Panel Of Pathologists Research Articles

Involvement of Peroxisome Proliferator-Activated Receptor-Alpha in Liver Tumor Production by Permethrin in the Female Mouse.

The nongenotoxic pyrethroid insecticide permethrin produced hepatocellular tumors in CD-1 mice but not in Wistar rats. Recently, based on findings of a Pathology Working Group involving an expert panel of pathologists, it was concluded that permethrin increased liver tumors at 2500 and 5000 ppm in female mice, but no treatment-related tumorigenic response occurred in male mice at dose levels examined in the 2-year bioassay. To evaluate a possible mode of action (MOA) for the permethrin female CD-1 mouse hepatocellular tumors, a number of investigative studies were conducted. In time-course studies in female CD-1 mice, permethrin increased relative liver weight and enhanced hepatocyte proliferation within 1 week. Treatment with permethrin resulted in marked increases in CYP4A enzyme activities and mRNA levels, but only slightly increased CYP2B markers, suggesting that permethrin primarily activates the peroxisome proliferator-activated receptor alpha (PPARα) and to a much lesser extent the constitutive androstane receptor. The effects of permethrin on relative liver weight, hepatocyte proliferation and CYP4A enzyme activities and mRNA levels were dose-dependent and were reversible within 5 weeks after cessation of treatment. The hepatic effects of permethrin observed in wild-type female mice were markedly reduced in PPARα knockout female mice. These results demonstrate that the MOA for hepatocellular tumor formation by permethrin in female mice involves activation of PPARα resulting in a mitogenic effect. The MOA for permethrin-induced mouse liver tumor formation due to PPARα activation is considered to be not plausible for humans. This conclusion is strongly supported by available epidemiological data for permethrin.

Reevaluation of Hepatocellular Neoplasms in CD-1 Mice from a 2-year Oral Carcinogenicity Study with Permethrin.

A 24-month oral carcinogenicity study of permethrin was conducted by feeding male and female CD-1 mice diets containing concentrations of 0, 20, 500, and 2,000 ppm of permethrin (males) or 0, 20, 2,500, and 5,000 ppm of permethrin (females). After approximately two years on study, surviving mice were sacrificed for the evaluation of chronic toxicity and/or carcinogenicity. An expert panel of pathologists was convened as a Pathology Working Group (PWG) to review coded liver histology sections from male and female mice and to classify all liver neoplasms according to current nomenclature and diagnostic criteria guidelines. The PWG results indicate that permethrin induced a significant dose-dependent increase in the incidence of hepatocellular neoplasms in treated female mice ( p < .01) as well as a nonstatistically significant increase in the incidence of hepatocellular tumors in treated male mice. Given the continuum of the diagnoses of adenoma and carcinoma, and the difficulty in distinguishing some of the lesions, it is appropriate to consider only the combined incidences of hepatocellular tumors (adenoma and/or carcinoma) for biological significance and risk assessment.

Weighting the Passive Acoustic Mapping Technique With the Phase Coherence Factor for Passive Ultrasound Imaging of Ultrasound-Induced Cavitation.

Ultrasound (US) cavitation is currently being explored for low-invasive therapy techniques applied to a wide panel of pathologies. Because of the random behavior of cavitation, a real-time spatial monitoring system may be required. For this purpose, the US passive imaging techniques have been recently investigated. In particular, the passive acoustic mapping (PAM) beamforming method enables the reconstruction of cavitation activity maps by beamforming acoustic signals passively recorded by an array transducer. In this paper, an optimized version of PAM, PAM weighted with a phase coherence factor (PAM-PCF), is considered. A general validation process is developed including simulations on a point source and experiments on a wire. Furthermore, using a focused regulated US-induced cavitation generator, reproducible cavitation experiments are conducted in water and in agar gel. The spatial behavior of a bubble cavitation cloud is determined using the PAM-PCF beamforming method to localize the focal cavitation point in two perpendicular imaging planes.

How to handle borderline/precursor thyroid tumors in management of patients with thyroid nodules.

Thyroid carcinomas originating from follicular cells have the prognosis of heterogeneous diseases, but pathologists classify them all as malignant disease. Epidemiologists have issued a stern warning regarding over-diagnosis and overtreatment of patients with indolent thyroid tumors that cause no harm to the patients. Review of the literature revealed that there were several proposals of borderline/precursor tumors to some indolent thyroid carcinomas. Thyroid tumor of uncertain malignant potential (UMP) was first proposed by Williams for encapsulated follicular pattern thyroid tumors to solve problems due to observer variation. Rosai et al. proposed to rename papillary microcarcinoma (PMC) to papillary micro-tumor as the overwhelming majority of them are of no clinical significance. Liu et al. proposed well-differentiated tumor with uncertain behavior (WDT-UB) which covered WDT of UMP (WDT-UMP) and non-invasive encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC). The EFVPTC without invasion was renamed as non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) by an international panel of pathologists. A new prognostic classification of thyroid tumors was proposed by Kakudo et al., in which extremely low risk tumors were grouped in a borderline tumors category. The borderline/precursor thyroid tumors included encapsulated tumors [capsular invasion only follicular carcinoma, encapsulated papillary carcinoma without invasion, WDT-UMP and follicular tumor of UMP (FT-UMP)] and non-encapsulated tumors (PMC). The UMP and NIFTP were incorporated in the 4th edition WHO classification of thyroid tumors as a new tumor entity in chapter 2-2A: other encapsulated follicular patterned thyroid tumors. Their behavior codes were decided to be 1 (borderline or uncertain behavior), and not 0 (benign), 2 (in situ carcinoma) or 3 (malignant). These borderline/precursor thyroid tumors are indolent tumors biologically and should be treated more conservatively than as previously recommended for thyroid follicular cell carcinomas [total thyroidectomy (TTX) followed by radio-active iodine (RAI) treatment] by western clinical guidelines.

Changes in the use of commercial and lab-developed IVD assays in the clinical setting for PD-L1 expression testing in NSCLC in the United States.

154 Background: In 2016 we observed a lack of standardization in the use of cut-off points to define positivity when testing for PD-L1 expression in NSCLC, despite these being specified by assay manufacturers or recommended based on trial data. One year on we look at how clinical practice has changed in light of new approvals for PD-(L)1 inhibitors, availability of new IVD assays and changes in clinical practice guidelines recommending the use of immunotherapy for stage IV NSCLC. Here we explore how the variety of test brands and cut-off points used in the US has changed since 2016 by examining real-world clinical usage data. Methods: Between June and August 2016 and June and August 2017, a panel of pathologists in the US (n = 21 in 2016 and n = 28 in 2017) was asked to report on their practices relating to PD-L1 expression testing in NSCLC, through the submission of online de-identified record forms (n = 167 and n = 224 PD-L1-tested samples in 2016 and 2017 respectively). Results: Of the 224 samples gathered in 2017, 187 (84%) were tested with the Dako 22C3 pharmDx assay (vs 67% in 2016), 16 (7%) with the Dako 28-8 pharmDx assay (vs 22% in 2016) and 11 (5%) with a lab-developed test (LDT). An increase in the use of 1% staining as the cut-off was observed for both 22C3 and 28-8 pharmDx. The full distribution of cut-offs used is shown in the table below. Conclusions: Following initial fragmentation of clinical practices in 2016, PD-L1 expression testing has seen consolidation towards greater use of the Dako 22C3 assay and higher conformity in testing at the recommended cut-off points. While greater standardization simplifies testing, the choice of assay has potential implications on subsequent treatment: current PD-L1 assays allow physicians to confirm whether a specific PD-(L)1 inhibitor is appropriate for a patient, but there is no single PD-L1 expression test that supports oncologists in making treatment decisions for the PD-(L)1 inhibitor class as a whole.[Table: see text]

Quantitative Image Analysis of Human Epidermal Growth Factor Receptor 2 Immunohistochemistry for Breast Cancer: Guideline From the College of American Pathologists.

Advancements in genomic, computing, and imaging technology have spurred new opportunities to use quantitative image analysis (QIA) for diagnostic testing. To develop evidence-based recommendations to improve accuracy, precision, and reproducibility in the interpretation of human epidermal growth factor receptor 2 (HER2) immunohistochemistry (IHC) for breast cancer where QIA is used. The College of American Pathologists (CAP) convened a panel of pathologists, histotechnologists, and computer scientists with expertise in image analysis, immunohistochemistry, quality management, and breast pathology to develop recommendations for QIA of HER2 IHC in breast cancer. A systematic review of the literature was conducted to address 5 key questions. Final recommendations were derived from strength of evidence, open comment feedback, expert panel consensus, and advisory panel review. Eleven recommendations were drafted: 7 based on CAP laboratory accreditation requirements and 4 based on expert consensus opinions. A 3-week open comment period received 180 comments from more than 150 participants. To improve accurate, precise, and reproducible interpretation of HER2 IHC results for breast cancer, QIA and procedures must be validated before implementation, followed by regular maintenance and ongoing evaluation of quality control and quality assurance. HER2 QIA performance, interpretation, and reporting should be supervised by pathologists with expertise in QIA.

Mitochondria and Sex-Specific Cardiac Function.

The focus of this chapter is the gender differences in mitochondria in cardiovascular disease. There is broad evidence suggesting that some of the gender differences in cardiovascular outcome may be partially related to differences in mitochondrial biology (Ventura-Clapier R, Moulin M, Piquereau J, Lemaire C, Mericskay M, Veksler V, Garnier A, Clin Sci (Lond) 131(9):803-822, 2017)). Mitochondrial disorders are causally affected by mutations in either nuclear or mitochondrial genes involved in the synthesis of respiratory chain subunits or in their posttranslational control. This can be due to mutations of the mtDNA which are transmitted by the mother or mutations in the nuclear DNA. Because natural selection on mitochondria operates only in females, mutations may have had more deleterious effects in males than in females (Ventura-Clapier R, Moulin M, Piquereau J, Lemaire C, Mericskay M, Veksler V, Garnier A, Clin Sci (Lond) 131(9):803-822, 2017; Camara AK, Lesnefsky EJ, Stowe DF. Antioxid Redox Signal 13(3):279-347, 2010). As mitochondrial mutations can affect all tissues, they are responsible for a large panel of pathologies including neuromuscular disorders, encephalopathies, metabolic disorders, cardiomyopathies, neuropathies, renal dysfunction, etc. Many of these pathologies present sex/gender specificity. Thus, alleviating or preventing mitochondrial dysfunction will contribute to mitigating the severity or progression of the development of diseases. Here, we present evidence for the involvement of mitochondria in the sex specificity of cardiovascular disorders.

Development and validation of a protocol for optimizing the use of paraffin blocks in molecular epidemiological studies: The example from the HPV-AHEAD study.

Worldwide use of formalin-fixed paraffin-embedded blocks (FFPE) is extensive in diagnosis and research. Yet, there is a lack of optimized/standardized protocols to process the blocks and verify the quality and presence of the targeted tissue. In the context of an international study on head and neck cancer (HNC)—HPV-AHEAD, a standardized protocol for optimizing the use of FFPEs in molecular epidemiology was developed and validated. First, a protocol for sectioning the FFPE was developed to prevent cross-contamination and distributed between participating centers. Before processing blocks, all sectioning centers underwent a quality control to guarantee a satisfactory training process. The first and last sections of the FFPEs were used for histopathological assessment. A consensus histopathology evaluation form was developed by an international panel of pathologists and evaluated for four indicators in a pilot analysis in order to validate it: 1) presence/type of tumor tissue, 2) identification of other tissue components that could affect the molecular diagnosis and 3) quality of the tissue. No HPV DNA was found in sections from empty FFPE generated in any histology laboratories of HPV-AHEAD consortium and all centers passed quality assurance for processing after quality control. The pilot analysis to validate the histopathology form included 355 HNC cases. The form was filled by six pathologists and each case was randomly assigned to two of them. Most samples (86%) were considered satisfactory. Presence of >50% of invasive carcinoma was observed in all sections of 66% of cases. Substantial necrosis (>50%) was present in <2% of samples. The concordance for the indicators targeted to validate the histopathology form was very high (kappa > 0.85) between first and last sections and fair to high between pathologists (kappa/pabak 0.21–0.72). The protocol allowed to correctly process without signs of contamination all FFPE of the study. The histopathology evaluation of the cases assured the presence of the targeted tissue, identified the presence of other tissues that could disturb the molecular diagnosis and allowed the assessment of tissue quality.

The histopathological classification, diagnosis and differential diagnosis of mucinous appendiceal neoplasms, appendiceal adenocarcinomas and pseudomyxoma peritonei.

The vermiform appendix is the primary site of several distinctive benign and malignant neoplasms. Some can produce the clinical syndrome of pseudomyxoma peritonei (PMP). A consensus on their terminology was reached by an international panel of pathologists and clinicians working under the auspices of the Peritoneal Surface Oncology Group International (PSOGI), and this review discusses the application of the PSOGI classification to routine reporting. We discuss diagnosis and differential diagnosis together with implications for patient management, covering low-grade appendiceal mucinous neoplasms, high-grade appendiceal mucinous neoplasms, serrated polyps, adenomas and adenocarcinomas. We do not cover goblet cell tumours or neuroendocrine neoplasms in this paper.

Final efficacy, immunogenicity, and safety analyses of a nine-valent human papillomavirus vaccine in women aged 16–26 years: a randomised, double-blind trial

Primary analyses of a study in young women aged 16-26 years showed efficacy of the nine-valent human papillomavirus (9vHPV; HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58) vaccine against infections and disease related to HPV 31, 33, 45, 52, and 58, and non-inferior HPV 6, 11, 16, and 18 antibody responses when compared with quadrivalent HPV (qHPV; HPV 6, 11, 16, and 18) vaccine. We aimed to report efficacy of the 9vHPV vaccine for up to 6 years following first administration and antibody responses over 5 years. We undertook this randomised, double-blind, efficacy, immunogenicity, and safety study of the 9vHPV vaccine study at 105 study sites in 18 countries. Women aged 16-26 years old who were healthy, with no history of abnormal cervical cytology, no previous abnormal cervical biopsy results, and no more than four lifetime sexual partners were randomly assigned (1:1) by central randomisation and block sizes of 2 and 2 to receive three intramuscular injections over 6 months of 9vHPV or qHPV (control) vaccine. All participants, study investigators, and study site personnel, laboratory staff, members of the sponsor's study team, and members of the adjudication pathology panel were masked to vaccination groups. The primary outcomes were incidence of high-grade cervical disease (cervical intraepithelial neoplasia grade 2 or 3, adenocarcinoma in situ, invasive cervical carcinoma), vulvar disease (vulvar intraepithelial neoplasia grade 2/3, vulvar cancer), and vaginal disease (vaginal intraepithelial neoplasia grade 2/3, vaginal cancer) related to HPV 31, 33, 45, 52, and 58 and non-inferiority (excluding a decrease of 1·5 times) of anti-HPV 6, 11, 16, and 18 geometric mean titres (GMT). Tissue samples were adjudicated for histopathology diagnosis and tested for HPV DNA. Serum antibody responses were assessed by competitive Luminex immunoassay. The primary evaluation of efficacy was a superiority analysis in the per-protocol efficacy population, supportive efficacy was analysed in the modified intention-to-treat population, and the primary evaluation of immunogenicity was a non-inferiority analysis. The trial is registered with ClinicalTrials.gov, number NCT00543543. Between Sept 26, 2007, and Dec 18, 2009, we recruited and randomly assigned 14 215 participants to receive 9vHPV (n=7106) or qHPV (n=7109) vaccine. In the per-protocol population, the incidence of high-grade cervical, vulvar and vaginal disease related to HPV 31, 33, 45, 52, and 58 was 0·5 cases per 10 000 person-years in the 9vHPV and 19·0 cases per 10 000 person-years in the qHPV groups, representing 97·4% efficacy (95% CI 85·0-99·9). HPV 6, 11, 16, and 18 GMTs were non-inferior in the 9vHPV versus qHPV group from month 1 to 3 years after vaccination. No clinically meaningful differences in serious adverse events were noted between the study groups. 11 participants died during the study follow-up period (six in the 9vHPV vaccine group and five in the qHPV vaccine group); none of the deaths were considered vaccine-related. The 9vHPV vaccine prevents infection, cytological abnormalities, high-grade lesions, and cervical procedures related to HPV 31, 33, 45, 52, and 58. Both the 9vHPV vaccine and qHPV vaccine had a similar immunogenicity profile with respect to HPV 6, 11, 16, and 18. Vaccine efficacy was sustained for up to 6 years. The 9vHPV vaccine could potentially provide broader coverage and prevent 90% of cervical cancer cases worldwide. Merck & Co, Inc.

Cervical intraepithelial neoplasia (CIN) in African women living with HIV: role and effect of rigorous histopathological review by a panel of pathologists in the HARP study endpoint determination

AIMSTo analyse the effect of the expert end-point committee (EPC) review on histological endpoint classification of cervical intraepithelial neoplasia (CIN).MethodsA cohort of women living with HIV were recruited in Burkina...

Long-term Behavior of Serous Borderline Tumors Subdivided Into Atypical Proliferative Tumors and Noninvasive Low-grade Carcinomas: A Population-based Clinicopathologic Study of 942 Cases.

Ovarian serous borderline tumors (SBTs) have been the subject of considerable controversy, particularly with regard to terminology and behavior. It has been proposed that they constitute a heterogenous group of tumors composed, for the most part, of typical SBTs that are benign and designated "atypical proliferative serous tumor (APST)" and a small subset of SBTs with micropapillary architecture that have a poor outcome and are designated "noninvasive low-grade serous carcinoma (niLGSC)". It also has been argued that the difference in behavior between the 2 groups is not due to the subtype of the primary tumor but rather the presence of extraovarian disease, specifically invasive implants. According to the terminology of the 2014 WHO Classification, typical SBTs are equivalent to APSTs and SBTs displaying micropapillary architecture are synonymous with niLGSC. In addition, "invasive implants" were renamed "low-grade serous carcinoma" (LGSC). The argument as to whether it is the appearance of the primary tumor or the presence of extraovarian LGSC that determines outcome remains unsettled. The current study was initiated in 2004 and was designed to determine what factors were predictive of outcome, with special attention to the appearance of the primary tumor (APST vs. niLGSC) and that of the extraovarian disease (noninvasive vs. invasive implants). Our study is population based, involving the entire female population of Denmark. None of the women in the study were lost to follow-up, which ranged up to 36 years (median, 15 y). All the microscopic slides from the contributing hospitals were rereviewed by a panel of 2 pathologists (R.V. and R.J.K.) who were blinded to the follow-up. After excluding those that were not SBTs by the pathology panel, as well as cases with a prior or concurrent cancer or undefined stage, 942 women remained, of which 867 were APSTs and 75 were niLGSCs. The median patient age was 50 years (range, 16 to 97 y). Eight hundred nine women (86%) presented with FIGO stage I disease, whereas 133 (14%) had advanced stage disease. Compared with APSTs, niLGSC exhibited a significantly greater frequency of bilaterality, residual gross disease after surgery, microinvasion/microinvasive carcinoma, advanced stage disease, and invasive implants at presentation (P-values <0.003). Because the cause of death is difficult to accurately ascertain from death certificates, we used development of invasive serous carcinoma as the primary endpoint as following development of carcinoma, the mortality is very high. In the entire cohort, subsequent development of carcinoma occurred in 4%, of which 93% were low grade and 7% high grade (median time, 10 y; range, up to 25 y). After adjusting for age at and time since diagnosis of APST or niLGSC, occurrence of subsequent carcinoma was significantly higher with niLGSC than APST among all stages combined (hazard ratio [HR]=3.8; 95% confidence interval [CI], 1.7-8.2). This difference was still significant for stage I but not advanced stage cases. Moreover, all-cause mortality was not statistically significantly different between APST and niLGSC. Of all women with advanced stage disease, 114 (86%) had noninvasive implants, whereas 19 (14%) were invasive. Noninvasive implants were significantly associated with subsequent development of carcinoma (HR=7.7; 95% CI, 3.9-15.0), but the risk with invasive implants was significantly higher (HR=42.3; 95% CI, 16.1-111.1). In conclusion, although invasive implants are the most important feature in predicting an adverse outcome, subclassification into APST and niLGSC is important as it stratifies women with respect to risk for advanced stage disease and invasive implants for all women and development of serous carcinoma for stage I cases.

Chemotherapy for pulmonary large cell neuroendocrine carcinomas: does the regimen matter?

Pulmonary large cell neuroendocrine carcinoma (LCNEC) is rare. Chemotherapy for metastatic LCNEC ranges from small cell lung carcinoma (SCLC) regimens to nonsmall cell lung carcinoma (NSCLC) chemotherapy regimens. We analysed outcomes of chemotherapy treatments for LCNEC.The Netherlands Cancer Registry and Netherlands Pathology Registry (PALGA) were searched for patients with stage IV chemotherapy-treated LCNEC (2003–2012). For 207 patients, histology slides were available for pathology panel review. First-line platinum-based combined chemotherapy was clustered as “NSCLC-t”, comprising gemcitabine, docetaxel, paclitaxel or vinorelbine; “NSCLC-pt”, with pemetrexed treatment only; and “SCLC-t”, consisting of etoposide chemotherapy.A panel review diagnosis of LCNEC was established in 128 out of 207 patients. NSCLC-t chemotherapy was administered in 46% (n=60), NSCLC-pt in 16% (n=20) and SCLC-t in 38% (n=48) of the patients. The median (95% CI) overall survival for NSCLC-t chemotherapy was 8.5 (7.0–9.9) months, significantly longer than patients treated with NSCLC-pt, with a median survival of 5.9 (5.0–6.9) months (hazard ratio 2.51, 95% CI 1.39–4.52; p=0.002) and patients treated with SCLC-t chemotherapy, with a median survival of 6.7 (5.0–8.5) months (hazard ratio 1.66, 95% CI 1.08–2.56; p=0.020).In patients with LCNEC, NSCLC-t chemotherapy results in longer overall survival compared to NSCLC-pt and SCLC-t chemotherapy.

Mitochondria: a central target for sex differences in pathologies.

It is increasingly acknowledged that a sex and gender specificity affects the occurrence, development, and consequence of a plethora of pathologies. Mitochondria are considered as the powerhouse of the cell because they produce the majority of energy-rich phosphate bonds in the form of adenosine tri-phosphate (ATP) but they also participate in many other functions like steroid hormone synthesis, reactive oxygen species (ROS) production, ionic regulation, and cell death. Adequate cellular energy supply and survival depend on mitochondrial life cycle, a process involving mitochondrial biogenesis, dynamics, and quality control via mitophagy. It appears that mitochondria are the place of marked sexual dimorphism involving mainly oxidative capacities, calcium handling, and resistance to oxidative stress. In turn, sex hormones regulate mitochondrial function and biogenesis. Mutations in genes encoding mitochondrial proteins are the origin of serious mitochondrial genetic diseases. Mitochondrial dysfunction is also an important parameter for a large panel of pathologies including neuromuscular disorders, encephalopathies, cardiovascular diseases (CVDs), metabolic disorders, neuropathies, renal dysfunction etc. Many of these pathologies present sex/gender specificity. Here we review the sexual dimorphism of mitochondria from different tissues and how this dimorphism takes part in the sex specificity of important pathologies mainly CVDs and neurological disorders.

Variability in the use of cut-off points with different commercial and lab-developed assays for PD-L1 expression testing in the NSCLC clinical setting in the United States.

46 Background: Following the recent approval of several companion diagnostic and complementary diagnostic assays for PD-L1 expression testing, as well as the availability of multiple antibodies for use in laboratory testing, pathologists have a range of tools at their disposal for measuring expression levels of this predictive biomarker. While specific cut-off points for positivity are specified by the assay manufacturer and/or recommended based on trial data, clinicians can choose different cut-off points to define positivity. In this study, we explore the variety of test brands and cut-off points that are being used in clinical practice in the US by examining real-world usage data. Methods: Between June and August 2016, a panel of pathologists (n = 27) in the US were asked to report on their practices relating to PD-L1 expression testing for NSCLC patients, through the submission of online de-identified record forms (n = 167 PD-L1-tested samples). Results: Of the 167 samples, 112 (67%) were tested with the Dako 22C3 pharmDx assay, 37 (22%) with the Dako 28-8 pharmDx assay and 16 (10%) with a lab-developed test (LDT). When using 22C3 pharmDx, 72% of samples were tested with the recommended 50% cut-off point, with the remaining 28% using lower cut-off points, ranging from 1% to 25%. For 28-8 pharmDx, both the 1% cut-off point (in 54% of cases) and the 5% cut-off point (in 35% of cases) were frequently used (1% recommended; 5% being investigated in clinical trials e.g. CHEKMATE-026). LDTs were mostly (88%) employed with a cut-off of 1% across antibodies. Conclusions: The use of PD-L1 expression testing to determine eligibility for PD-(L)1 inhibitors in the clinical setting shows significant fragmentation in the US, with multiple different assays being employed. Furthermore, there is a lack of standardization in terms of the cut-off points that are used when testing with each of those assays. This lack of consistency adds a level of complexity to oncologists treatment decisions when choosing whether or not to treat with a PD-(L)1 inhibitor, and which brand to choose.

PUB075 Survival of Patients with Stage I Lung Cancer Detected on CT Screening in South Indian Population

The outcome among patients with clinical stage I cancer that is detected on annual screening using spiral computed tomography (CT) is unknown among the south Indian population. In a large collaborative study, we screened 28351 asymptomatic persons at risk for lung cancer using low-dose CT from 2004 through 2014, and from 2005 through 2014, 25356 repeated screenings were performed 7 to 18 months after the previous screening. We estimated the 10-year lung-cancer-specific survival rate among participants with clinical stage I lung cancer that was detected on CT screening and diagnosed by biopsy, regardless of the type of treatment received, and among those who underwent surgical resection of clinical stage I cancer within 1 month. A pathology panel reviewed the surgical specimens obtained from participants who underwent resection. Screening resulted in a diagnosis of lung cancer in 480 participants. Of these participants, 410 (84%) had clinical stage I lung cancer, and the estimated 10-year survival rate was 87% in this subgroup (94% confidence interval [CI], 83 to 90). Among the 301 participants with clinical stage I cancer who underwent surgical resection within 1 month after diagnosis, the survival rate was 91% (94% CI, 87 to 94). The 8 participants with clinical stage I cancer who did not receive treatment died within 5 years after diagnosis. Annual spiral CT screening can detect lung cancer that is curable.

HG-85INTER-OBSERVER AGREEMENT IN NEUROPATHOLOGICAL HGG DIAGNOSIS : EXPERIENCE OF THE PRE-RANDOMISATION CENTRAL REVIEW IN THE HERBY TRIAL

HG-85. INTER-OBSERVER AGREEMENT IN NEUROPATHOLOGICAL HGG DIAGNOSIS : EXPERIENCE OF THE PRE-RANDOMISATION CENTRAL REVIEW IN THE HERBY TRIAL Pascale Varlet1, Marie-Cecile Le Deley2, Felice Giangaspero3, Christine Haberler4, Thomas S. Jacques5, Dominique Figarella-Branger6, Torsten Pietsch7, Felipe Andreiuolo1, Darren Hargrave5, Maura Massimino8, Tim Jaspan9, Chris Jones10, Amedeo A. Azizi11, Adela Canete12, Eric Bouffet13, Helen Smith14, Josep Garcia14, Gilles Vassal2, and Jacques Grill2; Sainte-Anne Hospital, Paris, France; Institut Gustave Roussy, Villejuif, France; Sapienza UniversityofRome,Roma, Italy; InstituteofNeurology,Wien,Austria; Great Ormond Street Hospital, London, UK; Hopital de la Timone, Marseille, France; University of Bonn, Bonn, Germany; Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy; University Hospital, Nottingham, UK; InstituteofCancerResearch,Sutton,UK;UniversitatsKlinik furKinderund Jugendheilkunde, Wien, Austria; H.U. LA FE, Valencia, Spain; Hospital for Sick Children, Toronto, ON, Canada; F. Hoffmann-La Roche Ltd, Basel, Switzerland In previous large paediatric multicentre trials for High-Grade Glioma (HGG), highproportions of diagnosticdisagreementacrossneuropathologists were reported. The HERBY trial is a Phase-II open-label, randomised, multicentre trial evaluating bevacizumab in paediatric patients with newly diagnosed supratentorial HGG. METHODS: Confirmation of HGG diagnosis by reference pathology was mandatory before randomisation, followed by a review by five independent expert neuropathologists. Inter-observer agreement was assessed using Cohen’s Kappa coefficients. RESULTS: Slides from 169/187 patients screened for eligibility were centrally reviewed, within 3 days in 69% of cases. HGG diagnosis was centrally confirmed in 149 cases (88%), whereas diagnosis was low-grade glioma in 5% (n 1⁄4 8), anaplastic ganglioglioma/PXA (n 1⁄4 8), miscellaneous diagnoses (n 1⁄4 4). 124 patients entered the randomised trial. Three cases were not confirmed by the pathology panel (reclassified in grade II oligodendroglioma or anaplastic gangliogliomas). The Kappa coefficient between local and reference pathologistwasmoderate for the subtype and substantial for the WHO grade (Kappa 1⁄4 0.45 and 0.68, respectively). Agreement varied according to the initial diagnosis with the confirmation of subtype and grade for 23% cases of oligodendroglioma or mixed oligo-astrocytoma, 76% of WHO grade III astrocytoma and 95% of glioblastoma. The review panel registered some degree of discordance for subtype or grade in 52% cases, with dispersed conclusions from the experts (. 3 out of 5) in 10% cases. However, Kappa coefficient reached 85% for the grading between the reference pathologist and the consensus. These data highlight the interest and feasibility of a pre-randomised real-time central neuropathological review in multicentre trials. Neuro-Oncology 18:iii48–iii77, 2016. doi:10.1093/neuonc/now073.81 #The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Human papillomavirus detection in cervical neoplasia attributed to 12 high-risk human papillomavirus genotypes by region

BackgroundWe estimated the proportion of cervical intraepithelial neoplasia (CIN) cases attributed to 14 HPV types, including quadrivalent (qHPV) (6/11/16/18) and 9-valent (9vHPV) (6/11/16/18/31/33/45/52/58) vaccine types, by region MethodsWomen ages 15–26 and 24–45 years from 5 regions were enrolled in qHPV vaccine clinical trials. Among 10,706 women (placebo arms), 1539 CIN1, 945 CIN2/3, and 24 adenocarcinoma in situ (AIS) cases were diagnosed by pathology panel consensus. ResultsPredominant HPV types were 16/51/52/56 (anogenital infection), 16/39/51/52/56 (CIN1), and 16/31/52/58 (CIN2/3). In regions with largest sample sizes, minimal regional variation was observed in 9vHPV type prevalence in CIN1 (~50%) and CIN2/3 (81–85%). Types 31/33/45/52/58 accounted for 25–30% of CIN1 in Latin America and Europe, but 14–18% in North America and Asia. Types 31/33/45/52/58 accounted for 33–38% of CIN2/3 in Latin America (younger women), Europe, and Asia, but 17–18% of CIN2/3 in Latin America (older women) and North America. Non-vaccine HPV types 35/39/51/56/59 had similar or higher prevalence than qHPV types in CIN1 and were attributed to 2–11% of CIN2/3. ConclusionsThe 9vHPV vaccine could potentially prevent the majority of CIN1-3, irrespective of geographic region. Notwithstanding, non-vaccine types 35/39/51/56/59 may still be responsible for some CIN1, and to a lesser extent CIN2/3.

Prognostic Value of Ki-67 Index, Cytology, and Growth Pattern in Mantle-Cell Lymphoma: Results From Randomized Trials of the European Mantle Cell Lymphoma Network.

Mantle-cell lymphoma (MCL) is a rather aggressive B-cell malignancy whose considerable variability of individual outcome is associated with clinical characteristics (Mantle Cell Lymphoma International Prognostic Index [MIPI]). The Ki-67 index is a strong independent prognostic factor; however, the biologic MIPI (MIPI-b) distinguishes only two groups, which does not appropriately depict the clinical heterogeneity. By using the cohort from the European MCL Younger and MCL Elderly trials, we aimed to evaluate the additional prognostic impact of cytology and growth pattern and to improve risk stratification with the Ki-67 index and MIPI. Diagnostic tumor biopsies were reviewed by the European Mantle Cell Lymphoma Pathology Panel to determine Ki-67 index by using published guidelines, cytology, and growth pattern. We evaluated prognostic effects for overall survival (OS) by Cox regression. For the cohort used for MIPI-b development (German Low-Grade Lymphoma Study Group [GLSG] 1996 and GLSG2000), we checked whether the equally weighted combination of Ki-67 index (dichotomized at the validated 30% cutoff) and MIPI risk groups was adequate and compared the prognostic power of this modified combination to MIPI and MIPI-b for the MCL Younger/MCL Elderly cohort. The Ki-67 index was assessed in 508 of 832 patients (median age, 62 years). Blastoid cytology was associated with inferior OS independently of MIPI but not independently of the Ki-67 index. Growth pattern was not independently prognostic. The modified combination of the Ki-67 index and MIPI separated four groups with 5-year OS: 85%, 72%, 43%, and 17% (P < .001) and was more discriminative than MIPI and MIPI-b. Using the Ki-67 index is superior to using cytology and growth pattern as prognostic factors in MCL. The modified combination of the Ki-67 index and MIPI showed a refined risk stratification, reflecting their strong complementary prognostic effects while integrating the most relevant prognostic factors available in clinical routine.

Assessment of a HER2 scoring system for colorectal cancer: results from a validation study

We sought to develop criteria for ERBB2-positivity (HER2) in colorectal cancer to ensure accurate identification of ERBB2-amplified metastatic colorectal cancer patients suitable for enrolment in a phase II trial of ERBB2-targeted therapy (HERACLES trial). A two-step approach was used. In step 1, a consensus panel of pathologists adapted existing protocols for use in colorectal cancer to test ERBB2 expression and amplification. Collegial revision of an archival test cohort of colorectal cancer samples led to specific recommendations for adapting current breast and gastric cancer criteria for scoring ERBB2 in colorectal cancer. In step 2, from September 2012 to January 2015, colorectal-specific ERBB2 testing protocols and ERBB2 scoring criteria were used to centrally screen for ERBB2-positive KRAS wild-type colorectal cancer patients to be enrolled in the HERACLES trial (clinical validation cohort). In both archival test (N=256) and clinical validation (N=830) cohorts, a clinically sizeable 5% fraction of KRAS wild-type colorectal cancer patients was found to be ERBB2-positive according to the colorectal cancer-specific ERBB2 scoring criteria. ERBB2-positive tumors showed ERBB2 immunostaining consisting of intense membranous ERBB2 protein expression, corresponding to homogenous ERBB2 amplification, in >50% of cells. None of the immunohistochemistry 0 or 1+ cases was amplified. Concordance between SISH and FISH was 100%. In conclusion, we propose specific criteria for defining ERBB2-positivity in colorectal cancer (HERACLES Diagnostic Criteria). In a phase II trial of trastuzumab and lapatinib in a cetuximab-resistant population, HERACLES Diagnostic Criteria shaped the selection of patients and defined ERBB2 as a predictive marker for response to ERBB2-targeted therapy in metastatic colorectal cancer.