Familial cancer database: a clinical aide-mémoire

Cancer is associated with a wide range of hereditary disorders. Recognizing these disorders in cancer patients may be of great importance for the medical management of both patients and their relatives. Conversely, recognizing the fact that cancer may develop in patients already diagnosed with a particular hereditary disorder may be important for the same reason. We have developed a stand-alone interactive computer program, Familial Cancer Database (FaCD), to assist the clinician in making a genetic differential diagnosis in cancer patients as well as in becoming aware of the tumour spectrum associated with a particular hereditary disorder. The program tries to match tumour and non-tumour features observed in patients and their families with any of the more than 300 disorders presently contained in its database and provides a clinical synopsis with literature references for each of these disorders. FaCD is offered free of charge in support of the Familial Cancer and Prevention project of the UICC Cancer Epidemiology and Prevention program. The software is primarily aimed at health care professionals with at least a basic knowledge of clinical cancer genetics, and can be downloaded from the internet at http://facd.uicc.org.     

Is clinical breast examination important for breast cancer detection?

BackgroundScreening clinical breast examination (cbe) is controversial; the use of cbe is declining not only as a screening tool, but also as a diagnostic tool. In the present study, we aimed to assess the value of cbe in breast cancer detection in a tertiary care centre for breast diseases.MethodsThis retrospective study of all breast cancers diagnosed between July 1999 and December 2010 at our centre categorized cases according to the mean of detection (cbe, mammography, or both). A cbe was considered “abnormal” in the presence of a mass, nipple discharge, skin or nipple retraction, edema, erythema, peau d’orange, or ulcers.ResultsDuring the study period, a complete dataset was available for 6333 treated primary breast cancers. Cancer types were ductal carcinoma in situ (15.3%), invasive ductal carcinoma (75.7%), invasive lobular carcinoma (9.0%), or others (2.2%). Of the 6333 cancers, 36.5% (n = 2312) were detected by mammography alone, 54.8% (n = 3470) by mammography and cbe, and 8.7% (n = 551) by physician-performed cbe alone (or 5.3% if considering ultrasonography). Invasive tumours diagnosed by cbe alone were more often triple-negative, her2-positive, node-positive, and larger than those diagnosed by mammography alone (p < 0.05).ConclusionsA significant number of cancers would have been missed if cbe had not been performed. Compared with cancers detected by mammography alone, those detected by cbe had more aggressive features. Clinical breast examination is a very low-cost test that could improve the detection of breast cancer and could prompt breast ultrasonography in the case of a negative mammogram.     

Colon cancer stem cells – From basic to clinical application

Based on cancer stem cell (CSC) concept of carcinogenesis, tumors represent complex heterogeneous organ-like systems with a hierarchical cellular organization, and only minority phenotypic subpopulations with stem-like properties possess a dual ability to self-renew indefinitely and produce all the heterogeneous cell phenotypes comprising the bulk tumor cells. Large experimental and clinical data indicate that conventional anti-cancer therapies cannot eradicate CSCs, and moreover, they usually increase their number leading to cancer recurrence and further drug resistance. In this review, several current controversies in the CSC field and recent studies, which help to shed light on their origin, are discussed. The emerging necessity for the development of complex, multimodal CSC-targeted treatment strategies, which combine conventional therapeutics with promising pathway-specific modulators, and natural compounds, which can improve the efficacy of conventional anti-cancer therapeutics and decrease their undesirable side effects is presented. Also, novel requirements and criteria necessary for evaluation of the CSC-targeted drug efficacy and relevant experimental models are discussed.     

Do clinical databases render population-based cancer registers obsolete? The example of breast cancer in Denmark

Objective: Clinical databases have been invented to monitor treatment outcomes, therapies or diseases, often in great detail. The traditional population-based cancer registry has been invented to collect a minimum of information about all incident cancers. Do clinical databases render population-based cancer registers obsolete as sources of cancer cases for epidemiological study? Methods: We compared the study base of first incident breast cancer cases in Denmark in 1978–1994 known from the national cancer register and from the national clinical database on breast cancer patients. The clinical database is used for monitoring protocoled treatment. Results: Combining the two data sources we found 48,522 first primary breast cancers in Denmark 1978–1994. Of these, 37,640 were included in both data sources, 2151 were included only in the clinical database, and 8731 were included only in the cancer register. A major part of the difference between the two data sources was due to treatment-focused data collection in the clinical database, and a minor part due to differences in the registration of second primaries, date of diagnosis and invasiveness. Conclusions: Cancer incidence data are sensitive to registration procedures and definitions. Clinical cancer databases cannot generally replace the traditional cancer register as a reliable data source for incident cancer cases in a national population.     

Ovarian cancer: can we make the clinical diagnosis earlier?

BACKGROUND: Patients with ovarian cancer often report having symptoms for months before diagnosis, but such findings are subject to recall bias. The aim of this study was to provide an objective evaluation of symptoms that precede a diagnosis of ovarian cancer. METHODS: Medicare provider claims linked to records in the California Surveillance, Epidemiology, and End Results data base were utilized to extract diagnosis and procedure codes for 1985 women age 68 years or older who resided in California with ovarian cancer, 6024 elderly women with localized breast cancer, and 10,941 age-matched, Medicare-enrolled women without cancer. Prevalence of rates of symptom-related diagnoses and procedure codes in Medicare claims records were obtained during 3-month periods up to 36 months before diagnosis of ovarian cancer. RESULTS: From 1 month to 3 months before patients were diagnosed with ovarian cancer, the frequency and adjusted odds ratios (ORs) with 95% confidence intervals (95%CIs) for 4 "target symptom" code groups were: abdominal pain (frequency, 30.6%; OR, 6.0; 95%CI, 5.1-6.9), abdominal swelling (frequency, 16.5%; OR, 30.9; 95%CI, 21.4-44.8), gastrointestinal symptoms (frequency, 8.4%; OR, 2.3; 95%CI, 1.8-3.0), and pelvic pain (frequency, 5.4%; OR, 4.3; 95%CI, 2.8-6.7). The adjusted odds for abdominal swelling codes was elevated 10-12 months before diagnosis (OR, 2.4; 95%CI, 1.2-4.6) for abdominal pain codes 7-9 months before diagnosis (OR, 1.3; 95%CI, 1.1-1.7). Abdominal imaging (frequency, 7.0%; OR, 1.3; 95%CI, 1.0-1.7) and pelvic imaging/CA125 (frequency, 3.7%; OR, 2.4; 95%CI, 1.7-3.4) showed an elevated frequency and adjusted odds 4-6 months before diagnosis. Patients with claims codes for "target symptoms" 4-36 months before diagnosis were more likely to have abdominal imaging (61.1%) or gastrointestinal procedures (30.8%) than pelvic imaging/CA125 (25.3%). CONCLUSIONS: Patients with ovarian cancer were more likely than patients with breast cancer and women in a cancer-free control group to have target symptom codes (particularly abdominal swelling and pain) > 6 months before diagnosis. The evaluation of women with unexplained "target symptoms" should include pelvic imaging and/or CA125.     

The evolving role of oestrogen receptor β in clinical breast cancer

Controversy surrounds the potential clinical importance of oestrogen receptor (ER)β in breast cancer, and three recent papers have sought to resolve this. In the present issue of Breast Cancer Research Novelli and colleagues explored the significance of ERβ1 expression in 936 breast cancer patients, and they showed diverse relationships according to lymph node status. A second paper examined 442 breast cancers in which ERβ1 was an independent predictor of recurrence, disease-free survival and overall survival. Finally a third paper showed that ERβ2 was a powerful prognostic indicator in 757 breast cancers but this was dependent on cellular location, with nuclear ERβ2 expression predicting good survival whilst cytoplasmic expression predicted worse outcome. These papers point to a clinical role for ERβ in breast cancer and shall be discussed.     

Expression and clinical significance of REGγ in gastric cancer tissue and variously differentiated gastric cancer cell lines

OBJECTIVE To evaluate the REGγ expression in gastric cancer tissue and gastric cancer cell lines of various differentiation levels and its clinical significance. METHODS Immunohistochemistry was used to detect the expression of REGγ protein in 70 specimens of gastric cancer and 30 specimens of normal gastric mucosa. The relationship between the expression of REGγ protein and the biological behaviors of gastric cancer was analyzed. RT-PCR and Western blot were used to detect the mRNA level and the protein expression of REGγ in normal gastric cell line GES-1, well differentiated gastric cancer cell line MKN-28, moderately differentiated gastric cancer cell line SGC-7901 and poorly differentiated gastric cancer cell line BGC-823. RESULTS The expression rate of REGγ protein in gastric cancer tissue （52/70, 74.29%） was significantly higher than that in normal gastric tissue （12/30, 40%） （P 〈 0.01）. The expression rate of REGγ was correlated with tumor size （P 〈 0.01）, lymph node metastasis （P 〈 0.05）, differentiation degree （P 〈 0.01）, infiltration depth （P 〈 0.01） and distant metastasis （P 〈 0.05）. RT-PCR analysis showed that the expression of REGγ mRNA was 0.459 ± 0.079 in the normal gastric mucosa cell ling 0.588 ±0.118 in the well differentiated gastric cancer cell line, 0.715±0.066 in the moderately differentiated gastric cancer cell line, and 0.873 ± 0.099 in the poorly differentiated gastric cancer cell line, showing a negative correlation between REGγ mRNA expression and differentiation level （P 〈 0.05）. Western blot analysis showed that the expression of REGγ protein was 0.712±0.065 in the normal gastric mucosa cell line, 1.176±0.185 in the well differentiated gastric cancer cell line, 1.533 ± 0.127 in the moderately differentiated gastric cancer cell line, and 2.061± 0.398 in the poorly differentiated gastric cancer cell line, showing a negative correlation between REGγ protein expression and differentiation level （P 〈 0.05）. CONCLUSION REGγ is expressed in gastric cancer tissue and normal gastric tissue. In gastric cancer tissues, REGγ expression is positively correlated with the tumor size, lymph node metastasis, differentiation degree, infiltration depth and distant metastasis. Detecting the expression of REGγ mRNA and protein is helpful for early diagnosis and predicting prognosis of gastric cancer.     

ASAP3 expression in non-small cell lung cancer: association with cancer development and patients’ clinical outcome

ASAP3 belongs to Arf-specific GTPase-activating proteins which regulate Arfs by stimulating their intrinsic GTP hydrolysis. ASAP3 expression and the clinical significance in malignant tumors are largely unknown. In this study, we examined ASAP3 expression in non-small cell lung cancer (NSCLC) to find out its clinicopathological significance. Immunohistochemistry shows elevated expression of ASAP3 in cancer tissues (54.8 % (57/104)) compared to normal lung tissues (18.0 % (9/50)) (p?<?0.05). Increased ASAP3 expression was associated with poor differentiation, lymph node metastasis, and advanced TNM stages in NSCLC (p?<?0.05). Survival analysis reveals that ASAP3 expression contributes to patients’ poor clinical outcome (p?<?0.05). We also examined ASAP3 expression in several lung cancer cell lines using Western blotting. We downregulated ASAP3 expression in LTE cell which has a relative high level of ASAP3 expression using siRNA and found that reduced ASAP3 leads to significant inhibition of cancer cell invasion (p?<?0.05). These data indicate that ASAP3 is elevated in NSCLC and may contribute to cancer development and patients’ poor clinical outcome, which is possibly due to its critical roles in regulating cancer invasion.     

Why don’t cancer patients enter clinical trials? A review

Despite widespread agreement about the value of clinical trials, the proportion of patients who are enrolled in such trials is often considered to be too low. A comprehensive literature search was carried out for the period 1980 to the present, in order to review current data on barriers and facilitators to the development of multicentre clinical trials. Of 364 articles initially identified, 35 articles and 1 book were selected in order to assess the reasons that doctors and/or patients participate in clinical trials. This review emphasises the fact that doctors play a key role in the development and non-development of clinical trials. More studies, in particular studies outside the United States of America (USA), are needed in order better to understand doctors' attitudes towards clinical trials. Such studies should combine multivariate analyses and comparative approaches in order to associate doctors' behaviours with their individual characteristics, with the organisational context of their working environment and with the healthcare system.     

Colorectal cancer in young patients: is it a distinct clinical entity?

Background

The incidence of colorectal cancer in young patients is increasing. It remains unclear if the disease has unique features in this age group.

Methods

This was a single-center, retrospective cohort study which included patients diagnosed with colorectal cancer at age ≤40 years in 1997–2013 matched 1:2 by year of diagnosis with consecutive colorectal cancer patients diagnosed at age >50 years during the same period. Patients aged 41–50 years were not included in the study, to accentuate potential age-related differences. Clinicopathological characteristics, treatment, and outcome were compared between groups.

Results

The cohort included 330 patients, followed for a median time of 65.9 months (range 4.7–211). Several significant differences were noted. The younger group had a different ethnic composition. They had higher rates of family history of colorectal cancer (p = 0.003), hereditary colorectal cancer syndromes (p < 0.0001), and inflammatory bowel disease (p = 0.007), and a lower rate of polyps (p < 0.0001). They were more likely to present with stage III or IV disease (p = 0.001), angiolymphatic invasion, signet cell ring adenocarcinoma, and rectal tumors (p = 0.02). Younger patients more frequently received treatment. Young patients had a worse estimated 5-year disease-free survival rate (57.6  vs. 70 %, p = 0.039), but this did not retain significance when analyzed by stage (p = 0.092). Estimated 5-year overall survival rates were 59.1 and 62.1 % in the younger and the control group, respectively (p = 0.565).

Conclusions

Colorectal cancer among young patients may constitute a distinct clinical entity. Further research is needed to validate our findings and define the optimal approach in this population.

     

Bladder cancer angiogenesis and metastasis—translation from murine model to clinical trial

In the majority of cases, death from bladder cancer results from metastatic disease. Understanding the closely linked mechanisms of invasion, metastasis and angiogenesis in bladder cancer has allowed us to develop new therapeutic strategies that harbor the promise of decisive improvements in patient survival. The essential link between cell based experiments and the translation of novel agents into human patients with bladder cancer is the animal model. With emphasis on the orthotopic xenograft model, this review outlines some key mechanisms relevant to angiogenesis and the development of metastasis in bladder cancer. We highlight especially pathways related to MMP-9, IL-8, VEGF and EGFR. Most commonly, expression patterns of these markers in patients have correlated to disease progression and patient survival, which has led to laboratory investigations of these markers and eventually novel targeted therapies that are translated back into the clinic by means of clinical trials. Although imperfect in their translatability into clinical efficacy, animal models remain a critical tool in bladder cancer research.     

Maintenance therapy for advanced non-small-cell lung cancer: ready for clinical practice?

The treatment paradigm for advanced non-small-cell lung cancer has changed in recent years with the importance of histological subtyping for the choice of chemotherapy, and the use of molecular markers to select patients for targeted therapy. Maintenance therapy (MT) is another focus of interest. The potential benefit of MT for the patient is that it prolongs tumor control reached with first-line chemotherapy in order to improve overall survival with little added toxicity. Historical studies have never reached this goal, as the agents used for MT were too poorly tolerated. We review the data of the two types of recent MT studies, 'continuation' and 'switch' or 'consolidation' MT. We comment on how the benefits demonstrated in these studies may change clinical practice and reflect on factors that may identify subgroups of patients who derive the greatest benefit from MT in general, as this will help in a rational use of MT.