Archive for October, 2007.
Posted on October 25th, 2007 by admin in
Cancer Basal cell carcinoma (BCC) is the most common malignant cutaneous neoplasm in humans. The most common presenting complaint is a bleeding or scabbing sore that heals and recurs. The tumor rarely metastasizes. BCC advances by direct extension and destroys normal tissue. Untreated, the cancer can destroy the whole side of the face or penetrate subcutaneous tissue into the bone and brain.
Risk factors.
Fair skin and the degree of sun exposure are important risk factors. Outdoor workers and people who live in southern latitudes with higher levels of ambient ultraviolet B radiation are at greater risk. Men have a significantly higher incidence than women. Tanning salons with equipment that emits ultraviolet A or B radiation are also damaging and increase the risk of BCC.
Location.
Eighty-five percent of all BCCs appear on the head and neck region; 25% to 30% occur on the nose alone, the most common site. BCC is rarely found on the backs of the hands, although this site receives a significant amount of solar radiation. Tumors also occur in sites protected from the sun, such as the genitals and breasts. BCC in blacks is rare.
PATHOPHYSIOLOGY
BCCs arise from basal keratinocytes of the epidermis and adnexal structures (hair follicles, eccrine sweat ducts). Ultraviolet B (UVB) radiation (sunburn spectrum, 290 to 320 nm) is important for the induction of BCC. UVB radiation damages DNA and its repair system and alters the immune system. Depletion of ozone in the earth’s atmosphere results in higher levels of UVB radiation at the earth’s surface. Longer wavelength UVA radiation damages DNA and is also carcinogenic.
BCC grows by direct extension and appears to require the surrounding stroma to support its growth. This may explain why the cells are not capable of metastasizing through blood vessels or lymphatics. The course of BCC is unpredictable. BCC can remain small for years with little tendency to grow, particularly in the elderly, or it may grow rapidly or proceed by successive spurts of extension of tumor and partial regression.
BCC occurs at the site of previous trauma, such as scars, thermal burns, and injury. BCC occurs years later at sites treated with ionizing radiation. The tumor appears 3 months to 7 or more years later at the site of a well-remembered injury.
CLINICAL TYPES
BCC occurs in many different clinical forms, which vary in appearance and malignant potential.
Nodular BCC.
Nodular BCC is the most common form. The lesion begins as a pearly white or pink, dome-shaped papule resembling a molluscum contagiosum or dermal nevus. The mass extends peripherally. The lesion may remain flat. Traction on the surrounding skin accentuates the pearly border. Telangiectatic vessels become prominent and easily recognizable through the thin epidermis as the lesion enlarges. The growth pattern is irregular, forming an oval mass whereby the surface may become multilobular. The center frequently ulcerates and bleeds and subsequently accumulates crust and scale. Ulcerated BCCs were formerly designated rodent ulcers.
Ulcerated areas heal with scarring, and patients often assume their conditions are improving. This cycle of growth, ulceration, and healing continues as the mass extends peripherally and deeper; masses of enormous size may be attained. BCCs may present as nonhealing leg ulcers. Biopsy specimens should be taken of leg ulcers that do not respond to treatment. The tissue mass of a nodular BCC has a distinctive consistency that can be appreciated during curettage or biopsy. It has poor cohesive forces and collapses or breaks down when manipulated with a curette. This is an important diagnostic feature that supports the clinical impression during the biopsy procedure.
Pigmented BCC.
BCCs may contain melanin that imparts a brown, black, or blue color through all or part of the lesion. Clinically, the lesion resembles a melanoma or pigmented seborrheic keratosis, but close inspection reveals the characteristically elevated, pearly white, translucent border, and the biopsy confirms the diagnosis. The histologic pattern most frequently associated with pigment is the nodular pattern.
Management and risk of recurrence
There are several factors to consider before choosing the best treatment modality. The most important are clinical presentation, cell type, tumor size, and location.
Clinical type.
Nodular and superficial BCCs are the least aggressive and can be completely removed by electrodesiccation and curettage or by simple surgical excision.
Histologic type.
The micronodular, infiltrative, and morpheaform BCCs have a higher incidence of positive tumor margins (18.6%, 26.5%, and 33.3%, respectively) after excision and have the greatest recurrence rate. Clinically, BCCs with these patterns have poorly defined borders and are not apparent during physical examination. They subtly extend into surrounding tissue and are easily missed by blind treatment techniques such as surgical excision. An average of 7.2 mm of subclinical tumor extension was found in mopheaform BCCs in one study, compared with 2.1 mm of extension in well-circumscribed nodular lesions. Routine pathologic examination of surgically excised BCCs may not detect a small nodule or strand of BCC on the other side of the excision margin. These tumors need more aggressive treatment with wide excision or microscopically controlled surgery.
Tumor size.
In general, electrodesiccation and curettage afford excellent results for small (less than 2 cm) nodular BCCs located on the forehead and cheeks. Nodular BCCs on the forehead and cheek that are larger and have well-defined margins should be excised and closed; electrosurgery for large tumors may result in large, unsightly scars. The margins of sclerosing BCCs cannot be determined by inspection, and either excision or, preferably, Mohs’ micrographic surgery should be performed. Superficial BCCs of any size can be adequately removed by electrosurgery.
Location.
Tumors about the nose, eye, and ear require special consideration. BCCs of the medial canthus are particularly dangerous. The skin rests close to bone and cartilage, and tumor cells initially invade and proceed to migrate undetected along periosteum or perichondrium. Healing occurs over inadequately treated tumors, and deep invasion and lateral extension can remain undetected, resulting in a tumor of massive proportions. Extension to the eye and brain is possible.
Use of Oral Contraceptives
Soon after the approval of oral contraceptives, a number of epidemiologic studies reported on the risk of breast cancer associated with them. Oral contraceptives are widely used, and any effect on the risk of breast cancer will have important public health implications. Studies suggest that, overall, there has been no increase in the risk of breast cancer for women who had ever used oral contraceptives; however, women who had used oral contraceptives for long periods were at higher risk of premenopausal breast cancer. This was noted among women who had used oral contraceptives before their first full-term pregnancy. It will be important to determine whether this finding in a subgroup of women using oral contraceptives is confirmed, and more important, whether the risk remains at advancing age.
Another study reexamined the data from the Cancer and Steroid Hormone Study to determine whether oral contraceptive use had different effects on the risk of breast cancer at different ages at diagnosis. Among women 20-34 years of age at diagnosis, those who had ever used oral contraceptives had a slightly higher risk of breast cancer than did women of the same ages who had never used oral contraceptives. The slightly increased risk in young women is compatible with the findings of other investigators. There appear to be no data to suggest changes in the prescribing practice for the use of oral contraceptives.
Dietary Fat Intake
International differences in rates of breast cancer and the striking increase among populations migrating from low-to high-incidence areas has suggested that environmental factors, possibly dietary, influence the occurrence of breast cancer. A number of studies addressing this issue have produced conflicting results and recommendations. In a recent study, no evidence was found of a positive association between total dietary fat intake and the risk of breast cancer. There was no reduction in risk, even among women whose energy intake from fat was less than 20% of the total energy intake. It appears unlikely that a reduction in total fat consumption by women in middle age and older will substantially reduce their risk of breast cancer.
Alcohol Consumption
A number of epidemiologic studies have shown a possible relationship between moderate drinking and breast cancer. However, the benefit of decreasing alcohol consumption, if any, needs to be evaluated by considering all the potential effects of alcohol on a woman’s overall risk profile. In that connection, data have also been published suggesting that among women, light to moderate alcohol consumption is associated with a reduced mortality rate. The apparent survival advantage is largely confined to women at greater risk for coronary heart disease.
Other Factors
Approximately 10% of patients with breast cancer have a history of trauma to the breast. This trauma probably results in increased attention to the breast and the discovery of a tumor or other changes that initiate breast self-examination.
Virus-like particles have been identified in human breast milk. There is no evidence, however, that viruses are involved in breast cancer risk.
A number of histologic changes have been noted in benign fibrocystic breasts, and some have been associated with the later development of breast cancer. The College of American Pathologists has published a consensus statement indicating that there is no increased risk for breast cancer in patients with conditions such as macrocysts or microcysts, duct ectasia, fibroadenoma, mild hyperplasia, mastitis, or squamous metaplasia. There is a slight increase in risk in patients with sclerosing adenosis; biopsy-proven hyperplasia that is moderate or florid, solid or papillary; and those who had papillomas with a fibrovascular core. Finally, risk increases substantially–fourfold to fivefold–in women with biopsy-proven atypical hyperplasia or a ductal or lobular carcinoma in situ.
Pathology
The histologic patterns of breast cancers can be divided into two types: 1) carcinomas of lobular epithelial original and 2) carcinomas of ductal epithelial origin. Carcinomas of lobular epithelial origin are generally classified on the basis of invasion: lobular cancer in situ or lobular neoplasia and invasive lobular cancer. In situ lobular carcinoma is almost always diagnosed as an incidental finding after the biopsy of a dominant mass or an occult lesion. The most important features of this lesion when planning treatment include bilaterality, multicentricity, and the relatively low rate of development of subsequent infiltrating carcinoma. If after biopsy the margins are clear, a reasonable treatment plan includes biannual physical examination and annual mammography. The alternative is to recommend mastectomy, usually bilateral.
In situ ductal carcinoma, if untreated, will develop in the ipsilateral breast in approximately 50% of cases. Standard treatment has been total mastectomy with or without conventional axillary dissection. Because of the advent of conservative techniques for small, invasive cancers, there has been considerable debate about conservative treatment for in situ ductal carcinoma. The most recent trial has suggested that appropriate treatment consists of wide local excision or segmental mastectomy followed by radiation therapy.
Reproductive History
Certain reproductive characteristics–nulliparity, early age of menarche, older age at menopause, and older age at first full-term pregnancy–have been associated with increased risk of breast cancer. Oophorectomy at an early age has been considered protective in reducing the risk of breast cancer in reproductive-age women by almost 70%. It has been suggested that the period between the onset of menses and the age of first pregnancy provides a “window of initiation” for the development of breast cancer. This theory presents a paradox, at least in terms of the functional activity of the breast. Anatomically and functionally the breasts undergo atrophy with advancing age. Less than 25% of breast cancers occur in premenopausal women.
It has been widely believed that lactation has no effect on the incidence or the risk of breast cancer. According to a recent study, however, there is a reduction in the risk of breast cancer among premenopausal women who have lactated, but no reduction among postmenopausal women with a history of lactation. Thus, the role of lactation, specifically the biologic effect of lactation on breast cells, is unclear. The stronger effect of lactation as a protective factor at an early age suggests that decreased exposure to ovarian hormones at a younger age may be important. This theory is in keeping with the previous discussion concerning early age of menarche and the effect of ovarian hormones on developing breast parenchyma. Lactation is a behavior that can be altered; although the apparent effect of lactation is not great, any reduction in breast cancer incidence would be significant, especially in younger women.
Estrogen Replacement Therapy
Physicians should understand the rationale for estrogen replacement therapy, especially in terms of the prevention of cardiovascular disease and osteoporosis, and at the same time be aware of the lack of data to support the unequivocal recommendations for estrogen replacement therapy in patients treated for breast cancer.
There are a number of interesting observations that suggest a relationship between estrogen replacement therapy and breast cancer. It has been known for many years that oophorectomy before the age of 35 years reduces the risk of breast cancer by 70%. Patients with metastatic breast cancer treated with aminoglutethimide, an aromatase inhibitor, have a marked reduction in estradiol from 15-20 pg/mL to about 5 pg/mL because of the failure of conversion of hormones into estrogen. The level of estradiol is increased to 30-35 pg/mL with estrogen replacement therapy.
A number of clinical studies have reported that the risk of breast cancer is slightly elevated among users of estrogen replacement therapy. A meta-analysis concluded that women who had used estrogen in the past are not at an increased risk, but that current use may be associated with increased risk, although the relationship to breast cancer mortality was less clear.
There is no question that breast cancer is related to reproductive events. Increasing attention to the contemporary preventive approach to breast cancer focuses on the physiologic effects of the sex steroid hormones and their possible interaction with family history. Adding to the potential risks of estrogen replacement therapy is that current use of estrogen replacement therapy may be associated with lower specificity and lower sensitivity of screening mammography.
Successful treatment of breast cancer depends on local control, and there is always the potential for distant metastasis. If the patient is free of metastatic disease, the question is moot. Unfortunately, not all of the patients with breast cancer are cured even with the most effective treatment. The effect of estrogen replacement therapy on occult metastatic disease is the basis for the caution regarding the use of estrogen replacement therapy in these patients. The receptor data and other prognostic factors appear to be of little value, at the present time at least, in deciding for or against estrogen replacement therapy in these patients. Although the original tumor may be estrogen receptor negative, the subsequent metastases may be estrogen receptor positive. Finally, it is important to understand that if overt metastatic disease is discovered, treatment–how-ever aggressive–will be ineffective.
In considering estrogen replacement therapy, therefore, the physician should discuss benefits and the risks with the patient, including the uncertainty of the available data regarding risk. Vaginal administration of estrogen is not without concern. Estrogen is absorbed readily from the vaginal mucosa, especially if it is atrophic. There is decreased absorption with increasing vaginal cornification, but the absorption is perhaps sufficient to stimulate occult micrometastases.
Epidemiology
The risk factors currently identified for breast cancer do not present a significant potential for control, nor are they as distinct as risk factors for lung cancer and cervical cancer. Other malignancies are associated with breast cancer, and multiple primary tumors of the ovary and uterus may be involved. Patients with endometrial cancer should be carefully screened with annual mammography; similarly, patients with breast cancer should be carefully observed for abnormal uterine bleeding.
Primary care physicians should be aware of a patient’s chances of developing breast cancer and the impact of breast cancer on the general public. Breast cancer is the most common cancer. The chance of developing breast cancer by age 25 is approximately 1 in 20,000; by the age of 60, it is 1 in 24. Another way of impressing this concept is that, in the absence of any major risk factors such as breast cancer in first-degree relatives, the chance of getting breast cancer between ages 30 and 40 is 1 in 1,000; between ages 40 and 50, it is 2 in 1,000; and between ages 50 and 60, it is 3 in 1,000.
Family History
The family history is an important factor in assessing an individual’s risk of a heritable predisposition to breast cancer. One should attempt to distinguish women carrying mutations in breast cancer susceptibility genes, in whom the risk of disease is very high, from women in those same families who have not inherited a susceptibility gene. The possibility of paternal transmission in affected families should be considered. Genetic studies suggest that a significant portion of familial breast cancer may be due to one or more dominantly inherited predisposing genes (see “Genetics and Gynecologic Cancer”).
The diagnosis and treatment of breast cancer have changed dramatically during the past two decades. Screening programs did not exist 25 years ago. The preferred treatment was radical mastectomy, and adjuvant therapy did not exist. This is in marked contrast to the current situation of well-organized screening programs, effective adjuvant therapy, and alternative treatment.
The most recent figures from the National Cancer Institute reveal that after a sharp rise in the percentage of women diagnosed with breast cancer from 1980 to 1987, there has been a decline in incidence, especially among women 50 years of age and older. The lifetime risk for developing breast cancer is one in nine. This reflects an increase in life expectancy of American women and the fact that breast cancer is a disease of older women. In addition, the increase is the result of the decision to include in the calculation women older than 85 years of age.
The American Cancer Society predicted 180,200 new cases of breast cancer and 43,900 deaths for 2006, representing 31% of all new cases of cancer and 17% of cancer deaths. The mortality rate for breast cancer has been unchanged since 1930, increasing on an average of 0.2% per year from 1973 to 1990, but decreasing in women under age 65 years by an average of 0.3% per year. Recent data, however, indicate that breast cancer mortality has decreased in whites by almost 5% from 1989 to 1992, probably as a result of an increase in the diagnosis of localized cancer and the increased use of adjuvant therapy and screening mammography.
The most important risk factor for breast cancer is advancing age. In women older than age 45 years, breast cancer occurs more frequently in upper socioeconomic classes, and whites are affected more than African Americans. Identified risk factors, either alone or in combination, explain only 21% of the risk among women age 30-54 years and 29% of the risk among women age 5584 years. Thus, from a practical standpoint, 80% of the women with breast cancer have none of the currently identified risk factors, and the clinician should assume that all women are at risk, particularly those older than 35 years of age.
Early detection is associated with increased survival and more cosmetic local treatment. Women should undergo screening and routine surveillance at timely intervals to assess risks and aid in early diagnosis. It is recommended that screening mammography be offered routinely every 1-2 years to women age 40-49 and annually to women older than age 50. Women age 35 and older with premenopausally diagnosed breast cancer in a first-degree relative also should be offered mammography.
Resection Margins
Although the importance of obtaining negative margins is intuitively evident, earlier studies of patients undergoing breast-conserving surgery with radiation therapy were not able to demonstrate that margin status was statistically significant, probably because standardized methods for accurately assessing histologic margins did not exist until the late 1980s and early 1990s. More recent research clearly shows the effect of margin status on local recurrence. In a large retrospective review with a mean follow-up of 70 months, Silverstein stratified patients by margin width (>10 mm, 1 to 9 mm, < 1 mm) and found that even in the irradiated group, the recurrence rate increased from 4% for those with the largest margins to 29% for those with margins smaller than 1 mm. In patients with the widest margins, the addition of radiation therapy did not significantly improve local control, even in those tumors associated with comedonecrosis (7% versus 3%, P = not statistically significant).
Applying Relative Risk Reduction to Treatment Decisions
Formulating an individual treatment algorithm for patients with DCIS is a complex and challenging process. Patients are increasingly interested in participating in treatment decisions and should be encouraged to do so. The survival differences among treatment options are usually small, and the optimal treatment varies, depending on each patient’s risk profile and value system. Often patients seek second or third opinions, all of which may be different. This difference more often reflects the spectrum of thresholds for intervention among surgeons and oncologists rather than indicating “bad” recommendations. Often there is not a clear “best medical practice,” and treatment must be tailored for patient preference and risk management.
Risk Assessment
It is critical to put the risk of recurrence of DCIS into perspective for the patient and to distinguish between relative and absolute risk reduction. Furthermore, the risk of a recurrence of either invasive or intraductal disease must be distinguished from the risk of dying from a consequent invasive cancer. The difference in mortality among the therapeutic choices is likely to range from 0 to 2%, but the risk of recurrence may range from 1% to 30%. Further perspective can be gained by addressing the risk of developing breast cancer in the contralateral breast. It should be remembered that all women face a 5% to 8% lifetime risk of developing breast cancer, and that any woman with a history of breast cancer is at increased risk of developing a contralateral breast cancer. Therefore, the goal should not be to reduce the ipsilateral risk of breast cancer to 0 to 1%, because the woman has accepted a 5% to 10% risk of breast cancer by not opting for bilateral prophylactic mastectomy. The magnitude of difference between the treatment options largely depends on the estimate of the natural history of a particular DCIS. For example, a woman with a 2-mm low-grade DCIS with a wide margin of greater than 1 cm might be estimated by the Van Nuys criteria to have a 3% to 4% ipsilateral long-term recurrence risk. Although irradiation and tamoxifen may be added to her treatment, the absolute benefit of either intervention would be minimal and probably would not be recommended to the patient unless she was personally committed to reducing her risk of ipsilateral recurrence to 1% to 2% with irradiation, or her risk of contralateral breast cancer below 5% at 5 years with tamoxifen therapy. Treatment decisions must be driven by absolute risk; therefore, the understanding of natural history and outcome after lumpectomy is critical.
Other considerations to include in the decision-making process are the time frame for progression of disease and the age of the patient. If the grade of DCIS does indeed affect the time to progression, this may be an important consideration. A risk of recurrence in 15 to 20 years may lead to different choices than a risk of recurrence in 5 years, and this may be affected by whether the woman is 40 or 70 years old. Finally, patients should always be informed about options to participate in clinical trials; this is especially important in a disease such as DCIS in which so many questions remain unanswered (Table 1).
Temporal Considerations
Time is an important variable in the management of DCIS, in which the window for progression of disease probably spans years rather than months.
The Biology of DCIS and the Future
Ductal carcinoma in situ is molecularly indistinguishable from invasive carcinoma, whether one looks at gains and losses over the entire set of chromosomes (CGH), evaluates more specific base pair abnormalities (LOH), or studies particular molecular markers. No patterns have yet been identified that are specific only to DCIS and not to invasive cancer, so from a purely genetic point of view, the transformation to malignancy has already occurred. Ductal carcinoma in situ and invasive cancer are, however, clearly different morphologically from normal cells and also from each other, and the mechanisms responsible for this phenotypic change are the subject of intense research.
Molecular analysis may yield clues for evaluating the extent of tissue at risk for progression to invasive disease, thereby leading to improved surgical intervention. One particular abnormality, LOH at 3p, is accompanied by consistent loss of genetic material from the short arm of chromosome 3. In a careful analysis of specimens from mastectomies performed for DCIS, Smith found that a wide region around the DCIS had evidence of 3p LOH, but the quadrants distant from the DCIS did not. The areas of 3p LOH extended beyond the area of abnormal pathology detected by light microscopy, suggesting that an entire region or ductal system may be affected. If the distribution of the cells demonstrating LOH could be marked preoperatively, it might be possible to resect the entire affected duct system more completely, possibly obviating the need for adjuvant irradiation following surgical excision.
The pattern of angiogenesis may also provide insight into how the biology of DCIS and invasive cancer differ. In DCIS, most increased angiogenesis is found periductally or within the stroma, but never within the malignant areas themselves. The ability to characterize angiogenic patterns on MR imaging may further the understanding of whether these patterns can change. Areas of increased angiogenesis may provide targets for therapy in the near future. By MR imaging, the most common denominator is the failure, in most cases, to see homogeneous uptake as a mass. Because the imaging techniques reflect patterns of intravenous contrast uptake and washout, the authors have investigated the pattern of CD34 staining in DCIS. The authors and others have noted a pattern of perivascular cuffing around the DCIS (both on hematoxylin and eosin stains and on CD34 staining) rather than a pattern of scattered blood vessels throughout the tumor. Further development of these imaging techniques to monitor treatment effects in vivo may make it possible to establish new surrogate end-points that will facilitate clinical testing of new treatments of DCIS and give further insight into the biology of intraductal cancers.
Vaccines
New and innovative treatment strategies are clearly needed to improve outcomes in breast cancer; too frequently, this disease still recurs or progresses despite aggressive multimodality therapy. Indeed, DCIS offers the best chance for truly preventive interventions, such as vaccine strategies, because the burden of disease is low and the patient’s immunocompetence is high. The authors’ data have shown that 50% of all DCIS tumors demonstrate HER-2/ neu over expression, including 85% to 100% of high-grade DCIS, which are the tumors most likely to progress to invasive cancer. Thus, an anti-HER-2 vaccine would be ideally suited to the treatment of DCIS.
Ductal carcinoma in situ offers a unique biological and clinical opportunity for the introduction of novel therapies such as vaccine strategies. Biologically, DCIS represents an early stage in tumor development that is not uniformly destined to progress, suggesting that tumor/host interactions and immune mechanisms may be important in determining the course of these tumors. It has become clear in other systems that the efficacy of immunotherapies, and particularly of vaccine strategies, can be severely limited by the bulkiness of solid tumors, by the emergence of resistant clones, by tumor-associated immunosuppressive effects, and by other factors associated with advanced cancer. The low tumor burden in most patients with DCIS greatly increases the chances that a vaccine strategy may be effective. A vaccine for DCIS that might possibly be used to treat existing cancer and to prevent its recurrence is a promising and exciting avenue of research.
Where Do We Go from Here?
Currently, no precise morphologic or biological prognostic factors reliably identify patients with DCIS who are at high risk of disease progression. Improved understanding of molecular and cellular characteristics of DCIS may help predict outcome. Although correlative studies have focused on protein and genetic markers of DCIS, the small number of cases in most series, the scant amount of tissue available for study, and the long follow-up time needed for analysis have hampered the ability to find clear associations.
With the molecular tools available today, DCIS lesions appear to be indistinguishable from invasive cancer. There are variable levels of ploidy, p53 abnormalities, HER-2/ neu over expression, and LOH and CGH changes in both. The nuclear grade of cells is more likely to predict their molecular characteristics, rather than their characterization as DCIS or invasive disease by light microscopy. Advanced MR imaging of DCIS confirms molecular studies showing that, like invasive breast cancer lesions, DCIS is heterogeneous. The similarities between DCIS and invasive cancer suggest that an important area for future research should be elucidating the processes that can either unleash or contain the invasive potential of DCIS cells. An understanding of the biology of DCIS can assist in the prevention, the assessment, and the treatment of invasive breast cancer.
Patients with DCIS should be reassured that their decisions can be made only with the facts at hand, and that future changes in disease management will not devalue the choices made at the time of their treatment. It is hoped that new knowledge will improve these options in the future and decrease recurrence rates. Physicians and patients should be encouraged to participate in trials and to support further studies to deepen the understanding of this challenging problem and to improve future management.