E-Manuscript Article Summaries ^†

Array Comparative Genomic Hybridization and Cytogenetic Analysis in Pediatric Acute Leukemias

A.J. Dawson PhD, R. Yanofsky MD, R. Vallente PhD, S. Bal MSc, I. Schroedter MLT, L. Liang BSc, and S. Mai PhD. Cytogenetics Laboratory and Hematopathology Laboratory, Diagnostic Services Manitoba; Departments of Biochemistry and Medical Genetics, of Pediatrics and Child Health, of Physiology, and of Human Anatomy and Cell Science, University of Manitoba; CancerCare Manitoba; and Genomic Centre for Cancer Research and Diagnostics, Winnipeg, Manitoba.

KEY WORDS

Acute lymphoblastic leukemia, chromosomes, microarray, aCGH

URL http://www.current-oncology.com/index.php/oncology/article/view/770/

E-JOURNAL LINKED ABSTRACT

Most patients with acute lymphoblastic leukemia (ALL) are reported to have acquired chromosomal abnormalities in their leukemic bone marrow cells. Many established chromosome rearrangements have been described, and their associations with specific clinical, biologic, and prognostic features are well defined. However, approximately 30% of pediatric and 50% of adult patients with ALL do not have cytogenetic abnormalities of clinical significance. Despite significant improvements in outcome for pediatric ALL, therapy fails in approximately 25% of patients, and these failures often occur unpredictably in patients with a favorable prognosis and “good” cytogenetics at diagnosis.

Karyotype analysis in hematologic malignancies, although genome-wide, is well known to have limitations because of altered cell kinetics (mitotic rate), a propensity of leukemic blasts in culture to undergo apoptosis, overgrowth by normal cells, and the presence of poor-quality chromosomes in the abnormal clone. In array comparative genomic hybridization (aCGH, “microarray”), genomic resolution is greatly increased over that in classical cytogenetics. Micro- array, a powerful tool that uses DNA in the analysis of unbalanced chromosome rearrangements such as copy number gains and losses, is the method of choice when the mitotic index is low and the quality of metaphases is suboptimal. The copy number profile obtained by microarray is often called the “molecular karyotype.” However, microarray cannot detect balanced chromosome rearrangements such as translocations or inversions that have no copy number changes, making the continued routine use of conventional cytogenetics essential.

In the present study, microarray was retrospectively applied to 9 cases of pediatric ALL with either initial high-risk features or at least 1 relapse. The conventional karyotype was compared with the microarray “molecular karyotype” to assess abnormalities as interpreted by classical cytogenetics. Microarray not only identified previously undetected chromosome losses and gains, but also showed discordances with several karyotypes interpreted by classical cytogenetics. This initial study has demonstrated that DNA microarray is a reliable method for the identification of cytogenetically visible and cryptic imbalances in pediatric ALL. The complementary use of aCGH and conventional cytogenetics can provide further information about relevant and repeated mutations in ALL. Clinical analysis could then focus on the specific mutations, with impacts on diagnosis, prognosis, and treatment. Based on our experience with these 9 cases, we propose the following algorithm for the cytogenetic evaluation of hematologic malignancies:

• Conventional karyotype
• Complementary microarray analysis
• If required, FISH (fluorescence in situ hybridization) analysis for microarray-identified abnormalities to confirm or revise conventional karyotype.

The complementary use of microarray and conventional cytogenetics would allow for more sensitive, comprehensive, and accurate analysis of the underlying genetic profile, with concomitant improvement in prognosis and treatment, not only for pediatric ALL, but for neoplastic disorders in general.

Survival and Treatment Patterns in Elderly Patients with Advanced Non- Small-Cell Lung Cancer in Manitoba

C.L. Baunemann Ott MD, N. Ratna BSc, R. Prayag PharmD, Z. Nugent PhD, K. Badiani PhD, and S. Navaratnam MD Ph D. Department of Internal Medicine, University of Manitoba, Faculty of Medicine; and Department of Epidemiology and Manitoba Institute of Cell Biology, CancerCare Manitoba, Winnipeg, Manitoba.

KEY WORDS

Non-small-cell lung cancer, elderly patients, chemotherapy

URL http://www.current-oncology.com/index.php/oncology/article/view/780/

E-JOURNAL LINKED ABSTRACT

Lung cancer is the leading cause of cancer death worldwide. Non-small-cell lung cancer (NSCLC) constitutes more than 75% of all lung cancer cases. Patients usually present at diagnosis with a median age of 75. These elderly patients are often underrepresented in the randomized clinical trials upon which chemotherapy plans are based. The objective of the present study was to determine the patterns of treatment and survival in elderly patients with NSCLC in Manitoba.

Using the provincial cancer registry database, an eligible cohort (n = 497) of elderly patients over the age of 70 years at diagnosis with stage III or IV NSCLC was identified for the period 2001–2004. Medical oncologists evaluated 147 of the 497 patients, and chemotherapy treatment was recommended only for 82, which is 16.5% of the initial cohort. Patients who received chemotherapy were significantly younger than those who did not, and we observed a significant difference in the number of patients with stage III compared with stage IV disease who were treated. In patients receiving chemotherapy, we observed greater representation for men (63.4%) than for women (36.6%). Most patients receiving chemotherapy received a platinum-based doublet (84%), almost equally divided between carboplatin and cisplatin. In 59% of cases, chemotherapy had to be halted because of lack of tolerability or disease progression. The median overall survival for patients in this cohort was, with chemotherapy, 64 and 56 weeks (stages III and IV respectively) and, without chemotherapy, 46 and 26 weeks. A log-rank test showed that the survival curves for stages III and IV patients were not different. However, median survival was significantly different between the patients who received chemotherapy and those who did not. Although 50% of patients with advanced NSCLC are over 70 years of age, few are evaluated by a medical oncologist, and even fewer are treated with chemotherapy. However, in treated patients, survival times for elderly and younger patients are comparable, indicative of a benefit for chemotherapy treatment in the elderly population.

Durable Remission of Inoperable Liver Metastasis from Rectal Cancer After Hepatic Arterial Infusion of Oxaliplatin and 5-Fluorouracil in Combination with Intravenous Cetuximab

K. Van Bael MD, M. Aerts MD, M. de Ridder MD PhD, J. de Gréve MD PhD, G. Delvaux MD PhD, and B. Neyns MD PhD. Departments of Surgical Oncology, of Medical Oncology, and of Radiotherapy, Oncologisch Centrum UZ Brussel, Brussels, Belgium.

KEY WORDS

Hepatic, arterial, infusion, colorectal, liver metastases, cetuximab, oxaliplatin, remission

URL http://www.current-oncology.com/index.php/oncology/article/view/789/

E-JOURNAL LINKED ABSTRACT

At diagnosis of a cT3N0M1 adenocarcinoma of the rectum with synchronous inoperable liver metastases, a 59-year-old man was treated with preoperative radiotherapy (5×5 Gy), followed by laparoscopy- assisted anterior resection of the rectum with total mesorectal excision. At the first postoperative evaluation, a new lung metastasis was detected. First-line chemotherapy with FOLFIRI [5-fluorouracil (5FU)–irinotecan–leucovorin] resulted in a transient stabilization of the metastatic liver disease. At progression, oxaliplatin and 5FU–folinic acid were administered by intrahepatic arterial infusion (HAI), in combination with intravenous cetuximab. A partial radiologic response was obtained, with complete metabolic response on fluorodeoxyglucose positronemission tomography (FDG-PET) and normalization of carcinoembryonic antigen values. This solitary lung metastasis was sequentially treated by radiotherapy and resection. Six years after the initial diagnosis, this patient remains free from progression, with residual cystic remnants of the liver metastases visible on conventional computed tomography imaging, but non-enhancing on FDG-PET.

The unexpected durable remission in this patient was obtained during treatment in a phase I study. The feasibility of combining cetuximab, a monoclonal antibody targeted to the epidermal growth factor receptor (EGFR), with combination chemotherapy by HAI was recently published.

In the neoadjuvant setting, HAI was associated with superior survival and better physical functioning than was obtained with systemic administration (24.4 months vs. 20 months, p = 0.0034) during a comparison of a fluoropyrimidine with HAI in single-agent cytotoxic therapy, which did not unequivocally demonstrate superiority in terms of survival compared with the systemic route of administration. The median overall survival observed in the experimental arms of two recently conducted phase III trials using FOLFIRI plus cetuximab or FOLFOX (5FU–leucovorin–oxaliplatin) plus bevacizumab were 24.9% (wild type KRAS patients only) and 21.3% respectively.

Patients with liver metastases from colorectal cancer have a poor survival prognosis when no R0 surgical resection of the LMs can be offered. Despite improvements in the activity of combination chemotherapy and of combinations with therapeutics targeting vascular endothelial growth factor or EGFR, most of the patients diagnosed with extrahepatic metastases and those with inoperable LMs cannot be offered cure and long-term disease control. At the time of writing, the patient reported here remains in complete remission in response to the combination of HAI chemotherapy (oxaliplatin–leucovorin–5FU) and an intravenous EGFR inhibitor (cetuximab, a monoclonal antibody with demonstrated activity against KRAS wild-type colorectal cancer). This case merits further investigation; combination therapy including HAI may open a promising era of tailored therapy in which only patients known to benefit will be treated.

Caring for Survivors of Breast Cancer: Perspective of the Primary Care Physician

S.L. Smith BSc MD, E.S. Wai BSc MS MD, C. Alexander CHIM, and S. Singh–Carlson RN BSN MSN PhD. Division of Radiation Oncology, Department of Surgery, Faculty of Medicine, University of British Columbia, Vancouver, and Breast Cancer Outcomes Unit, BC Cancer Agency–Vancouver Island Centre, Victoria, British Columbia; and School of Nursing, California State University–Long Beach, Long Beach, California, U.S.A.

KEY WORDS

Breast cancer survivors, primary care physician perspective, follow-up cancer care, survivorship care plans

URL http://www.current-oncology.com/index.php/oncology/article/view/793/

E-JOURNAL LINKED ABSTRACT

Background and Objectives: The concept of survivorship care has received increased attention in the last several years, which may largely be a result of the increasing number of patients surviving breast cancer. In the Canadian province of British Columbia, survivors of breast cancer (SBC) are usually followed by their primary care physicians (PCP) after completion of active oncology treatment. The present study offers insight into PCP confidence in their ability to provide such care and explores potential ways to assist them in this aspect of their practice.

Methods: In British Columbia, typical practice is to discharge SBC to the care of their PCP in the first year after completion of active oncology treatment. A one-page, 31-item check box and open-answer questionnaire assessing perceptions and preferences about this aspect of practice was designed and mailed to 1000 PCP known to be following SBC in their practice. Questions addressed self-rated PCP confidence in the ability to provide follow-up care for SBC, preferences for the format and content of discharge communication from oncologists and preferred resources for obtaining information about breast cancer. Descriptive statistics and the Pearson chi-square test were used to summarize findings.

Results: A total of 587 PCP returned completed surveys (response rate: 59%). Discharge information deemed most useful in assisting PCP to manage SBC included: diagnosis and treatment summary, recommended follow-up protocol, and recommended adjuvant hormonal therapy. Preference for the format of discharge information was point form for 43% of respondents, detailed description for 19%, and both formats for 38%. PCP were most confident screening for recurrence and managing patient anxiety, and least confident in managing lymphedema and providing counseling on sex, body image, and family concerns. PCP following more SBC displayed higher confidence in managing the biomedical aspects of follow-up and in providing counselling about nutrition and exercise than in those following fewer SBC. Respondents most commonly used online resources and continuing medical education seminars to access information about breast cancer.

Conclusions: The PCP providing follow-up care for SBC are confident managing most aspects of care. Discharge information that includes a record of diagnosis and care received, surveillance recommendations, and recommended hormonal therapy is considered very useful in their provision of care to this population. Most PCP use online resources and continuing medical education events to obtain information about breast cancer. It follows that current breast cancer information should be made available in those formats.

Health Care Strategies to Promote Earlier Presentation of Symptomatic Breast Cancer: Perspectives of Women and Family Physicians

R. Heisey MD, M. Clemons MD, L. Granek PhD, K. Fergus PhD, S. Hum MsC, B. Lord RN MN, D.R. McCready MD MsC, and B. Fitzgerald RN MScN. Department of Family and Community Medicine, Women’s College Hospital; Departments of Surgical Oncology and of Nursing, Princess Margaret Hospital, University of Toronto; and Department of Psychology, Sunnybrook Odette Cancer Centre, York University, Toronto; Division of Medical Oncology, The Ottawa Hospital Cancer Centre, Ottawa; and Department of Pediatrics, McMaster Children’s Hospital, Hamilton, Ontario.

KEY WORDS

Cancer, diagnosis, qualitative, family physician

URL http://www.current-oncology.com/index.php/oncology/article/view/869/

E-JOURNAL LINKED ABSTRACT

Background: Many women with symptoms suggestive of breast cancer delay presentation to their family physician. Factors associated with delay have been well described, but data on strategies to mitigate delay are lacking.

Objectives: In a qualitative study, factors related to delay were examined and changes to the health care system that might encourage earlier presentation were identified.

Methods: Individual semi-structured interviews were conducted with women who sought care 12 weeks or more after self-detection of breast cancer symptoms (n = 14) and with family physicians having patients in their practice who met that criterion (n = 10).

Results: By examining the perspectives of these women and family physicians, we were able to develop a pattern recognition aid for the “at-risk situation for delay” in a diagnosis of breast cancer and to identify changes to the health care system that might encourage women with self-identified breast cancer symptoms to present earlier.

The “at-risk situation for delay” in presentation occurs when a woman has

• a non-lump presenting breast symptom.
• a history of a previous breast complaint that was benign or a “false alarm.”
• no regular periodic health care or screening.
• a comorbid condition such as fibromyalgia or chronic fatigue syndrome.
• a history of a previous negative health care experience.
• competing life demands—for example, a busy job, caring for children or parents.

Changes to the health care system to encourage earlier presentation include

• more consistent messaging about screening mammography guidelines (40-49 years of age).
• better messaging about breast awareness.
• better compliance tracking and reminders for screening mammography and periodic health exams.
• improved access to a rapid diagnostic process.
• education initiatives:
  • Improving awareness that a previous benign breast diagnosis does not ensure that future symptoms are not cancer
  • Improving the awareness of non-lump presentations of breast cancer
• presentation of additional hopeful testimonials: “Breast cancer is not a death sentence.”
• validation of women presenting with breast complaints.
• improved recognition of subtle clues and indirect communication (doorknob syndrome, “Do I need a mammogram?”).

Conclusions: Family physicians are uniquely positioned to encourage women with breast cancer symptoms to present earlier. Our work emphasizes the benefit of establishing an ongoing supportive therapeutic relationship with patients and the value of regular periodic health exams and mammographic screening. Education about non-lump breast cancer symptoms and physician recognition of the “at risk situation for delay” may reduce the likelihood of women presenting late with breast cancer symptoms. More consistent messaging about breast awareness, screening mammography recommendations in women 40–49 years of age, and hopeful testimonials from women living with breast cancer is also warranted.

Establishing a Multicentre Clinical Research Network: Lessons Learned

N.A. Hagen MD, C.R. Stiles BN, P.D. Biondo PhD, G.G. Cummings RN PhD, R.L. Fainsinger MD, D.E. Moulin MD, J.L. Pereira MBChB MSc, and R. Spice BMedSc MD. Tom Baker Cancer Centre, Alberta Health Services Cancer Care, and Division of Palliative Medicine and Department of Family Medicine, University of Calgary, Calgary, Alberta; Faculty of Nursing and Division of Palliative Medicine, University of Alberta, Edmonton, Alberta; and London Regional Cancer Program, Clinical Neurological Sciences and Oncology, University of Western Ontario, London, and Division of Palliative Care, University of Ottawa, Ottawa, Ontario.

KEY WORDS

Clinical cancer research, research network, multicentre, network evaluation, collaboration

URL http://www.current-oncology.com/index.php/oncology/article/view/814/

E-JOURNAL LINKED ABSTRACT

Background: Research networks have emerged within many health care disciplines to connect researchers who are physically separated, with the aim of sharing expertise and resources, working collaboratively on multicentre projects, and exchanging valuable skills. A multicentre research network committed to studying difficult cancer pain problems was launched in 2004 as part of a Canadian initiative to increase research capacity in palliative and end-of- life care. Funding was received for 5 years to support network activities.

Methods: Mid-way through the 5-year granting period, an external review panel provided a formal midgrant evaluation. Concurrently, an internal evaluation of the network by its members was conducted using a survey. Based on feedback from those internal and external evaluations, and a review of the literature, we identified several components believed to be relevant to the development of a successful clinical cancer research network. Upon completion of the term of the grant, we reviewed those components and reflected on their broader application.

Results: The elements found to be important to our success as a clinical cancer research network were these: shared vision, formal governance policies and terms of reference, infrastructure support so that busy clinicians can use their research time most effectively, regular and effective communication, an account- ability framework, a succession planning strategy to address membership changes over time, multiple strategies to engage network members on an ongoing basis, regular review of goals and timelines, and a balance between structure and creativity.

Conclusions: A program of cancer research can be complex to undertake and is most effectively implemented (and fun!) when approached as a team sport. Drawing together individuals with diverse skills can greatly enhance the strength of a research team, but typically involves inviting membership at several diverse sites. Managing a team spread across a large geographic area poses special challenges. Electronic and other means of communication greatly facilitate the establishment and nurturance of a network of individuals drawn together by common goals and values, and working in a complementary manner. The successful establishment and conduct of a multi-year, multicentre clinical cancer research network led its members to reflect on what most contributed to achieving network goals. We identified several specific factors that seem to be highly relevant in promoting success. We hope that these observations will foster further discussion on the successful design and operation of research networks.

Canadian College of Medical Geneticists Guidelines for the Indications, Analysis, and Reporting of Cancer Specimens

A.J. Dawson PhD, J. McGowan–Jordan PhD, J. Chernos PhD, J. Xu PhD, J. Lavoie PhD, J.C. Wang PhD, M. Steinraths MD, and S. Shetty PhD. McGill University Cytogenetics, Montreal Children’s Hospital, Montreal, QC; Cytogenetics laboratories, Children’s Hospital of Eastern Ontario (Ottawa), McMaster University (Hamilton), and Health Sciences Centre (London), ON; Cytogenetics Laboratory, Diagnostic Services, Manitoba, Winnipeg, MB; Cytogenetics Laboratory, Alberta Children’s Hospital, Calgary, AB; Division of Medical Genetics, Victoria General Hospital, Victoria, BC; ARUP Laboratory, Salt Lake City, UT, U.S.A.; and CCMG Cytogenetic Committee 2009–2010.

KEY WORDS

Cytogenetics, cancer, hematopoietic, lymphoid, tumours

URL http://www.current-oncology.com/index.php/oncology/article/view/775/

E-JOURNAL LINKED ABSTRACT

The Canadian College of Medical Geneticists (CCMG) is a national organization of medical and laboratory geneticists. The mission of the CCMG is to establish and maintain high-quality professional and ethical standards for medical genetics services in Canada and to help to ensure that service of the highest quality is delivered to the Canadian public.

Cancer cytogenetics is one of the sections of practice of the CCMG. The CCMG Cytogenetic Committee has, therefore, put forward guidelines to provide oncologists and CCMG cytogeneticists with a comprehensive review of the cytogenetic diagnostic tests that are recommended as a minimum standard of care for tumours of hematopoietic and lymphoid tissues and for tumours of soft tissue and bone. The guidelines were approved by the CCMG board of directors in June 2010.