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METHODS IN MOLECULAR BIOLOGY™

Series Editor
John M. Walker
School of Life Sciences
University of Hertfordshire
Hatfield, Hertfordshire, AL10 9AB, UK

For further volumes:

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 Molecular Profiling

Methods and Protocols

Edited by

Virginia Espina and Lance A. Liotta

Center for Applied Proteomics and Molecular Medicine, George Mason University,
Manassas, VA, USA
Editors
Virginia Espina Lance A. Liotta
Center for Applied Proteomics Center for Applied Proteomics
and Molecular Medicine and Molecular Medicine
George Mason University George Mason University
Manassas, VA, USA Manassas, VA, USA
[email protected] [email protected]

ISSN 1064-3745 e-ISSN 1940-6029

ISBN 978-1-60327-215-5 e-ISBN 978-1-60327-216-2
DOI 10.1007/978-1-60327-216-2
Springer New York Dordrecht Heidelberg London

Library of Congress Control Number: 2011940328

© Springer Science+Business Media, LLC 2012

All rights reserved. This work may not be translated or copied in whole or in part without the written permission of the
publisher (Humana Press, c/o Springer Science+Business Media, LLC, 233 Spring Street, New York, NY 10013, USA),
except for brief excerpts in connection with reviews or scholarly analysis. Use in connection with any form of information
storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or
hereafter developed is forbidden.
The use in this publication of trade names, trademarks, service marks, and similar terms, even if they are not identified
as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights.

Printed on acid-free paper

Humana Press is part of Springer Science+Business Media (www.springer.com)

Dedication

This book is proudly dedicated to Mary Anne and Len Schiff. Len’s encouragement to
pursue a life-long interest in research, and Mary Anne’s personal sacrifices so I could pursue
a graduate degree, were the catalysts that initiated numerous collaborations resulting in the
publication of this book.

Virginia Espina
Preface

The next revolution in molecular medicine is the application of molecular profiling to

individualized patient therapy. Molecular profiling technology has advanced dramatically,
particularly in the field of cancer tissue biomarkers. It is now possible to gather complex
genomic and proteomic information from a routine clinical needle biopsy or surgical specimen.
This means that translational research scientists can finally begin to address urgent applied
research questions that were not possible in the past: (a) How can tissue molecular informa-
tion be gathered in a reliable and reproducible fashion that is suitable for routine applica-
tion to the clinic? (b) How does the molecular signature of diseased tissues provide insights
into pathogenesis, prognosis, and therapeutic options? (c) What is the best means of com-
bining molecular data with other classes of clinical data (imaging, pathologic staging, clinical
chemistry panels) to optimize the treatment plan for the individual patient? (d) How can
new classes of clinical research trials be created that are biomarker guided, hypothesis driven,
and individualized? The purpose of this volume is to provide an accelerated tutorial to assist
students, entrepreneurs, new investigators, and established investigators who want to
quickly become versed in, and immersed in, the entire process from discovery to clinical
trial validation and commercial public benefit. Our internationally recognized chapter
authors have provided the background science, the vision, and the practical experimental
protocols, with tips and troubleshooting guides. Since the aim is to span the full process
from discovery to commercialization, our practical guides are not limited to experimental
methods. We have included tutorials on patents and intellectual property, small business
development, FDA review guidelines for molecular profiling, and grant writing tips for
investigators seeking funding in translational research.
Molecular Profiling is designed to step the reader through a project/experiment in
molecular medicine. The protocol chapters describe detailed techniques for evaluating tissue
samples, tissue collection and storage, analytical platforms, and bioinformatics/biostatis-
tics. The narrative chapters are designed to provide the reader with a well-rounded discus-
sion of intellectual property issues in biotechnology, human subjects research requirements,
regulatory agency approval processes, and an overview of technology transfer (patent)
issues. Although other books have been published covering the topics of genomic profiling,
or protein chemistry, we believe this is the first book dedicated to incorporating genomics,
proteomics, and bioinformatics with experimental protocols and detailed discussions of
future requirements and challenges for commercialization and practical use in the field. An
emphasis is placed on tissue-based molecular profiling, a rapidly emerging field that is not
covered in pathology text books.
Molecular Profiling covers eleven topics in relation to human disease: Cancer medicine
and medical ethics relevant to individualized therapy, genomics, proteomics, microscopic
imaging, bioinformatics, tissue preservation/biobanking, individualized therapy regimens,
intellectual property, regulatory approval, business development, and grant funding in
translational research. A set of core Chapters 1–24 covering genomics, proteomics, imag-
ing, and bioinformatics, illustrate current laboratory protocols for generating data relevant
to molecular medicine. Each of these disciplines is complementary and the grouping simply

vii
viii Preface

provides a means for differentiating the classes of molecular analytes. The four topics covered
in Chapters 25–28 are unique aspects of this volume of the Methods in Molecular Biology
series. These latter chapters discuss, in a narrative or tutorial style, future real-world needs
in personalized molecular medicine. Important points are highlighted in the Notes section
for each chapter.
Although many of the techniques discussed in this volume use commercially available
reagents and instrumentation, it is imperative for the user/reader to understand the prin-
ciples and nuances of these techniques, because they are designed for use with irreplaceable
human tissue specimens. In an attempt to provide basic assay information, we have included
overview principles in the introduction to each analytical chapter as well as providing trou-
bleshooting tips and tricks for the experienced scientist.
We hope that the readers of this volume will use it as a practical guide at the lab bench
as well as the boardroom. The intended readership spans the range of scientists, patholo-
gists, oncologists, residents, biotechnologists, medical students, and nurses involved in
clinical trial research. We have a personal hope that this volume will attract new investiga-
tors who can apply their creative talents to realize the promise of individualized molecular
medicine.
We thank our esteemed chapter authors for their valuable contributions to this volume.

Manassas, VA, USA Virginia Espina

Lance A. Liotta
Contents

Preface. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vii
Contributors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xi

1 Tumor Staging and Grading: A Primer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

Stacy M. Cowherd
2 Clinical Trial Design in the Age of Molecular Profiling . . . . . . . . . . . . . . . . . . 19
Alexander Spira and Kirsten H. Edmiston
3 Personalized Medicine: Ethics for Clinical Trials . . . . . . . . . . . . . . . . . . . . . . . 35
G. Terry Sharrer
4 Reduction of Preanalytical Variability in Specimen Procurement
for Molecular Profiling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
Virginia Espina and Claudius Mueller
5 The Human Side of Cancer Biobanking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
Eoin F. Gaffney, Deirdre Madden, and Geraldine A. Thomas
6 Introduction to Genomics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
Luca Del Giacco and Cristina Cattaneo
7 Genomic Profiling: cDNA Arrays and Oligoarrays . . . . . . . . . . . . . . . . . . . . . . 89
Francesco Gorreta, Walter Carbone, and Dagania Barzaghi
8 Genome-Wide Methylation Profiling in Archival Formalin-Fixed
Paraffin-Embedded Tissue Samples . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
J. Keith Killian, Robert L. Walker, Sven Bilke, Yidong Chen,
Sean Davis, Robert Cornelison, William I. Smith,
and Paul S. Meltzer
9 An Overview of MicroRNA Methods: Expression Profiling
and Target Identification. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
Sinéad M. Smith and David W. Murray
10 Antibody Validation by Western Blotting. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139
Michele Signore and K. Alex Reeder
11 Laser Capture Microdissection: ArcturusXT Infrared Capture
and UV Cutting Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157
Rosa I. Gallagher, Steven R. Blakely, Lance A. Liotta,
and Virginia Espina
12 Antibody Microarrays: Analysis of Cystic Fibrosis . . . . . . . . . . . . . . . . . . . . . . 179
Catherine E. Jozwik, Harvey B. Pollard, Meera Srivastava,
Ofer Eidelman, QingYuan Fan, Thomas N. Darling,
and Pamela L. Zeitlin
13 Tissue Microarrays as a Tool in the Discovery and Validation
of Predictive Biomarkers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201
Stephen M. Hewitt

ix
x Contents

14 Reverse-Phase Protein Microarrays . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215

Mariaelena Pierobon, Amy J. VanMeter, Noemi Moroni,
Francesca Galdi, and Emanuel F. Petricoin III
15 Serum Low-Molecular-Weight Protein Fractionation
for Biomarker Discovery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237
Amy J. VanMeter, Serena Camerini, Maria Letizia Polci,
Alessandra Tessitore, Nishant Trivedi, Michael Heiby,
Yasmin Kamal, Jonathan Hansen, and Weidong Zhou
16 Mass Spectrometry-Based Biomarker Discovery. . . . . . . . . . . . . . . . . . . . . . . . 251
Weidong Zhou, Emanuel F. Petricoin III, and Caterina Longo
17 Mitochondrial Proteome: Toward the Detection and Profiling
of Disease Associated Alterations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265
Paul C. Herrmann and E. Clifford Herrmann
18 Adult Neural Stem Cells: Isolation and Propagation . . . . . . . . . . . . . . . . . . . . 279
Jamin M. Letcher and Daniel N. Cox
19 Evanescent-Wave Field Imaging: An Introduction to Total Internal
Reflection Fluorescence Microscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295
Bryan A. Millis
20 Construction and Hyperspectral Imaging of Quantum
Dot Lysate Arrays . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 311
Kevin P. Rosenblatt, Michael L. Huebschman,
and Harold R. Garner
21 Microarray Data Analysis: Comparing Two Population Means. . . . . . . . . . . . . 325
Jianghong Deng, Valerie Calvert, and Mariaelena Pierobon
22 Bioinformatics/Biostatistics: Microarray Analysis. . . . . . . . . . . . . . . . . . . . . . . 347
Gabriel S. Eichler
23 Structure-Based Functional Design of Drugs: From Target
to Lead Compound . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 359
Amy C. Anderson
24 Personalized Medicine: Changing the Paradigm
of Drug Development. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 367
Robin D. Couch and Bryan T. Mott
25 Grant Writing Tips for Translational Research . . . . . . . . . . . . . . . . . . . . . . . . . 379
Lindsay Wescott and Michael Laskofski
26 Inventions and Patents: A Practical Tutorial. . . . . . . . . . . . . . . . . . . . . . . . . . . 391
J. Lille Tidwell and Lance A. Liotta
27 Regulatory Approval Pathways for Molecular Diagnostic Technology . . . . . . . 409
Lance A. Liotta and Emanuel F. Petricoin III
28 Small Business Development for Molecular Diagnostics. . . . . . . . . . . . . . . . . . 421
Anthanasia Anagostou and Lance A. Liotta
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 439
Contributors

ANTHANASIA ANAGOSTOU • Tatari Design Center and Zorba Marketing Incorporated,

Alexandria, VA, USA
AMY C. ANDERSON • School of Pharmacy, University of Connecticut, Storrs, CT, USA
DAGANIA BARZHAGI • Medestea Research and Production S.p.A,
Colleretto Giacosa (TO), Italy
SVEN BILKE • Cancer Genetics Branch, National Institutes of Health/
National Cancer Institute, Bethesda, MD, USA
STEVEN R. BLAKELY • Applied Biosystems/Life Technologies Corporation,
Foster City, CA, USA
VALERIE CALVERT • Center for Applied Proteomics and Molecular Medicine,
George Mason University, Manassas, VA, USA
SERENA CAMERINI • Istituto Superiore di Sanità, Rome (RO), Italy
WALTER CARBONE • Merck Serono, Colleretto Giacosa (TO), Italy
CRISTINA CATTANEO • Department of Biology, University of Milan, Milan (MI), Italy
YIDONG CHEN • Cancer Genetics Branch, National Institutes of Health/
National Cancer Institute, Bethesda, MD, USA
ROBERT CORNELISON • Cancer Genetics Branch, National Institutes of Health/
National Cancer Institute, Bethesda, MD, USA
ROBIN D. COUCH • Department of Chemistry and Biochemistry, George Mason
University, Manassas, VA, USA
STACY M. COWHERD • Internal Medicine, University of North Carolina
School of Medicine, Chapel Hill, NC, USA
DANIEL N. COX • Krasnow Institute for Advanced Study, George Mason University,
Fairfax, VA, USA
THOMAS N. DARLING • Department of Anatomy, Physiology and Genetics, Uniformed
Services University School of Medicine, Bethesda, MD, USA
SEAN DAVIS • Cancer Genetics Branch, National Institutes of Health/
National Cancer Institute, Bethesda, MD, USA
LUCA DEL GIACCO • Division of Functional and Reproductive Biology,
Department of Biology, University of Milan, Milan (MI), Italy
JIANGHONG DENG • Center for Applied Proteomics and Molecular Medicine,
George Mason University, Manassas, VA, USA
KIRSTEN H. EDMISTON • Inova Fairfax Hospital Cancer Center, Fairfax, VA, USA
GABRIEL S. EICHLER • InnoCentive Inc., Waltham, MA, USA
OFER EIDELMAN • Department of Anatomy, Physiology and Genetics,
Uniformed Services University School of Medicine, Bethesda, MD, USA
VIRGINIA ESPINA • Center for Applied Proteomics and Molecular Medicine,
George Mason University, Manassas, VA, USA
QINGYUAN FAN • Department of Neurosciences, Cleveland Clinic, Cleveland, OH, USA

xi
xii Contributors

EOIN F. GAFFNEY • Department of Histopathology, Biobank Ireland Trust, St James’s

Hospital, Dublin, Ireland
FRANCESCA GALDI • Center for Applied Proteomics and Molecular Medicine,
George Mason University, Manassas, VA, USA
ROSA I. GALLAGHER • Center for Applied Proteomics and Molecular Medicine,
George Mason University, Manassas, VA, USA
HAROLD R. GARNER • Virginia Polytechnic Institute and State University,
Virginia Bioinformatics Institute, Blacksburg, VA, USA
FRANCESCO GORRETA • Genetics and Biomarkers – Exploratory Medicine,
Merck Serono Ivrea, Colleretto Giacosa (TO), Italy
JONATHAN HANSEN • Center for Applied Proteomics and Molecular Medicine,
George Mason University, Manassas, VA, USA
MICHAEL HEIBY • University of Virginia School of Medicine, Charlottesville, VA, USA
PAUL C. HERRMANN • Department of Pathology and Human Anatomy,
Loma Linda University, Loma Linda, CA, USA
E. CLIFFORD HERRMANN • Department of Biochemistry and Microbiology,
Loma Linda University, Loma Linda, CA, USA
STEPHEN M. HEWITT • Tissue Array Research Program/Laboratory of Pathology,
National Institutes of Health/National Cancer Institute, Bethesda, MD, USA
MICHAEL L. HUEBSCHMAN • McDermott Center for Human Genetics,
UT Southwestern Medical Center, Dallas, TX, USA
CATHERINE E. JOZWIK • Department of Anatomy, Physiology and Genetics,
Uniformed Services University School of Medicine, Bethesda, MD, USA
YASMIN KAMAL • Children’s National Medical Center, Washington, DC, USA
J. KEITH KILLIAN • Cancer Genetics Branch, National Institutes of Health/
National Cancer Institute, Bethesda, MD, USA
MICHAEL LASKOFSKI • Office of Sponsored Programs, George Mason University,
Fairfax, VA, USA
JAMIN M. LETCHER • Krasnow Institute for Advanced Study, George Mason University,
Fairfax, VA, USA
LANCE A. LIOTTA • Center for Applied Proteomics and Molecular Medicine,
George Mason University, Manassas, VA, USA
CATERINA LONGO • Department of Dermatology, University of Modena
and Reggio Emilia, Modena (MO), Italy
DEIRDRE MADDEN • Faculty of Law, University College, Cork, Ireland
PAUL S. MELTZER • Cancer Genetics Branch, National Institutes of Health/National
Cancer Institute, Bethesda, MD, USA
BRYAN A. MILLIS • National Center for Biodefense and Infectious Disease,
George Mason University, Manassas, VA, USA
NOEMI MORONI • Center for Applied Proteomics and Molecular Medicine,
George Mason University, Manassas, VA, USA
BRYAN T. MOTT • Department of Chemistry, Johns Hopkins University,
Baltimore, MD, USA
CLAUDIUS MUELLER • Center for Applied Proteomics and Molecular Medicine,
George Mason University, Manassas, VA, USA
 Contributors xiii

DAVID W. MURRAY • Department of Physiology and Medical Physics,

Royal College of Surgeons in Ireland, Dublin, Ireland
EMANUEL F. PETRICOIN III • Center for Applied Proteomics and Molecular Medicine,
George Mason University, Manassas, VA, USA
MARIAELENA PIEROBON • Center for Applied Proteomics and Molecular Medicine,
George Mason University, Manassas, VA, USA
MARIA LETIZIA POLCI • Istituto Superiore di Sanità-Ministero della Salute,
Rome (RO), Italy
HARVEY B. POLLARD • Department of Anatomy, Physiology and Genetics, Uniformed
Services University School of Medicine, Bethesda, MD, USA
K. ALEX REEDER • Center for Applied Proteomics and Molecular Medicine,
George Mason University, Manassas, VA, USA
KEVIN P. ROSENBLATT • The Brown Foundation Institute of Molecular Medicine/UT
Health Science Center CCTS Proteomics Core, Houston, TX, USA
G. TERRY SHARRER • Inova Health System, Inova Fairfax Hospital, Fairfax, VA, USA
MICHELE SIGNORE • Department of Hematology, Oncology, and Molecular Medicine,
Istituto Superiore di Sanità, Rome (RO), Italy
WILLIAM I. SMITH • Department of Pathology, Suburban Hospital, Bethesda, MD, USA
SINÉAD M. SMITH • Institute of Molecular Medicine, Trinity College Dublin,
Dublin, Ireland
ALEXANDER SPIRA • Virginia Cancer Specialists, Fairfax, VA, USA
MEERA SRIVASTAVA • Department of Anatomy, Physiology and Genetics,
Uniformed Services University School of Medicine, Bethesda, MD, USA
ALESSANDRA TESSITORE • Department of Experimental Medicine,
University of L’Aquila, L’Aquila (AQ), Italy
GERALDINE A. THOMAS • Department of Surgery and Cancer, Hammersmith Hospital/
Wales Cancer Bank, London, UK
J. LILLE TIDWELL • Office of Technology Transfer, George Mason University,
Fairfax, VA, USA
NISHANT TRIVEDI • University of Virginia, Charlottesville, VA, USA
AMY J. VANMETER • Center for Applied Proteomics and Molecular Medicine,
George Mason University, Manassas, VA, USA
ROBERT L. WALKER • Cancer Genetics Branch, National Institutes of Health/National
Cancer Institute, Bethesda, MD, USA
LINDSAY WESCOTT • Office of Sponsored Programs, George Mason University,
Fairfax, VA, USA
PAMELA L. ZEITLIN • Department of Pediatrics, Johns Hopkins School of Medicine,
Baltimore, MD, USA
WEIDONG ZHOU • Center for Applied Proteomics and Molecular Medicine,
George Mason University, Manassas, VA, USA
 Chapter 1

Tumor Staging and Grading: A Primer

Stacy M. Cowherd

Abstract
Cancer staging and grading are used to predict the clinical behavior of malignancies, establish appropriate
therapies, and facilitate exchange of precise information between clinicians. The internationally accepted
criteria for cancer staging, the tumor-node-metastasis (TNM) system, includes: (1) tumor size and local
growth (T); (2) extent of lymph node metastases (N); and (3) occurrence of distant metastases (M).
Clinical stage is established before initiation of therapy and depends on the physical examination, labora-
tory findings, and imaging studies. Pathologic stage is determined following surgical exploration of disease
spread and histological examination of tissue. The TNM classification system has evolved over 50 years to
accommodate increasing knowledge about cancer biology. Efforts are ongoing to keep the system both
synchronized with the most sophisticated cancer technology and simple for ease of clinician/patient use.
Upcoming molecular technologies, such as genomic and proteomic profiling of tumors, microRNA profil-
ing, and even ex vivo living tumor tissue treatment, could improve the current TNM staging system. This
chapter describes the current TNM system using breast, lung, ovarian, and prostate cancer examples.

Key words: Breast cancer, Grade, Lung cancer, Lymph node, Metastasis, Prostate cancer, Ovarian
cancer, Stage, Tumor

1. Introduction

Tumor staging and grading is integral to the practice of clinical

oncology because these classifications are the starting point for
patient care. Cancer staging and grading are used to predict the
clinical behavior of malignancies, establish appropriate therapies,
and facilitate exchange of precise information between clinicians.
During the staging/grading process, patients are placed in
standardized categories according to the anatomical location of
dissemination and the pathologic characteristics of their tumors.
Therefore, clinicians, pathologists, and radiologists must work
together to achieve the most precise classification of neoplasms.

Virginia Espina and Lance A. Liotta (eds.), Molecular Profiling: Methods and Protocols, Methods in Molecular Biology, vol. 823,
DOI 10.1007/978-1-60327-216-2_1, © Springer Science+Business Media, LLC 2012

1
2 S.M. Cowherd

Cancer staging refers to the anatomic extent of the disease

spread. The internationally accepted criteria for cancer staging, the
tumor-node-metastasis (TNM) system, include: (a) tumor size and
local growth (T); (b) extent of lymph node metastases (N); and (c)
occurrence of distant metastases (M). Cancers are categorized as
primary tumor size between T1 and T4, nodes between N0 and
N3, and metastases between M0 and M1. Generally, as the size of
the primary untreated cancer (T) increases, regional lymph node
involvement (N) and distant metastasis (M) become more fre-
quent. The most common sites of metastases are lung, bone, bone
marrow, liver, and brain (1).
Different cancer types have unique anatomical patterns of
spread, and therefore require distinct TNM classification systems.
Following is a general TNM schema for all cancers (1, 2):
Primary Tumor (T)
TX: Tumor cannot be assessed
T0: No evidence of primary tumor
Tis: Carcinoma in situ
T1, T2, T3, T4: Increasing size and/or local extent of tumor
Regional Lymph Nodes (N)
NX: Regional lymph nodes cannot be assessed
N0: No evidence of disease in lymph nodes
N1, N2, N3: Increasing disease involvement of regional lymph
nodes
Distant Metastasis (M)
MX: Distant metastasis cannot be assessed
M0: No distant metastasis
M1: Distant metastasis
TNM values are used to classify a patient’s cancer into stages
between I and IV. Cancers can be assigned both a clinical stage and
a pathologic stage. Clinical stage is established before initiation of
therapy and depends on the physical examination, laboratory find-
ings, and imaging studies. Pathologic stage is determined follow-
ing surgical exploration of disease spread and histological
examination of tissue (2). Pathologic stage is particularly signifi-
cant for cancers which are not easily accessible in a clinical setting,
such as pancreatic or ovarian carcinoma (1). Both clinical and
pathologic stages should be recorded in a patient’s permanent
medical record, with the clinical stage guiding initial therapy and
the pathologic stage guiding adjuvant therapy.
 1 Tumor Staging and Grading: A Primer 3

2. Typical
Descriptions
of the Different
Stages and Grades Stage I: Tumor limited to organ of origin, without nodular or
(1, 2) vascular spread.
Stage II: Local spread of tumor into surrounding tissue and
2.1. Tumor Stages regional lymph nodes. The lesion is resectable, but there is
uncertainty about completeness of removal due to tumor
microinvasion of surrounding tissue.
Stage III: Extensive primary tumor with invasion into deeper struc-
tures, bone, and lymph nodes. The lesion is operable but not
resectable, and gross disease is left behind.
Stage IV: Evidence of distant metastasis beyond tumor organ of
origin; primary tumor is inoperable.

2.2. Tumor Grades Cancer grade is a subjective scoring by the pathologist based on
tumor histology and cytomorphology of the tumor lesion.
Histopathologic grading is of equal importance to anatomic staging
for predicting patient prognosis and guiding treatment (1, 2).
Therefore, surgical biopsy or excision of suspicious lesions is essential
to confirm cancer diagnosis and classify tumor cellular architecture
(1). By definition, malignant tumors invade the basement mem-
brane and extracellular matrix to invade surrounding tissue with
indistinct borders (3). Additional microscopic evidence of abnor-
mal, or malignant, aggressiveness includes giant tumor cells, high
numbers of mitoses, nucleoli and chromatin morphology, unusual
mitoses, aneuploidy, and nuclear pleomorphism (3, 4).
In general, low-grade cancers are well differentiated, resembling
healthy cellular counterparts, and high-grade cancers are anaplas-
tic, and disorderly, not resembling normal tissue at that site. The
most poorly differentiated part of the tumor determines overall
tumor grade (1). In general, high-grade cancers are more clinically
aggressive than low-grade cancers. Most grading systems divide
tumors into three or four grades according to cellular differentia-
tion (2):
GX: Grade cannot be evaluated
G1: Well differentiated
G2: Moderately differentiated
G3–G4: Poorly differentiated
Using cancer grading and staging in addition to other clinical
data, clinicians can construct nomograms to predict treatment out-
comes, cure rates, and disease-free survival times. Following is a
discussion of specific cancer staging and grading for lung, prostate,
breast, and ovarian cancers. Clinical staging information is from
the sixth (2002) edition of the American Joint Committee on
Cancer’s (AJCC) Staging Manual (2).
4 S.M. Cowherd

3. Cancer
Classification
Examples
Lung cancer is one of the most common malignancies in the
3.1. Lung Cancer Western hemisphere, and the leading cause of cancer death in men
Clinical Staging and women (2, 5). The stage of lung carcinomas at diagnosis is the
single most important prognostic factor for patients (2, 6). Patients
Work-Up
with clinically suspected lung carcinoma should receive detailed
history and physical exam, chest radiograph, chest computed
tomography (CT) scan with intravenous contrast, and laboratory
tests including complete blood count, electrolytes, liver function
tests, and serum calcium. CT scan is the most important radiologic
procedure to visualize lung cancer because the image shows central
masses and peripheral nodules, and may suggest tumor invasion
into the pleura, mediastinum, and regional lymph nodes (5). Lung
cancer spreads locally to intrathoracic, scalene, and supraclavicular
lymph nodes (2).
Primary tumor tissue must be procured for confirmation of
pathology and definition of histology. Tissue may be collected either
through bronchoscopy for central lesions or CT-guided needle biopsy
for peripheral lesions. Thoracentesis should also be performed in
patients with pleural effusions to determine whether the effusion cells
are malignant or paramalignant, exudative with negative cytology.
Scalene and intrathoracic lymph nodes, which appear irregular or
enlarged on CT scan, should be sampled using mediastinoscopy. This
regional lymph node sampling is important for lung cancer patients
because therapy is different for N2 versus N3 disease (5, 7).
More extensive CT scanning is useful to detect lung cancer
metastases to the liver, adrenal glands, contralateral lung, and
brain. Patients with potentially resectable disease may also undergo
fluorodeoxyglucose positron emission tomography (FDG-PET)
scan to identify occult lymph node infiltrations or distant metasta-
ses (5, 7). Metastatic cancer cells appear on PET scan, in addition
to infection and severe inflammation, because these cells take up
proportionately higher volumes of glucose analog. Any suspicious
lesions at distant sites should be sampled (5). See Table 1 for specific
TMN staging criteria.
Small cell lung carcinoma (SCLC), a common subtype of lung
cancer, is most commonly categorized using a two-stage system
rather than TNM staging (5, 6, 8). SCLC tends to be disseminated
at the time of diagnosis, with only 25% of patients presenting with
“limited” disease (5). SCLC is considered “limited” when it is con-
fined to one radiotherapy port and “extensive” when it extends
beyond the ipsilateral hemithorax, or is not confined to a single
radiation port. “Limited” SCLC corresponds to stages I through
III in the TNM system, and “extensive” SCLC corresponds to
stage IV disease (2). All patients diagnosed with SCLC must have
a bone scan and brain CT because disease most commonly metas-
tasizes to these sites (5).
 1 Tumor Staging and Grading: A Primer 5

Table 1
TNM classification and stage grouping for NSCLC

Stage Grouping Descriptions

Occult carcinoma TX, N0, M0 TX: Primary tumor cannot be assessed, or tumor proven
by the presence of malignant cells in sputum or
bronchial washings but not visualized with imaging
N0: No regional lymph node metastasis
M0: No distant metastasis
Stage 0 Tis, N0, M0 Tis: Carcinoma in situ
Stage IA T1, N0, M0 T1: Tumor 3 cm or less in greatest dimension, sur-
rounded by lung or visceral pleura, without evidence of
invasion more proximal than the lobar bronchus
Stage IB T2, N0, M0 T2: Tumor with any of the following features:
• More than 3 cm in greatest dimension
• Involves main bronchus, 2 cm or more distal to the
carina
• Invades the visceral pleura
• Associated with atelectasis or obstructive pneumonia
that extends to the hilar region but does not involve
the entire lung
Stage IIA T1, N1, M0 N1: Metastasis to ipsilateral peribronchial and/or
ipsilateral hilar lymph nodes, and intrapulmonary
nodes including involvement by direct extension of the
primary tumor
Stage IIB T2, N1, M0 T3: Tumor of any size that invades any of the following:
chest wall, diaphragm, mediastinal pleura, parietal
pericardium; or tumor in the main bronchus less than
2 cm distal to the carina, but without involvement of
the carina; or associated atelectasis or obstructive
pneumonia of the entire lung
T3, N0, M0
Stage IIIA T1, N2, M0 N2: Metastasis to ipsilateral mediastinal and/or subcari-
T2, N2, M0 nal lymph node(s)
T3, N1, M0
T3, N2, M0
Stage IIIB Any T, N3, M0 N3: Metastasis to contralateral mediastinal, contralateral
T4, Any N, M0 hilar, ipsilateral or contralateral scalene, or supraclavic-
ular lymph node(s)
T4: Tumor of any size that invades any of the following:
mediastinum, heart, great vessels, trachea, esophagus,
vertebral body, carina; or separate tumor nodules in the
same lobe; or tumor with malignant pleural effusion
Stage IV Any T, Any N, M1 M1: Distant metastasis present
6 S.M. Cowherd

3.1.1. Histology Lung cancers are classified into histological types using light
and Grading microscopy with routinely stained preparations. The two most
common subtypes of lung carcinoma are bronchogenic NSCLC
and neuroendocrine carcinoma. Bronchogenic NSCLC encom-
passes several variants, including squamous cell carcinoma, adeno-
carcinoma, and anaplastic large cell carcinoma. Neuroendocrine
carcinomas are further subdivided according to cellular differentia-
tion, with SCLC a poorly differentiated variant of neuroendocrine
tumor (6, 8).
Lung cancer grading usually applies to squamous cell carci-
noma and adenocarcinoma, the two most common types of
NSCLC (6). Large cell carcinomas are inherently high-grade, con-
taining sheets of poorly differentiated cells that do not show
differentiation toward either squamous cell carcinoma or adeno-
carcinoma (6, 8). SCLC is also high-grade by definition (Fig. 1A).
Microscopically, SCLC cells are primitive appearing with scant
cytoplasm, granular chromatin, and high mitotic activity.
Encrustation, with basophilic deposition of DNA within blood
vessel walls, is a distinctive histological feature of SCLC (6, 8).
Squamous cell cancers commonly arise from epithelial cells in
the proximal tracheobronchial tree, and may therefore present
with signs of airway obstruction (5, 6). These carcinomas are
graded based on proportion of intercellular bridges and other
characteristics of keratinization (Fig. 1B) (6, 8). Most patholo-
gists use a three-tiered grading system to distinguish well,
moderately, and poorly differentiated tumors. Grade one or well-
differentiated tumors have sheets of cells with ample eosinophilic
cytoplasm, round nuclei, prominent nucleoli, and well-defined
cellular borders with intercellular bridges. These well-differenti-
ated tumors may contain concentric laminated deposits of amor-
phous, keratinous material called “squamous pearls” (6, 8). Areas
of comedo-like necrosis characterize grade two tumors. Grade
three tumors are poorly differentiated and cells tend to grow in

Fig. 1. Lung carcinoma histology. (A) Small cell lung carcinoma (SCLC) histology demonstrating poor differentiation. SCLC
cells are primitive appearing with scant cytoplasm, granular chromatin, and high mitotic activity. (B) Area of normal lung
epithelium adjacent to squamous cell carcinoma in situ. Squamous cell carcinomas are graded based on proportion of
intercellular bridges and other characteristics of keratinization. Courtesy of William Funkhouser, MD.
 1 Tumor Staging and Grading: A Primer 7

Fig. 2. Lung adenocarcinoma showing glandular formation. Adenocarcinomas are usually

located at the periphery of the lung and graded according to number and appearance of
glandular structures. Courtesy of William Funkhouser, MD.

confluent sheets. Cells are characterized by bizarre nuclei, cyto-

logical atypia, increased mitotic figures, and areas of necrosis and/
or hemorrhage (6).
Adenocarcinomas are glandular tumors, usually located at the
periphery of the lung and graded according to number and appear-
ance of glandular structures (Fig. 2). As compared to squamous
cell carcinomas, adenocarcinomas are more likely to be widely met-
astatic at the time of diagnosis (5, 8). Grade one or well-differentiated
tumors consist of distinctive gland structures throughout 90% of
the tumor mass. The glands resemble healthy lung tissue, with tall
columnar or mucinous epithelium, eosinophilic cytoplasm, basal
nuclei, and prominent nucleoli. A key variant of well-differentiated
adenocarcinoma is the bronchioalveolar type, characterized by
bland-appearing tumor cells growing continuously along alveolar
walls (8). Grade two adenocarcinomas, which are moderately differ-
entiated, consist of glandular or acinar structures throughout at
least 50% of the tumor mass. These glands display either poorly
formed lumens or atypical, anaplastic cells lining the lumens. Grade
three, or poorly differentiated adenocarcinomas, show 5–50% glan-
dular proliferation. The majority of grade three tumors contain
solid stromal areas with atypical mucinous cells (6, 8).

3.2. Prostate Cancer Widespread screening for prostate cancer, with digital rectal exam
Clinical Staging (DRE) and/or serum prostate-specific antigen (PSA) serum levels,
Work-Up has allowed the majority of cancers to be diagnosed in an asymp-
tomatic and localized stage (9). Prostate biopsy, which is usually
8 S.M. Cowherd

performed transrectally with ultrasound guidance, is necessary

for a definitive diagnosis of prostate adenocarcinoma following
abnormal PSA or DRE. Approximately, ten core needle biopsies
are necessary to sample all potentially affected lobes of the pros-
tate (9, 10).
Staging prostate cancer is unique because of the nonspecific
nature of PSA and prevalence of equivocal biopsies, many which
show histology suggesting “increased risk” for adenocarcinoma.
The risk of newly diagnosed prostate cancer progressing over the
short-term is low (9, 10); therefore, many patients with “increased
risk” or premalignant biopsies choose watchful waiting rather than
treatment. Physicians help patients make decisions regarding exten-
sive staging and treatment with mathematical nomograms like the
Partin model, the Kattan nomogram, or the D’Amico model.
These models are rough predictors of treatment outcome and dis-
ease-free survival given an individual patient’s PSA level, biopsy
Gleason grade, and clinical T stage (9). The Gleason grade is a
qualitative assessment of the loss of normal glandular prostate tis-
sue architecture as observed from a stained prostate tissue section
(11, 12). The score is based on a grading system of 1–5, with 5
being the worst, or showing the largest loss of normal glandular
morphology.
Definitively high-grade biopsy specimens require additional
staging work-up and either radical prostatectomy, external beam
radiation therapy, or brachytherapy (radioactive seed implants).
The primary staging goal of surgery is to determine whether ade-
nocarcinoma extends beyond the prostate capsule. In general,
tumors confined to the prostate gland are curable but tumors with
extraprostatic extension to the seminal vesicles and regional lymph
nodes are not curable (9, 10).
Men with elevated PSA, high Gleason grade, and/or clinical
tumor stage greater than T2 may have additional preoperative
studies to determine the extent of cancer spread. These studies
include radionucleotide bone scan, axial skeleton magnetic reso-
nance imaging (MRI), and CT scan of the abdomen and pelvis.
Regional prostate lymph nodes, which are located in the true pelvis
below the bifurcation of the common iliac arteries, are difficult to
visualize with CT scan (2). Therefore, MRI of the prostate gland
with endorectal probe is used to specifically examine seminal vesi-
cle and/or regional lymph node spread (10). Prostate adenocarci-
noma most commonly metastasizes to distant lymph nodes and
bone, but lung and liver metastases are common in late-stage dis-
ease (2). See Table 2 for specific TMN staging criteria.

3.2.1. Histology The vast majority of prostate cancers are epithelial adenocarcino-
and Grading mas, although variants include neuroendocrine tumors, stromal
tumors, and mesenchymal tumors such as leiomyosarcoma or sar-
comatoid carcinoma (13, 14). Putative premalignant lesions
 1 Tumor Staging and Grading: A Primer 9

Table 2
TNM classification and stage grouping for prostate adenocarcinoma

Stage Grouping Descriptions

I T1a, N0, M0, G1 T1a: Tumor clinically inapparent. Tumor incidental

histological finding in 5% or less of prostate tissue
resected
N0: No regional lymph node metastasis
M0: No distant metastasis
G1: Gleason grade 1
II T1a, N0, M0, G2-4 T1b: Tumor clinically inapparent. Tumor incidental
T1b, N0, M0, Any G histological finding in more than 5% of tissue resected
T1c, N0, M0, Any G T1c: Tumor clinically inapparent. Tumor identified by
T2, N0, M0, Any G needle biopsy
T2: Tumor confined within prostate
G2-4: Gleason grades 2, 3, and 4
III T3, N0, M0, Any G T3: Tumor extends through the prostate capsule
IV T4, N0, M0, Any G T4: Tumor is fixed or invades adjacent structures other
Any T, N1, M0, Any G than seminal vesicles: bladder neck, external sphinc-
Any T, Any N, M1, Any G ter, rectum, levator muscles, and/or pelvic wall
N1: Metastasis in regional lymph node(s)
M1: Distant metastasis

include prostatic intraepithelial neoplasia (PIN) and atypical

adenomatous hyperplasia (AAH); however, AAH has not proved a
true premalignant lesion (14). Low-grade PIN is characterized by
a slight increase in cellularity with irregular spacing of epithelial
cells. High-grade PIN displays a marked increase in cellularity with
nuclear enlargement and hyperchromasia. Both low- and high-
grade PIN have preservation of the basal cell layer (9, 14).
Prostate adenocarcinomas are graded using the Gleason sys-
tem, which classifies specimens between one and five based on
glandular architecture and cellular cytomorphology (9, 10, 13).
Several clinical trials have validated the prognostic value of the
Gleason system, with higher scores predicting widespread disease
and worse prognosis (9, 14). Pathologists report both primary and
secondary scores, with the primary score representing the most
common histological grade in the specimen and the secondary
score reflecting the second most common grade. The primary and
secondary scores are added to yield overall Gleason score. Thus,
Gleason scores between one and three represent well-differentiated
adenocarcinomas and scores between eight and ten represent
poorly differentiated cancers (9, 13).
Gleason score pattern one cannot be reliably distinguished
from adenomatous hyperplasia lesions using needle biopsies (13).
10 S.M. Cowherd

Generally, however, simple round glands with uniform size, shape,

and spacing characterize pattern one. The nuclei and nucleoli are
markedly enlarged. Gleason pattern score two tumors show more
variation in glandular size and shape, and appear incompletely cir-
cumscribed. Haphazardly separated glands among bands of fibrous
stroma characterize pattern three, the most common microscopic
pattern of prostate adenocarcinoma. Pattern four tumor cells are
organized into closely packed or fused glands, which invade the
stroma with ragged infiltrative edges. Gleason pattern score five
tumors contain solid sheets of anaplastic cells with comedo-like
necrosis in cribriform nests (13, 14).

3.3. Breast Cancer Breast cancer, the most common solid-organ malignancy diagnosed
Clinical Staging among North American women, is usually discovered either
Work-Up through screening mammography or detection of a breast lump
(2, 15). Abnormal mammogram findings include breast masses,
microcalcifications, asymmetries between the breasts, and architec-
tural distortions. Malignant breast lumps typically present in
women over 30 years old as asymptomatic, painless masses which
are fixed to surrounding tissue (16). Patients with an abnormal
mammogram and/or suspicious breast mass must undergo large
core needle biopsies for pathologic diagnosis. Approximately ten
core biopsies are usually necessary, each with diameter between 14
and 18 gauge and length between 1 and 3 cm. For women without
palpable masses, mammogram or ultrasound guidance is used to
precisely localize the lesion (15, 16).
Extensive use of screening mammography has lead to increased
diagnoses of noninvasive breast carcinoma or ductal carcinoma in
situ (DCIS) (15, 17). DCIS encompasses a wide spectrum of dis-
ease with multiple staging and treatment options. In general, DCIS
has low metastatic potential but must be completely excised with
either radical mastectomy or lumpectomy to prevent local recur-
rence (17, 18). The most important prognostic factors influencing
local recurrence of DCIS include lesion size, adequacy of resec-
tion, patient age, and histological grade (15). It is therefore impor-
tant for surgeons to obtain a wide surgical margin, preferably
10 mm in each dimension. In addition, pathologists must examine
biopsy tissue for areas of microscopic stromal invasion or microin-
vasion. The AJCC Cancer Staging Manual classifies microinvasion
as T1mic, a subset of T1 breast cancer (2). Sentinel lymph node
biopsy and axillary lymph node dissections (ALNDs) are not nec-
essary with DCIS unless the patient has high-grade disease, docu-
mentation of microinvasion, or high risk for invasive disease (18).
Invasive breast cancers require complete operative excision
plus sentinel lymph node biopsy and/or ALND. Important opera-
tive findings for staging include size of the primary tumor and
presence of chest wall invasion. If the primary tumor is invasive and
sentinel lymph node biopsy is positive, ALND must be performed
Discovering Diverse Content Through
Random Scribd Documents
bravest and the best,’ said I again, seeing it pleased him. But he
didn’t answer. I heard the girl giggle outside the door, for
occasionally we’d had just a bit of innocent laughter, you know, at
his ways. I looked at his face, and his eyes were closed, and it was
just as if somebody had punched in his nose on either side. But he
was still smiling. It’s queer to think of—he lay dead, lay dead there,
an utter failure, with the smile of success on his face.
“That was the end of my uncle. You can imagine me and my
mother saw that he had a decent funeral. Then, of course, came the
hunt for the will. We began decent and respectful at first, and before
the day was out we were ripping chairs, and smashing bureau
panels, and sounding walls. Every hour we expected those others to
come in. We asked the housekeeper, and found she’d actually
witnessed a will—on an ordinary half-sheet of notepaper it was
written, and very short, she said—not a month ago. The other
witness was the gardener, and he bore her out word for word. But
I’m hanged if there was that or any other will to be found. The way
my mother talked must have made him turn in his grave. At last a
lawyer at Reigate sprang one on us that had been made years ago
during some temporary quarrel with my mother. I’m blest if that
wasn’t the only will to be discovered anywhere, and it left every
penny he possessed to that ‘Take ’im away’ youngster of his second
cousin’s—a chap who’d never had to stand his talking not for one
afternoon of his life.”
The man with the glass eye stopped.
“I thought you said”—I began.
“Half a minute,” said the man with the glass eye. “I had to wait for
the end of the story till this very morning, and I was a blessed sight
more interested than you are. You just wait a bit too. They executed
the will, and the other chap inherited, and directly he was one-and-
twenty he began to blew it. How he did blew it, to be sure! He bet,
he drank, he got in the papers for this and that. I tell you, it makes
me wriggle to think of the times he had. He blewed every ha’penny
of it before he was thirty, and the last I heard of him was—Holloway!
Three years ago.
 “Well, I naturally fell on hard times, because, as you see, the only
trade I knew was legacy-cadging. All my plans were waiting over to
begin, so to speak, when the old chap died. I’ve had my ups and
downs since then. Just now it’s a period of depression. I tell you
frankly, I’m on the look-out for help. I was hunting round my room
to find something to raise a bit on for immediate necessities, and the
sight of all those presentation volumes—no one will buy them, not to
wrap butter in, even—well, they annoyed me. I’d promised him not
to part with them, and I never kept a promise easier. I let out at
them with my boot, and sent them shooting across the room. One
lifted at the kick, and spun through the air. And out of it flapped—
You guess?
“It was the will. He’d given it me himself in that very last volume
of all.”
He folded his arms on the table, and looked sadly with the active
eye at his empty tankard. He shook his head slowly, and said softly,
“I’d never opened the book, much more cut a page!” Then he looked
up, with a bitter laugh, for my sympathy. “Fancy hiding it there!
Eigh? Of all places.”
He began to fish absently for a dead fly with his finger. “It just
shows you the vanity of authors,” he said, looking up at me. “It
wasn’t no trick of his. He’d meant perfectly fair. He’d really thought I
was really going home to read that blessed book of his through. But
it shows you, don’t it?”—his eye went down to the tankard again,
—“It shows you, too, how we poor human beings fail to understand
one another.”
But there was no misunderstanding the eloquent thirst of his eye.
He accepted with ill-feigned surprise. He said, in the usual subtle
formula, that he didn’t mind if he did.
 THE SAD STORY OF A DRAMATIC CRITIC

I
WAS—you shall hear immediately why I am not now—Egbert
Craddock Cummins. The name remains. I am still (Heaven help
me!) Dramatic Critic to the Fiery Cross. What I shall be in a little
while I do not know. I write in great trouble and confusion of mind. I
will do what I can to make myself clear in the face of terrible
difficulties. You must bear with me a little. When a man is rapidly
losing his own identity, he naturally finds a difficulty in expressing
himself. I will make it perfectly plain in a minute, when once I get
my grip upon the story. Let me see—where am I? I wish I knew. Ah,
I have it! Dead self! Egbert Craddock Cummins!
In the past I should have disliked writing anything quite so full of
“I” as this story must be. It is full of “I’s” before and behind, like the
beast in Revelation—the one with a head like a calf, I am afraid. But
my tastes have changed since I became a Dramatic Critic and
studied the masters—G.R.S., G.B.S., G.A.S., and the others.
Everything has changed since then. At least the story is about myself
—so that there is some excuse for me. And it is really not egotism,
because, as I say, since those days my identity has undergone an
entire alteration.
That past!... I was—in those days—rather a nice fellow, rather shy
—taste for grey in my clothes, weedy little moustache, face
“interesting,” slight stutter which I had caught in early life from a
schoolfellow. Engaged to a very nice girl, named Delia. Fairly new,
she was—cigarettes—liked me because I was human and original.
Considered I was like Lamb—on the strength of the stutter, I believe.
Father, an eminent authority on postage stamps. She read a great
deal in the British Museum. (A perfect pairing ground for literary
people, that British Museum—you should read George Egerton and
Justin Huntly M’Carthy and Gissing and the rest of them.) We loved
in our intellectual way, and shared the brightest hopes. (All gone
now.) And her father liked me because I seemed honestly eager to
hear about stamps. She had no mother. Indeed, I had the happiest
prospects a young man could have. I never went to theatres in those
days. My Aunt Charlotte before she died had told me not to.
Then Barnaby, the editor of the Fiery Cross, made me—in spite of
my spasmodic efforts to escape—Dramatic Critic. He is a fine,
healthy man, Barnaby, with an enormous head of frizzy black hair
and a convincing manner, and he caught me on the staircase going
to see Wembly. He had been dining, and was more than usually
buoyant. “Hullo, Cummins!” he said. “The very man I want!” He
caught me by the shoulder or the collar or something, ran me up the
little passage, and flung me over the waste-paper basket into the
arm-chair in his office. “Pray be seated,” he said, as he did so. Then
he ran across the room and came back with some pink and yellow
tickets and pushed them into my hand. “Opera Comique,” he said,
“Thursday; Friday, the Surrey; Saturday, the Frivolity. That’s all, I
think.”
“But”—I began.
“Glad you’re free,” he said, snatching some proofs off the desk
and beginning to read.
“I don’t quite understand,” I said.
“Eigh?” he said, at the top of his voice, as though he thought I
had gone, and was startled at my remark.
“Do you want me to criticise these plays?”
“Do something with ’em.... Did you think it was a treat?”
“But I can’t.”
“Did you call me a fool?”
“Well, I’ve never been to a theatre in my life.”
“Virgin soil.”
“But I don’t know anything about it, you know.”
“That’s just it. New view. No habits. No clichés in stock. Ours is a
live paper, not a bag of tricks. None of your clockwork professional
journalism in this office. And I can rely on your integrity”—
“But I’ve conscientious scruples”—
 He caught me up suddenly and put me outside his door. “Go and
talk to Wembly about that,” he said. “He’ll explain.”
As I stood perplexed, he opened the door again, said, “I forgot
this,” thrust a fourth ticket into my hand (it was for that night—in
twenty minutes’ time), and slammed the door upon me. His
expression was quite calm, but I caught his eye.
I hate arguments. I decided that I would take his hint and become
(to my own destruction) a Dramatic Critic. I walked slowly down the
passage to Wembly. That Barnaby has a remarkably persuasive way.
He has made few suggestions during our very pleasant intercourse
of four years that he has not ultimately won me round to adopting.
It may be, of course, that I am of a yielding disposition; certainly I
am too apt to take my colour from my circumstances. It is, indeed,
to my unfortunate susceptibility to vivid impressions that all my
misfortunes are due. I have already alluded to the slight stammer I
had acquired from a schoolfellow in my youth. However, this is a
digression.... I went home in a cab to dress.
I will not trouble the reader with my thoughts about the first-night
audience, strange assembly as it is,—those I reserve for my
Memoirs,—nor the humiliating story of how I got lost during the
entr’acte in a lot of red plush passages, and saw the third act from
the gallery. The only point upon which I wish to lay stress was the
remarkable effect of the acting upon me. You must remember I had
lived a quiet and retired life, and had never been to the theatre
before, and that I am extremely sensitive to vivid impressions. At the
risk of repetition I must insist upon these points.
The first effect was a profound amazement, not untinctured by
alarm. The phenomenal unnaturalness of acting is a thing
discounted in the minds of most people by early visits to the theatre.
They get used to the fantastic gestures, the flamboyant emotions,
the weird mouthings, melodious snortings, agonising yelps, lip-
gnawings, glaring horrors, and other emotional symbolism of the
stage. It becomes at last a mere deaf-and-dumb language to them,
which they read intelligently pari passu with the hearing of the
dialogue. But all this was new to me. The thing was called a modern
comedy, the people were supposed to be English and were dressed
like fashionable Americans of the current epoch, and I fell into the
natural error of supposing that the actors were trying to represent
human beings. I looked round on my first-night audience with a kind
of wonder, discovered—as all new Dramatic Critics do—that it rested
with me to reform the Drama, and, after a supper choked with
emotion, went off to the office to write a column, piebald with “new
paragraphs” (as all my stuff is—it fills out so) and purple with
indignation. Barnaby was delighted.
But I could not sleep that night. I dreamt of actors—actors
glaring, actors smiting their chests, actors flinging out a handful of
extended fingers, actors smiling bitterly, laughing despairingly, falling
hopelessly, dying idiotically. I got up at eleven with a slight
headache, read my notice in the Fiery Cross, breakfasted, and went
back to my room to shave. (It’s my habit to do so.) Then an odd
thing happened. I could not find my razor. Suddenly it occurred to
me that I had not unpacked it the day before.
“Ah!” said I, in front of the looking-glass. Then “Hullo!”
Quite involuntarily, when I had thought of my portmanteau, I had
flung up the left arm (fingers fully extended) and clutched at my
diaphragm with my right hand. I am an acutely self-conscious man
at all times. The gesture struck me as absolutely novel for me. I
repeated it, for my own satisfaction. “Odd!” Then (rather puzzled) I
turned to my portmanteau.
After shaving, my mind reverted to the acting I had seen, and I
entertained myself before the cheval glass with some imitations of
Jafferay’s more exaggerated gestures. “Really, one might think it a
disease,” I said—“Stage-Walkitis!” (There’s many a truth spoken in
jest.) Then, if I remember rightly, I went off to see Wembly, and
afterwards lunched at the British Museum with Delia. We actually
spoke about our prospects, in the light of my new appointment.
But that appointment was the beginning of my downfall. From
that day I necessarily became a persistent theatre-goer, and almost
insensibly I began to change. The next thing I noticed after the
gesture about the razor, was to catch myself bowing ineffably when I
met Delia, and stooping in an old-fashioned, courtly way over her
hand. Directly I caught myself, I straightened myself up and became
very uncomfortable. I remember she looked at me curiously. Then,
in the office, I found myself doing “nervous business,” fingers on
teeth, when Barnaby asked me a question I could not very well
answer. Then, in some trifling difference with Delia, I clasped my
hand to my brow. And I pranced through my social transactions at
times singularly like an actor! I tried not to—no one could be more
keenly alive to the arrant absurdity of the histrionic bearing. And I
did!
It began to dawn on me what it all meant. The acting, I saw, was
too much for my delicately-strung nervous system. I have always, I
know, been too amenable to the suggestions of my circumstances.
Night after night of concentrated attention to the conventional
attitudes and intonation of the English stage was gradually affecting
my speech and carriage. I was giving way to the infection of
sympathetic imitation. Night after night my plastic nervous system
took the print of some new amazing gesture, some new emotional
exaggeration—and retained it. A kind of theatrical veneer threatened
to plate over and obliterate my private individuality altogether. I saw
myself in a kind of vision. Sitting by myself one night, my new self
seemed to me to glide, posing and gesticulating, across the room.
He clutched his throat, he opened his fingers, he opened his legs in
walking like a high-class marionette. He went from attitude to
attitude. He might have been clockwork. Directly after this I made
an ineffectual attempt to resign my theatrical work. But Barnaby
persisted in talking about the Polywhiddle Divorce all the time I was
with him, and I could get no opportunity of saying what I wished.
And then Delia’s manner began to change towards me. The ease
of our intercourse vanished. I felt she was learning to dislike me. I
grinned, and capered, and scowled, and posed at her in a thousand
ways, and knew—with what a voiceless agony!—that I did it all the
time. I tried to resign again, and Barnaby talked about “X” and “Z”
and “Y” in the New Review, and gave me a strong cigar to smoke,
and so routed me. And then I walked up the Assyrian Gallery in the
manner of Irving to meet Delia, and so precipitated the crisis.
“Ah!—Dear!” I said, with more sprightliness and emotion in my
voice than had ever been in all my life before I became (to my own
undoing) a Dramatic Critic.
She held out her hand rather coldly, scrutinising my face as she
did so. I prepared, with a new-won grace, to walk by her side.
“Egbert,” she said, standing still, and thought. Then she looked at
me.
I said nothing. I felt what was coming. I tried to be the old Egbert
Craddock Cummins of shambling gait and stammering sincerity,
whom she loved, but I felt even as I did so that I was a new thing, a
thing of surging emotions and mysterious fixity—like no human
being that ever lived, except upon the stage. “Egbert,” she said, “you
are not yourself.”
“Ah!” Involuntarily I clutched my diaphragm and averted my head
(as is the way with them).
“There!” she said.
“What do you mean?” I said, whispering in vocal italics—you know
how they do it—turning on her, perplexity on face, right hand down,
left on brow. I knew quite well what she meant. I knew quite well
the dramatic unreality of my behaviour. But I struggled against it in
vain. “What do you mean?” I said, and, in a kind of hoarse whisper,
“I don’t understand!”
She really looked as though she disliked me. “What do you keep
on posing for?” she said. “I don’t like it. You didn’t use to.”
“Didn’t use to!” I said slowly, repeating this twice. I glared up and
down the gallery, with short, sharp glances. “We are alone,” I said
swiftly. “Listen!” I poked my forefinger towards her, and glared at
her. “I am under a curse.”
I saw her hand tighten upon her sunshade. “You are under some
bad influence or other,” said Delia. “You should give it up. I never
knew anyone change as you have done.”
“Delia!” I said, lapsing into the pathetic. “Pity me. Augh! Delia! Pit
—y me!”
 She eyed me critically. “Why you keep playing the fool like this I
don’t know,” she said. “Anyhow, I really cannot go about with a man
who behaves as you do. You made us both ridiculous on Wednesday.
Frankly, I dislike you, as you are now. I met you here to tell you so—
as it’s about the only place where we can be sure of being alone
together”—
“Delia!” said I, with intensity, knuckles of clenched hands white.
“You don’t mean”—
“I do,” said Delia. “A woman’s lot is sad enough at the best of
times. But with you”—
I clapped my hand on my brow.
“So, good-bye,” said Delia, without emotion.
“Oh, Delia!” I said. “Not this?”
“Good-bye, Mr. Cummins,” she said.
By a violent effort I controlled myself and touched her hand. I
tried to say some word of explanation to her. She looked into my
working face and winced. “I must do it,” she said hopelessly. Then
she turned from me and began walking rapidly down the gallery.
Heavens! How the human agony cried within me! I loved Delia.
But nothing found expression—I was already too deeply crusted with
my acquired self.
“Good-baye!” I said at last, watching her retreating figure. How I
hated myself for doing it! After she had vanished, I repeated in a
dreamy way, “Good-baye!” looking hopelessly round me. Then, with
a kind of heart-broken cry, I shook my clenched fists in the air,
staggered to the pedestal of a winged figure, buried my face in my
arms, and made my shoulders heave. Something within me said
“Ass!” as I did so. (I had the greatest difficulty in persuading the
Museum policeman, who was attracted by my cry of agony, that I
was not intoxicated, but merely suffering from a transient
indisposition.)
But even this great sorrow has not availed to save me from my
fate. I see it, everyone sees it; I grow more “theatrical” every day.
And no one could be more painfully aware of the pungent silliness of
theatrical ways. The quiet, nervous, but pleasing E. C. Cummins
vanishes. I cannot save him. I am driven like a dead leaf before the
winds of March. My tailor even enters into the spirit of my disorder.
He has a peculiar sense of what is fitting. I tried to get a dull grey
suit from him this spring, and he foisted a brilliant blue upon me,
and I see he has put braid down the sides of my new dress trousers.
My hairdresser insists upon giving me a “wave.”
I am beginning to associate with actors. I detest them, but it is
only in their company that I can feel I am not glaringly conspicuous.
Their talk infects me. I notice a growing tendency to dramatic
brevity, to dashes and pauses in my style, to a punctuation of bows
and attitudes. Barnaby has remarked it too. I offended Wembly by
calling him “Dear Boy” yesterday. I dread the end, but I cannot
escape from it.
The fact is, I am being obliterated. Living a grey, retired life all my
youth, I came to the theatre a delicate sketch of a man, a thing of
tints and faint lines. Their gorgeous colouring has effaced me
altogether. People forget how much mode of expression, method of
movement, are a matter of contagion. I have heard of stage-struck
people before, and thought it a figure of speech. I spoke of it
jestingly, as a disease. It is no jest. It is a disease. And I have got it
bad! Deep down within me I protest against the wrong done to my
personality—unavailingly. For three hours or more a week I have to
go and concentrate my attention on some fresh play, and the
suggestions of the drama strengthen their awful hold upon me. My
manners grow so flamboyant, my passions so professional, that I
doubt, as I said at the outset, whether it is really myself that
behaves in such a manner. I feel merely the core to this dramatic
casing, that grows thicker and presses upon me—me and mine. I
feel like King John’s abbot in his cope of lead.
I doubt, indeed, whether I should not abandon the struggle
altogether—leave this sad world of ordinary life for which I am so ill-
fitted, abandon the name of Cummins for some professional
pseudonym, complete my self-effacement, and—a thing of tricks and
tatters, of posing and pretence—go upon the stage. It seems my
only resort—“to hold the mirror up to Nature.” For in the ordinary
life, I will confess, no one now seems to regard me as both sane and
sober. Only upon the stage, I feel convinced, will people take me
seriously. That will be the end of it. I know that will be the end of it.
And yet ... I will frankly confess ... all that marks off your actor from
your common man ... I detest. I am still largely of my Aunt
Charlotte’s opinion, that playacting is unworthy of a pure-minded
man’s attention, much more participation. Even now I would resign
my dramatic criticism and try a rest. Only I can’t get hold of
Barnaby. Letters of resignation he never notices. He says it is against
the etiquette of journalism to write to your Editor. And when I go to
see him, he gives me another big cigar and some strong whisky and
soda, and then something always turns up to prevent my
explanation.
 A SLIP UNDER THE MICROSCOPE

O
UTSIDE the laboratory windows was a watery-grey fog, and
within a close warmth and the yellow light of the green-
shaded gas lamps that stood two to each table down its
narrow length. On each table stood a couple of glass jars containing
the mangled vestiges of the crayfish, mussels, frogs, and guineapigs,
upon which the students had been working, and down the side of
the room, facing the windows, were shelves bearing bleached
dissections in spirits, surmounted by a row of beautifully executed
anatomical drawings in whitewood frames and overhanging a row of
cubical lockers. All the doors of the laboratory were panelled with
blackboard, and on these were the half-erased diagrams of the
previous day’s work. The laboratory was empty, save for the
demonstrator, who sat near the preparation-room door, and silent,
save for a low, continuous murmur, and the clicking of the rocker
microtome at which he was working. But scattered about the room
were traces of numerous students: hand-bags, polished boxes of
instruments, in one place a large drawing covered by newspaper,
and in another a prettily bound copy of News from Nowhere, a book
oddly at variance with its surroundings. These things had been put
down hastily as the students had arrived and hurried at once to
secure their seats in the adjacent lecture theatre. Deadened by the
closed door, the measured accents of the professor sounded as a
featureless muttering.
Presently, faint through the closed windows came the sound of the
Oratory clock striking the hour of eleven. The clicking of the
microtome ceased, and the demonstrator looked at his watch, rose,
thrust his hands into his pockets, and walked slowly down the
laboratory towards the lecture theatre door. He stood listening for a
moment, and then his eye fell on the little volume by William Morris.
He picked it up, glanced at the title, smiled, opened it, looked at the
name on the fly-leaf, ran the leaves through with his hand, and put it
down. Almost immediately the even murmur of the lecturer ceased,
there was a sudden burst of pencils rattling on the desks in the
lecture theatre, a stirring, a scraping of feet, and a number of voices
speaking together. Then a firm footfall approached the door, which
began to open, and stood ajar, as some indistinctly heard question
arrested the new-comer.
The demonstrator turned, walked slowly back past the microtome,
and left the laboratory by the preparation-room door. As he did so,
first one, and then several students carrying notebooks entered the
laboratory from the lecture theatre, and distributed themselves
among the little tables, or stood in a group about the doorway. They
were an exceptionally heterogeneous assembly, for while Oxford and
Cambridge still recoil from the blushing prospect of mixed classes,
the College of Science anticipated America in the matter years ago—
mixed socially, too, for the prestige of the College is high, and its
scholarships, free of any age limit, dredge deeper even than do
those of the Scotch universities. The class numbered one-and-
twenty, but some remained in the theatre questioning the professor,
copying the blackboard diagrams before they were washed off, or
examining the special specimens he had produced to illustrate the
day’s teaching. Of the nine who had come into the laboratory three
were girls, one of whom, a little fair woman, wearing spectacles and
dressed in greyish-green, was peering out of the window at the fog,
while the other two, both wholesome-looking, plain-faced
schoolgirls, unrolled and put on the brown holland aprons they wore
while dissecting. Of the men, two went down the laboratory to their
places, one a pallid, dark-bearded man, who had once been a tailor;
the other a pleasant-featured, ruddy young man of twenty, dressed
in a well-fitting brown suit; young Wedderburn, the son of
Wedderburn the eye specialist. The others formed a little knot near
the theatre door. One of these, a dwarfed, spectacled figure, with a
hunch back, sat on a bent wood stool; two others, one a short, dark
youngster, and the other a flaxen-haired, reddish-complexioned
young man, stood leaning side by side against the slate sink, while
the fourth stood facing them, and maintained the larger share of the
conversation.
This last person was named Hill. He was a sturdily built young
fellow, of the same age as Wedderburn; he had a white face, dark
grey eyes, hair of an indeterminate colour, and prominent, irregular
features. He talked rather louder than was needful, and thrust his
hands deeply into his pockets. His collar was frayed and blue with
the starch of a careless laundress, his clothes were evidently
readymade, and there was a patch on the side of his boot near the
toe. And as he talked or listened to the others, he glanced now and
again towards the lecture theatre door. They were discussing the
depressing peroration of the lecture they had just heard, the last
lecture it was in the introductory course in zoology. “From ovum to
ovum is the goal of the higher vertebrata,” the lecturer had said in
his melancholy tones, and so had neatly rounded off the sketch of
comparative anatomy he had been developing. The spectacled
hunchback had repeated it, with noisy appreciation, had tossed it
towards the fair-haired student with an evident provocation, and had
started one of those vague, rambling discussions on generalities, so
unaccountably dear to the student mind all the world over.
“That is our goal, perhaps—I admit it—as far as science goes,”
said the fair-haired student, rising to the challenge. “But there are
things above science.”
“Science,” said Hill confidently, “is systematic knowledge. Ideas
that don’t come into the system—must anyhow—be loose ideas.” He
was not quite sure whether that was a clever saying or a fatuity until
his hearers took it seriously.
“The thing I cannot understand,” said the hunchback, at large, “is
whether Hill is a materialist or not.”
“There is one thing above matter,” said Hill promptly, feeling he
had a better thing this time, aware, too, of someone in the doorway
behind him, and raising his voice a trifle for her benefit, “and that is,
the delusion that there is something above matter.”
“So we have your gospel at last,” said the fair student. “It’s all a
delusion, is it? All our aspirations to lead something more than dogs’
lives, all our work for anything beyond ourselves. But see how
inconsistent you are. Your socialism, for instance. Why do you
trouble about the interests of the race? Why do you concern yourself
about the beggar in the gutter? Why are you bothering yourself to
lend that book”—he indicated William Morris by a movement of the
head—“to everyone in the lab.?”
“Girl,” said the hunchback indistinctly, and glanced guiltily over his
shoulder.
The girl in brown, with the brown eyes, had come into the
laboratory, and stood on the other side of the table behind him, with
her rolled-up apron in one hand, looking over her shoulder, listening
to the discussion. She did not notice the hunchback, because she
was glancing from Hill to his interlocutor. Hill’s consciousness of her
presence betrayed itself to her only in his studious ignorance of the
fact; but she understood that, and it pleased her. “I see no reason,”
said he, “why a man should live like a brute because he knows of
nothing beyond matter, and does not expect to exist a hundred
years hence.”
“Why shouldn’t he?” said the fair-haired student.
“Why should he?” said Hill.
“What inducement has he?”
“That’s the way with all you religious people. It’s all a business of
inducements. Cannot a man seek after righteousness for
righteousness’ sake?”
There was a pause. The fair man answered, with a kind of vocal
padding, “But—you see—inducement—when I said inducement,” to
gain time. And then the hunchback came to his rescue and inserted
a question. He was a terrible person in the debating society with his
questions, and they invariably took one form—a demand for a
definition. “What’s your definition of righteousness?” said the
hunchback at this stage.
Hill experienced a sudden loss of complacency at this question,
but even as it was asked, relief came in the person of Brooks, the
laboratory attendant, who entered by the preparation-room door,
carrying a number of freshly killed guineapigs by their hind legs.
“This is the last batch of material this session,” said the youngster,
who had not previously spoken. Brooks advanced up the laboratory,
smacking down a couple of guineapigs at each table. The rest of the
class, scenting the prey from afar, came crowding in by the lecture
theatre door, and the discussion perished abruptly as the students
who were not already in their places hurried to them to secure the
choice of a specimen. There was a noise of keys rattling on split
rings as lockers were opened and dissecting instruments taken out.
Hill was already standing by his table, and his box of scalpels was
sticking out of his pocket. The girl in brown came a step towards
him, and, leaning over his table, said softly, “Did you see that I
returned your book, Mr. Hill?”
During the whole scene she and the book had been vividly present
in his consciousness; but he made a clumsy pretence of looking at
the book and seeing it for the first time. “Oh yes,” he said, taking it
up. “I see. Did you like it?”
“I want to ask you some questions about it—some time.”
“Certainly,” said Hill. “I shall be glad.” He stopped awkwardly. “You
liked it?” he said.
“It’s a wonderful book. Only some things I don’t understand.”
Then suddenly the laboratory was hushed by a curious braying
noise. It was the demonstrator. He was at the blackboard ready to
begin the day’s instruction, and it was his custom to demand silence
by a sound midway between the “Er” of common intercourse and
the blast of a trumpet. The girl in brown slipped back to her place: it
was immediately in front of Hill’s, and Hill, forgetting her forthwith,
took a notebook out of the drawer of his table, turned over its leaves
hastily, drew a stumpy pencil from his pocket, and prepared to make
a copious note of the coming demonstration. For demonstrations
and lectures are the sacred text of the College students. Books,
saving only the Professor’s own, you may—it is even expedient to—
ignore.

Hill was the son of a Landport cobbler, and had been hooked by a
chance blue paper the authorities had thrown out to the Landport
Technical College. He kept himself in London on his allowance of a
guinea a week, and found that, with proper care, this also covered
his clothing allowance, an occasional waterproof collar, that is; and
ink and needles and cotton, and such-like necessaries for a man
about town. This was his first year and his first session, but the
brown old man in Landport had already got himself detested in
many public-houses by boasting of his son, “the Professor.” Hill was
a vigorous youngster, with a serene contempt for the clergy of all
denominations, and a fine ambition to reconstruct the world. He
regarded his scholarship as a brilliant opportunity. He had begun to
read at seven, and had read steadily whatever came in his way,
good or bad, since then. His worldly experience had been limited to
the island of Portsea, and acquired chiefly in the wholesale boot
factory in which he had worked by day, after passing the seventh
standard of the Board school. He had a considerable gift of speech,
as the College Debating Society, which met amidst the crushing
machines and mine models in the metallurgical theatre downstairs,
already recognised—recognised by a violent battering of desks
whenever he rose. And he was just at that fine emotional age when
life opens at the end of a narrow pass like a broad valley at one’s
feet, full of the promise of wonderful discoveries and tremendous
achievements. And his own limitations, save that he knew that he
knew neither Latin nor French, were all unknown to him.
At first his interest had been divided pretty equally between his
biological work at the College and social and theological theorising,
an employment which he took in deadly earnest. Of a night, when
the big museum library was not open, he would sit on the bed of his
room in Chelsea with his coat and a muffler on, and write out the
lecture notes and revise his dissection memoranda, until Thorpe
called him out by a whistle,—the landlady objected to open the door
to attic visitors,—and then the two would go prowling about the
shadowy, shiny, gas-lit streets, talking, very much in the fashion of
the sample just given, of the God Idea, and Righteousness, and
Carlyle, and the Reorganisation of Society. And, in the midst of it all,
Hill, arguing not only for Thorpe, but for the casual passer-by, would
lose the thread of his argument glancing at some pretty painted face
that looked meaningly at him as he passed. Science and
Righteousness! But once or twice lately there had been signs that a
third interest was creeping into his life, and he had found his
attention wandering from the fate of the mesoblastic somites or the
probable meaning of the blastopore, to the thought of the girl with
the brown eyes who sat at the table before him.
She was a paying student; she descended inconceivable social
altitudes to speak to him. At the thought of the education she must
have had, and the accomplishments she must possess, the soul of
Hill became abject within him. She had spoken to him first over a
difficulty about the alisphenoid of a rabbit’s skull, and he had found
that, in biology at least, he had no reason for self-abasement. And
from that, after the manner of young people starting from any
starting-point, they got to generalities, and while Hill attacked her
upon the question of socialism,—some instinct told him to spare her
a direct assault upon her religion,—she was gathering resolution to
undertake what she told herself was his æsthetic education. She was
a year or two older than he, though the thought never occurred to
him. The loan of News from Nowhere was the beginning of a series
of cross loans. Upon some absurd first principle of his, Hill had never
“wasted time” upon poetry, and it seemed an appalling deficiency to
her. One day in the lunch hour, when she chanced upon him alone in
the little museum where the skeletons were arranged, shamefully
eating the bun that constituted his midday meal, she retreated, and
returned to lend him, with a slightly furtive air, a volume of
Browning. He stood sideways towards her and took the book rather
clumsily, because he was holding the bun in the other hand. And in
the retrospect his voice lacked the cheerful clearness he could have
wished.
That occurred after the examination in comparative anatomy, on
the day before the College turned out its students, and was carefully
locked up by the officials, for the Christmas holidays. The excitement
of cramming for the first trial of strength had for a little while
dominated Hill, to the exclusion of his other interests. In the
forecasts of the result in which everyone indulged, he was surprised
to find that no one regarded him as a possible competitor for the
Harvey Commemoration Medal, of which this and the two
subsequent examinations disposed. It was about this time that
Wedderburn, who so far had lived inconspicuously on the uttermost
margin of Hill’s perceptions, began to take on the appearance of an
obstacle. By a mutual agreement, the nocturnal prowlings with
Thorpe ceased for the three weeks before the examination, and his
landlady pointed out that she really could not supply so much lamp
oil at the price. He walked to and fro from the College with little slips
of mnemonics in his hand, lists of crayfish appendages, rabbits’
skull-bones, and vertebrate nerves, for example, and became a
positive nuisance to foot passengers in the opposite direction.
But, by a natural reaction, Poetry and the girl with the brown eyes
ruled the Christmas holiday. The pending results of the examination
became such a secondary consideration that Hill marvelled at his
father’s excitement. Even had he wished it, there was no
comparative anatomy to read in Landport, and he was too poor to
buy books, but the stock of poets in the library was extensive, and
Hill’s attack was magnificently sustained. He saturated himself with
the fluent numbers of Longfellow and Tennyson, and fortified himself
with Shakespeare; found a kindred soul in Pope, and a master in
Shelley, and heard and fled the siren voices of Eliza Cook and Mrs.
Hemans. But he read no more Browning, because he hoped for the
loan of other volumes from Miss Haysman when he returned to
London.
He walked from his lodgings to the College with that volume of
Browning in his shiny black bag, and his mind teeming with the
finest general propositions about poetry. Indeed, he framed first this
little speech and then that with which to grace the return. The
morning was an exceptionally pleasant one for London; there was a
clear, hard frost and undeniable blue in the sky, a thin haze softened
every outline, and warm shafts of sunlight struck between the house
blocks and turned the sunny side of the street to amber and gold. In
the hall of the College he pulled off his glove and signed his name
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