS. There was 1 case of CPAM type 3, which was not included in the analysis due to low incidence. Maternal age, race/ethnicity, insurance status, and parity were similar between histologic categories. There was no difference in gestational age at delivery, IUGR, mode of delivery, birthweight, or Apgar scores between groups. PPROM was the only adverse outcome that approached statistical significance (0% in CPAM type 1, 33.3% in CPAM type 2, 6.2% in BPS, p = 0.07). Neonatal respiratory distress was not statistically different between the groups (30.0% in CPAM type 1, 22.2% in CPAM type 2, 43.8% in BPS, p = 0.66), and there was no difference in neonatal length of stay, time to postnatal resection, or neonatal mortality (Table). Final histology of a prenatally diagnosed fetal lung mass may not be associated with different obstetric and neonatal outcomes, including respiratory distress at birth. Our results can inform fetal surveillance and maternal counseling.

MRI of testicular malignancies.

Although testicular carcinoma represents approximately only 1% of solid neoplasms in men, it is the most common malignancy between young men. The two main histologic categories are testicular germ cell tumors (TGCTs), including seminomas and nonseminomas, accounting for 90-95% of testicular neoplasms and sex cord-stromal tumors. Scrotal MRI, including a multiparametric protocol, has been proposed as a valuable supplemental imaging technique in the investigation of testicular pathology. Recently, the Scrotal and Penile Imaging Working Group appointed by the board of the European Society of Urogenital Radiology has produced recommendations on when to perform scrotal MRI. Regarding intratesticular masses, MRI of the scrotum may be used for their characterization, when US findings are indeterminate and for local staging of TGCTs, when organ-sparing surgery is planned. Differentiation between seminomas and nonseminomas is possible based on MRI features, when clinically needed. Scrotal MRI may also help in differentiating between TGCTs and nongerm cell tumors. Functional information based on diffusion-weighted imaging and dynamic contrast-enhanced MRI data improve testicular mass lesion characterization. Preliminary observations on diffusion tensor imaging, magnetization transfer imaging, and proton MR spectroscopy bring about new data in the understanding of testicular microstructure and pathophysiology.

Hepatocellular carcinoma: a review of diagnostic challenges for the pathologist.

Histopathologists retain a critical role in the diagnosis and management of hepatocellular carcinoma (HCC). HCC arises usually but not exclusively in a background of advanced-stage chronic liver disease. The histological diagnosis of HCC poses many challenges particularly when dealing with liver biopsy specimens due to the heterogeneity of HCC and the difficulty to confirm hepatocellular differentiation in some instances. Primary liver tumors should be considered as a continuum with typical hepatocellular and cholangiocarcinoma at the two ends and a whole range of tumors showing both hepatocellular and cholangiocellular differentiation with or without an associated progenitor/stem cell component in the middle. Characterization of combined (or mixed) hepatocellular-cholangiocarcinoma can be very challenging. In advanced-stage chronic liver disease, the main challenge for the histopathologist is still to differentiate between HCC and its precursors, although this is rarely critical in the clinical setting at present. HCC originating in non-cirrhotic livers needs to be differentiated from other primary and extrahepatic tumors and from hepatocellular adenoma, bearing in mind that progression to malignancy is more through a continuum that watertight histological categories.

MS05.03 Tumor Heterogeneity in Lung Cancer

MS05.03 Tumor Heterogeneity in Lung Cancer

Needle-based optical coherence tomography for the detection of prostate cancer: a visual and quantitative analysis in 20 patients.

Diagnostic accuracy of needle-based optical coherence tomography (OCT) for prostate cancer detection by visual and quantitative analysis is defined. 106 three-dimensional (3-D)-OCT data sets were acquired in 20 prostates after radical prostatectomy and precisely matched with pathology. OCT images were grouped per histological category. Two reviewers performed blind assessments of the OCT images. Sensitivity and specificity for malignancy detection were calculated. Quantitative analyses by automated optical attenuation coefficient calculation were performed. OCT can reliably differentiate between fat, cystic, and regular atrophy and benign glands. The overall sensitivity and specificity for malignancy detection was 79% and 88% for reviewer 1 and 88% and 81% for reviewer 2. Quantitative analysis for differentiation between stroma and malignancy showed a significant difference (4.6 mm - 1 versus 5.0 mm - 1 Mann-Whitney U-test p < 0.0001). A Kruskal-Wallis test showed a significant difference in median attenuation coefficient between stroma, inflammation, Gleason 3, and Gleason 4 (4.6, 4.1, 5.9, and 5.0 mm - 1, respectively). However, attenuation coefficient varied per patient and a related-samples Wilcoxon signed-rank test showed no significant difference per patient (p = 0.17). This study confirmed the one to one correlation of histopathology and OCT. Precise matching showed that most histological tissues categories in the prostate could be distinguished by their unique pattern in OCT images. In addition, the optical attenuation coefficient can play a role in the differentiation between stroma and malignancy; however, a per patient analysis of the optical attenuation coefficient did not show a significant difference.

Cell mediated rejection revisited: Past, current, and future directions.

The Banff histopathology classification system is the gold standard for assessing the causes of kidney allograft dysfunction triggered by antibody-mediated and T-cell-mediated immune reactions, thereby providing mechanistic insight and guiding therapeutic decisions. The original Banff classification (1993) consisted of four histological categories representing cell-mediated rejection: interstitial inflammation (i), tubulitis (t), endoarteritis (v), and transplant glomerulitis (g). The revised Banff 2007 classification added total inflammation score (ti) from both scarred and unscarred areas based on evolving interpretations of interstitial infiltrates. Further reappraisal of cell-mediated interstitial inflammation led to the introduction of a new inflammation score specific for areas of interstitial fibrosis and tubular atrophy, termed i-IF/TA, in the Banff 2015 scheme, establishment of a new Banff working group on T-cell-mediated rejection (TCMR), and revised criteria of chronic active TCMR in Banff 2017 classification. These Banff scheme updates reflect the general recognition that chronic interstitial inflammation is a common denominator of poor kidney allograft outcome. However, revised theories on the pathogenic importance of interstitial infiltrates have created difficulties in interpretation of chronic tubulointerstitial inflammation, as there are currently no histological criteria to discriminate immune-mediated tissue injury from 'non-specific' injury. Evolving theories on vascular lesions, both active and chronic, have also complicated histological assessment by obscuring the distinction between antibody-mediated and T-cell-mediated tissue injury. This review provides an overview of recent ideas on interstitial inflammation and vascular lesions based on emerging concepts of T-cell-mediated rejection.

Treatment patterns and survival among older adults in the United States with advanced soft-tissue sarcomas

BackgroundTo describe patient and tumor characteristics, treatments, and survival among older adults in the United States with advanced soft-tissue sarcoma (STS), across and by categories of specifically defined histologic subtypes.MethodsWe conducted a retrospective cohort analysis using the SEER. The study population comprised patients ≥ 65 years old with advanced STS (excluding osteosarcoma, Kaposi sarcoma, and gastrointestinal stromal tumors) diagnosed from January 1, 2001 to December 31, 2011.ResultsOf 4274 study patients, 2103 (49.2%) were male. Mean age was 77.8 years, and 1539 (36.0%) had distant disease at initial diagnosis. The most common histologic categories were leiomyosarcoma (922[21.6%]), undifferentiated pleomorphic sarcoma (652[15.3%]), and liposarcoma (554[13.0%]). Overall, 1227 (28.7%) patients received first-line systemic therapy. Among these patients, 325 (26.5%) received docetaxel plus gemcitabine and 231 (18.8%) received doxorubicin alone. Only 476 patients received second-line therapy (11.1%), most commonly doxorubicin alone (n = 101). Median overall survival (95% confidence interval) from advanced STS diagnosis was 8.9 (8.3, 9.7) months.ConclusionsAlthough previous studies of younger populations reported anthracycline-based therapy predominated in first line, our study of older advanced STS patients found that docetaxel plus gemcitabine was most commonly used. Despite variation by histologic category, prognosis remains poor for older adult patients with advanced STS.

Role of high-throughput sequencing in the diagnosis of cutaneous T-cell lymphoma

AimsSubstantial clinicopathological overlap exists between cutaneous T-cell lymphoma (CTCL) and benign conditions, leading to diagnostic difficulties. We sought to delineate the utility of high-throughput sequencing (HTS) across a spectrum of...

Comparison of breast cancers detected in the Verona screening program following transition to digital breast tomosynthesis screening with cancers detected at digital mammography screening.

The Verona population-based breast cancer (BC) screening program provides biennial mammography to women aged 50-69years. Based on emerging evidence of enhanced detection, the program transitioned to digital breast tomosynthesis (DBT) screening. This is a prospective pilot evaluation of DBT with synthesised 2D mammography screening implemented during April 2015-March 2017; the rate and characteristics of cancers detected at DBT screening were compared with those detected at the preceding digital mammography (DM) screening round (April 2013-March 2015) in the same screening program. Distribution of imaging and tumour characteristics were compared. Amongst 34,071 women screened in the Verona DBT pilot, 315 BCs were detected; 153 BCs were detected amongst 29,360 women in the DM screening round. Estimated CDRs were 9.2/1000 (95% CI 8.3-10.3) DBT screens versus 5.2/1000 (95% CI 4.4-6.1) DM screens, P < 0.001. Statistically significant differences were found in the distribution of whether recall by one/both screen readers (more BCs recalled by both readers at DBT than DM); whether detected on one/two views (higher proportion detected on only one view at DBT than DM); type of radiological lesions; tumour stage, pT and histological categories (lower proportion of DCIS/pTis, higher proportions of pT1a and pT1b, and higher proportion of invasive cancers of special types, at DBT than DM); and tumour grade (higher proportion of grade I at DBT than DM). There were no differences in distributions of nodal and hormone receptor (ER/PR) status. Our findings provide early insights into the extent that transitioning to DBT screening may modify the characteristics of screen-detected breast cancer to inform discussion regarding pros and cons of DBT screening; although our data provide some reassurance that DBT does not increase the proportion of screen-detected DCIS, they highlight mixed findings on comparative tumour characteristics, suggesting a potential for enhancing screening benefit and possibly also over-diagnosis from DBT screening.

Predictive factors of endocrine and exocrine insufficiency after resection of a benign tumour of the pancreas

BackgroundThe aim of the present study is to evaluate the risk factors of endocrine and exocrine insufficiency occurring few years after pancreatic resections in a consecutive series of patients who underwent pancreatoduodenectomy (PD), left pancreatectomy (LP) or enucleation for benign neoplasms at a referral centre. MethodsPancreatic exocrine insufficiency (PEI) was defined by the onset of steatorrhea associated with weight loss, and endocrine insufficiency was determinate by fasting plasma glucose. Association between pancreatic insufficiency and clinical, pathological, and perioperative features was studied using univariate and multivariate Cox regression analysis. ResultsA prospective cohort of 92 patients underwent PD (48%), LP (44%) or enucleation (8%) for benign tumours, from 2005 to 2016 in the University Hospital in Poitiers (France). The median follow-up was 68.6±42.4months. During the following, 54 patients developed exocrine insufficiency whereas 32 patients presented endocrine insufficiency. In the Cox model, a BMI>28kg/m2, being a man and presenting a metabolic syndrome were significantly associated with a higher risk to develop postoperative diabetes. The risks factors for the occurrence of PEI were preoperative chronic pancreatitis, a BMI<18.5kg/m2, tumours located in the pancreatic head, biological markers of chronic obstruction and fibrotic pancreas. Undergoing LP or enucleation were protective factors of PEI. Histological categories such as neuroendocrine tumours and cystadenomas were also associated with a decreased incidence of PEI. ConclusionMen with metabolic syndrome and obesity should be closely followed-up for diabetes, and patients with obstructive tumours, pancreatic fibrosis or chronic pancreatitis require a vigilant follow up on their pancreatic exocrine function.

Reproducibility of Malignant Pleural Mesothelioma Histopathologic Subtyping.

- Malignant pleural mesothelioma (MPM) is a rare tumor with poor prognosis. Several studies have analyzed potential prognostic markers, but histologic type remains the single most important prognostic factor. Histologic subtypes of epithelioid MPM seem to have prognostic and therapeutic implications. Interobserver agreement in histologic pattern classification should be high. - To assess interobserver and intraobserver reproducibility in histologic differentiation between the main types of MPMs, and in further subtyping of epithelioid-type mesothelioma. - One representative hematoxylin-eosin-stained slide was selected from the archive for each of 200 patients with MPM. They were reviewed independently by 3 pathologists and classified according to the current World Health Organization classification of pleural tumors. After the first round of evaluations, a consensus meeting was organized where problems were addressed and representative images for each histologic category were selected. Two months later, cases were reevaluated by all 3 pathologists. - After the first round, overall interobserver agreement for histologic subtyping of mesothelioma was fair (κ, 0.36). The agreement was increased to substantial (κ, 0.63) in the second round. Improvement was found in interobserver agreement for all types of MPM and for most epithelioid subtypes. - Moderate to substantial agreement in histologic typing and subtyping of MPM can be achieved. However, training with additional clarification of diagnostic criteria, their strict application, and help from consensus-based illustrative images is needed.

Progress on the Study of Targeting FGFR in Squamous Non-small Cell Lung Cancer

肺鳞状细胞癌（squamous-cell lung cancer, SqCLC）是非小细胞肺癌中一类独特的病理类型，患者多为高龄、发病隐匿、发现时常属晚期、常伴有心肺合并症、缺乏有效的靶向治疗药物等因素，相对于非鳞非小细胞肺癌，SqCLC的治疗面临着更大的挑战。近年针对肺癌的分子靶向药物迅速发展，我们发现，FGFR家族（FGFR1-4）基因改变存在于约12%的SqCLC中，是SqCLC中突变频率最高的酪氨酸激酶家族基因，同时许多靶向FGFR的小分子药物都在各类肿瘤中发挥了较好的治疗效果。目前，许多FGFR抑制治疗SqCLC的临床试验也都正在进行当中，可能为SqCLC治疗提供新的策略和方向。

Macrophagic "Crown-like Structures" Are Associated with an Increased Risk of Breast Cancer in Benign Breast Disease.

In breast adipose tissue, macrophages that encircle damaged adipocytes form "crown-like structures of breast" (CLS-B). Although CLS-B have been associated with breast cancer, their role in benign breast disease (BBD) and early carcinogenesis is not understood. We evaluated breast biopsies from three age-matched groups (n = 86 each, mean age 55 years), including normal tissue donors of the Susan G. Komen for the Cure Tissue Bank (KTB), and subjects in the Mayo Clinic Benign Breast Disease Cohort who developed cancer (BBD cases) or did not develop cancer (BBD controls, median follow-up 14 years). Biopsies were classified into histologic categories, and CD68-immunostained tissue sections were evaluated for the frequency and density of CLS-B. Our data demonstrate that CLS-B are associated with BBD: CLS-B-positive samples were significantly less frequent among KTB biopsies (3/86, 3.5%) than BBD controls (16/86 = 18.6%, P = 0.01) and BBD cases (21/86 = 24%, P = 0.002). CLS-B were strongly associated with body mass index (BMI); BMI < 25: 7% CLS-B positive, BMI 25-29: 13%, and BMI ≥ 30: 29% (P = 0.0005). Among BBD biopsies, a high CLS-B count [>5 CLS-B/sample: 10.5% (BBD cases) vs 4.7% (BBD controls), P = 0.007] conferred a breast cancer OR of 6.8 (95% CI, 1.4-32.4), P = 0.02, after adjusting for adipose tissue area (cm2), histologic impression, and BMI. As high CLS-B densities are independently associated with an increased breast cancer risk, they may be a promising histologic marker of breast cancer risk in BBD. Cancer Prev Res; 11(2); 113-9. ©2017 AACR.

Treatment Patterns and Survival among Adult Patients with Advanced Soft Tissue Sarcoma: A Retrospective Medical Record Review in the United Kingdom, Spain, Germany, and France.

Objective To describe real-world treatment patterns and outcomes for patients with advanced soft tissue sarcoma (STS) not amenable to surgery or radiotherapy in the United Kingdom, Spain, Germany, and France. Methods Physicians completed a web-based medical record abstraction for adult patients with advanced STS (other than Kaposi's sarcoma or gastrointestinal stromal tumor) who received ≥1 line of systemic therapy. Clinical characteristics, treatments, tumor responses, and mortality data were recorded. Results A total of 130 physicians provided data for 807 patients. Patients' mean age at advanced STS diagnosis was 57.1 (±12.3) years; 59% were male. The most commonly identified histologic categories were leiomyosarcoma (28%), liposarcoma (13%), and rhabdomyosarcoma (11%). Overall, 57% of patients received only 1 line of therapy, 32% received 2 lines of therapy, and 11% received ≥3 lines of therapy. The most common first-line regimens were doxorubicin alone (41%), doxorubicin plus ifosfamide (19%), docetaxel plus gemcitabine (9%), paclitaxel alone (4%), and ifosfamide (4%). Median overall survival from start of treatment was estimated to be 17.6 months (95% confidence interval, 15.6–19.0 months). Conclusions In real-world clinical practice, advanced STS is most commonly treated with older therapies in the United Kingdom, Spain, Germany, and France. New therapies that improve overall survival in advanced STS are needed.

Epidemiology of Adult Soft-Tissue Sarcomas in Germany.

We conducted a retrospective cohort study using data compiled from the regional German cancer registries by the Centre for Cancer Registry Data (ZfKD) at the Robert Koch Institut (RKI) to describe the epidemiology of adult soft-tissue sarcomas (STS) in Germany in 2003–2012, focusing on advanced STS. We identified 33,803 incident adult cases of STS (other than the Kaposi sarcoma and gastrointestinal stromal tumors). The incidence of STS was 6.05 (95% confidence interval (CI), 5.82–6.29) per 100,000 in 2012 (4,079 cases). During 2003–2012, the most common histologic categories were leiomyosarcoma (19%), liposarcoma (16%), and STS not otherwise specified (14%). The overall STS-specific mortality rate in 2012 was 2.31 (95% CI, 2.06–2.57) per 100,000, and the median overall survival from initial diagnosis was 5.83 (95% CI, 5.50–6.08) years. Using STS mortality rates as a proxy for incidence of advanced STS in Germany and applying the age- and sex-specific rates to the corresponding German population, we estimated that 1,581 incident adult advanced STS cases occurred in Germany in 2012. Our findings contribute to a refined understanding of the population burden of STS in Germany, including the number of patients with advanced STS who may be candidates for systemic treatment.

About rearranged during transfection in non-small cell lung cancer

Lung cancers represent a more large landscape than well-known histological categories including lung adenocarcinoma (45% of cases), squamous cell carcinoma (25%), large cell carcinoma (10%) and small cell lung carcinoma (20%). Since 2004, when epidermal growth factor receptor (EGFR) mutations were discovered to give sensitivity to tyrosine kinase inhibitors (TKIs) in lung adenocarcinomas, developments had showed that lung cancer are molecularly distinct with different therapeutic vulnerabilities (1).

Whole-genome analysis of human papillomavirus genotypes 52 and 58 isolated from Japanese women with cervical intraepithelial neoplasia and invasive cervical cancer

BackgroundHuman papillomavirus genotypes 52 and 58 (HPV52/58) are frequently detected in patients with cervical intraepithelial neoplasia (CIN) and invasive cervical cancer (ICC) in East Asian countries including Japan. As with other HPV genotypes, HPV52/58 consist of multiple lineages of genetic variants harboring less than 10% differences between complete genome sequences of the same HPV genotype. However, site variations of nucleotide and amino acid sequences across the viral whole-genome have not been fully examined for HPV52/58. The aim of this study was to investigate genetic variations of HPV52/58 prevalent among Japanese women by analyzing the viral whole-genome sequences.MethodsThe entire genomic region of HPV52/58 was amplified by long-range PCR with total cellular DNA extracted from cervical exfoliated cells isolated from Japanese patients with CIN or ICC. The amplified DNA was subjected to next generation sequencing to determine the complete viral genome sequences. Phylogenetic analyses were performed with the whole-genome sequences to assign variant lineages/sublineages to the HPV52/58 isolates. The variability in amino acid sequences of viral proteins was assessed by calculating the Shannon entropy scores at individual amino acid positions of HPV proteins.ResultsAmong 52 isolates of HPV52 (CIN1, n = 20; CIN2/3, n = 21; ICC, n = 11), 50 isolates belonged to lineage B (sublineage B2) and two isolates belonged to lineage A (sublineage A1). Among 48 isolates of HPV58 (CIN1, n = 21; CIN2/3, n = 19; ICC, n = 8), 47 isolates belonged to lineage A (sublineages A1/A2/A3) and one isolate belonged to lineage C. Single nucleotide polymorphisms specific for individual variant lineages were determined throughout the viral genome based on multiple sequence alignments of the Japanese HPV52/58 isolates and reference HPV52/58 genomes. Entropy analyses revealed that the E1 protein was relatively variable among the HPV52 isolates, whereas the E7, E4, and L2 proteins showed some variations among the HPV58 isolates.ConclusionsAmong the HPV52/58-positive specimens from Japanese women with CIN/ICC, the variant distributions were strongly biased toward lineage B for HPV52 and lineage A for HPV58 across histological categories. Different patterns of amino acid variations were observed in HPV52 and HPV58 across the viral whole-genome.

MAXILLARY RHABDOMYOSSARCOMA: CASE REPORT

Rhabdomyosarcoma (RMS) accounts for approximately half of all pediatric soft tissue sarcomas and 15% of all pediatric solid tumors. RMS is divided into 5 major histologic categories: embryonal, alveolar, botryoid embryonal, spindle cell embryonal, and anaplastic. Treatment is determined by the extent of disease, ease of resectability, and precise site. Superficially placed tumors can be managed either with excision and relatively non-toxic adjuvant chemotherapy or by biopsy. More deeply placed lesions generally are not removable and require radiation therapy and very aggressive chemotherapy. Herein we report a case of a 9-year-old male patient with maxillary swelling present for 3 months that started with pain episodes in the last 2 weeks. Incisional biopsy was performed and showed variable cell population consisting of small, round tumor cells with hyperchromatic nuclei and of large, polygonal-shaped tumor cells with abundant eosinophilic cytoplasm. Immunohistochemical was positive to Myo-D1, vimentin, and desmin. The patient is under chemotherapy.

Effect of 11β-hydroxyandrostenedione on European whitefish Coregonus lavaretus (Linnaeus, 1758)

The goal of the present research was to evaluate the efficiency of 11β-hydroxyandrostenedione (OHA) applied in the diet to achieve sex reversal in the European whitefish (Coregonus lavaretus). At 32day post-hatching, fish were reared in four groups: fish fed with 10ppm of OHA (10 OHA), fish fed with 20ppm of OHA (20 OHA), fish fed without OHA (C) and fish fed without OHA and reared in the water from 20 OHA group (R). The experimental groups were conducted in separate recirculation systems and the first phase of the experiment lasted 63days. For the histological analysis of the gonads, fish from all groups were reared without OHA treatment for an additional 91days (second phase). At the end of the first phase of the experiment, survival of the whitefish ranged from 34.5±11.1% to 51.5±7.3%. The final body weight and coefficient of variation in the weight ranged from 5.6±1.2g to 6.9±1.5g and from 21.5 to 22.7%, respectively. No negative effects of OHA treatment on the growth and the survival of the whitefish were found. Six histological categories of the whitefish gonads were observed. Apart from the typical ovaries and testes, two types of the intersexual gonads (ovotestis and testis-ova) and two types of the sterile-altered gonads were distinguished. No gonadal females were found among fish from any of OHA groups. Gonadal males constituted of 60% and 50% of the fish from 10 OHA and 20 OHA groups, respectively. Intersexes were observed in all groups with the highest proportion found among fish from R variant. Rate of sterile individuals in 10 OHA and 20 OHA groups was 17% and 30%, respectively. The proportion of fish with normal testes to fish with other types of gonad varied from 0.43:1 to 1.5:1 with the higher ratio observed in both OHA groups. Lack of the females among fish from OHA groups suggested OHA affected growth and development of ovaries in the whitefish. However, a high percentage of the sterile fish in both OHA treated groups indicated application of lower doses of OHA for masculinization of the whitefish in the further research.

Assessing rejection-related disease in kidney transplant biopsies based on archetypal analysis of molecular phenotypes.

Conventional histologic diagnosis of rejection in kidney transplants has limited repeatability due to its inherent requirement for subjective assessment of lesions, in a rule-based system that does not acknowledge diagnostic uncertainty. Molecular phenotyping affords opportunities for increased precision and improved disease classification to address the limitations of conventional histologic diagnostic systems and quantify levels of uncertainty. Microarray data from 1,208 kidney transplant biopsies were collected prospectively from 13 centers. Cross-validated classifier scores predicting the presence of antibody-mediated rejection (ABMR), T cell-mediated rejection (TCMR), and 5 related histologic lesions were generated using supervised machine learning methods. These scores were used as input for archetypal analysis, an unsupervised method similar to cluster analysis, to examine the distribution of molecular phenotypes related to rejection. Six archetypes were generated: no rejection, TCMR, 3 associated with ABMR (early-stage, fully developed, and late-stage), and mixed rejection (TCMR plus early-stage ABMR). Each biopsy was assigned 6 scores, one for each archetype, representing a probabilistic assessment of that biopsy based on its rejection-related molecular properties. Viewed as clusters, the archetypes were similar to existing histologic Banff categories, but there was 32% disagreement, much of it probably reflecting the "noise" in the current histologic assessment system. Graft survival was lowest for fully developed and late-stage ABMR, and it was better predicted by molecular archetype scores than histologic diagnoses. The results provide a system for precision molecular assessment of biopsies and a new standard for recalibrating conventional diagnostic systems.