Mahmoud El-Tamer

Medicinal Plants and Cancer Chemoprevention

Cancer is the second leading cause of death worldwide. Although great advancements have been made in the treatment and control of cancer progression, significant deficiencies and room for improvement remain. A number of undesired side effects sometimes occur during chemotherapy. Natural therapies, such as the use of plant-derived products in cancer treatment, may reduce adverse side effects. Currently, a few plant products are being used to treat cancer. However, a myriad of many plant products exist that have shown very promising anti-cancer properties in vitro, but have yet to be evaluated in humans. Further study is required to determine the efficacy of these plant products in treating cancers in humans. This review will focus on the various plant-derived chemical compounds that have, in recent years, shown promise as anticancer agents and will outline their potential mechanism of action.

Open and Laparoscopic Adrenalectomy: Analysis of the National Surgical Quality Improvement Program

BACKGROUNDnNumerous series demonstrate the benefits of laparoscopic versus open adrenalectomy, but fail to adjust for confounding factors. This study uses the Veterans Affairs National Surgical Quality Improvement Program database to compare these two approaches, adjusting for baseline differences.nnnSTUDY DESIGNnLaparoscopic (n=358) and open (n=311) adrenalectomy data were collected at 123 Department of Veterans Affairs and 14 university hospitals from October 1, 2001 to September 30, 2004. Preoperative characteristics, operative data, and 30-day outcomes were compared using the chi-square or Fishers exact test for categorical variables and the t-test for continuous variables. Unadjusted odds ratio (OR) and 95% confidence interval (CI) were computed for the effect of operative approach on postoperative morbidity. Adjusted odds ratios and 95% CI were computed for this same effect, adjusting for variables that were predictive of outcomes or imbalanced at baseline. Data are reported as means +/-SD, unless otherwise indicated.nnnRESULTSnPatients undergoing open adrenalectomy were more likely to be older (57.8+/-11.9 years versus 53.5+/-13.2 years, p < 0.0001), harbor malignancy (44.5% versus 13.5%, p < 0.0001), have higher American Society of Anesthesiologists classifications (p=0.0037), smoke (35.4% versus 22.6%, p=0.0003), and have lower serum albumin levels (3.9+/-0.5 g/dL versus 4.0+/-0.5 g/dL, p=0.0241). Open procedures had increased operative times (3.9+/-1.8 hours versus 2.9+/-1.3 hours, p < 0.0001), transfusion requirements (0.7+/-1.8 U versus 0.1+/-0.5 U, p<0.0001), reoperations (4.8% versus 1.4%, p=0.0094), length of stay (9.4+/-11.0 days versus 4.1+/-4.7 days, p < 0.0001) and 30-day morbidity rates (17.4% versus 3.6%, p < 0.0001) with unadjusted and adjusted odds ratio (95% CI) of 5.52 (2.94, 10.33), and 3.97 (1.92, 8.22), respectively. Open procedures resulted in more pneumonia, unplanned intubation, unsuccessful ventilator wean, systemic sepsis, cardiac arrest, renal insufficiency, and wound infections.nnnCONCLUSIONSnEven after adjustment for confounding factors, 30-day morbidity was much higher for patients having open adrenalectomy.

The Management of Lobular Neoplasia Identified on Percutaneous Core Breast Biopsy

Abstract: The management of lobular neoplasia (LN) found on percutaneous core biopsy remains a clinical dilemma. The purpose of this study was to establish guidelines for the management of LN when obtained on percutaneous core needle biopsy. A retrospective review of the Breast Imaging Tissue Sampling Database at New York Presbyterian Hospital–Columbia Comprehensive Breast Center was performed from 1998 to 2000. A total of 1460 percutaneous core breast biopsies were performed using 11‐ or 14‐gauge needles with LN identified in 43 biopsies from 34 patients. Eleven biopsies were ultrasound guided for nonpalpable masses and 32 were stereotactically guided for mammographically detected densities (10) and microcalcifications (22). The 43 LN biopsies were divided into three groups based on additional findings associated with LN on core biopsy: group I (n = 19), LN with invasive cancer or ductal carcinoma in situ (DCIS); group II (n = 11), LN plus a second indication for open surgical biopsy, such as atypical ductal hyperplasia (ADH), radial scar, phyllodes tumor, or intraductal papilloma; and group III (n = 13), LN plus benign fibrocystic changes. In group I, 19 of 19 biopsies (100%) yielded invasive cancer or DCIS on surgical biopsy versus 3 of 11 (27%) for group II, and 1 of 13 (8%) for group III. Outcomes in group III are described as follows: three patients were lost to follow‐up, three patients did not undergo surgical biopsy but demonstrated more than 1 year of mammographic stability following core biopsy. Of the remaining seven patients, two had LN and ADH on surgical biopsy (one had a contralateral cancer), one had atypical lobular hyperplasia (with a contralateral cancer), two had LN and benign fibrocystic changes, one had LN and intraductal papilloma, and one had LN and invasive ductal carcinoma (IDC) with DCIS (with a contralateral cancer). These results suggest that surgical biopsy is indicated for patients with LN when found on core biopsy and when the biopsy demonstrates invasive cancer, DCIS, or other indications for surgical biopsy such as ADH, or in the examination of a patient with a synchronous contralateral breast cancer. The diagnosis of LN alone without these indications on percutaneous biopsy may not warrant routine surgical biopsy.u2002

Estrogen-induced breast cancer: Alterations in breast morphology and oxidative stress as a function of estrogen exposure

Epidemiological evidence indicates that prolonged lifetime exposure to estrogen is associated with elevated breast cancer risk in women. Oxidative stress and estrogen receptor-associated proliferative changes are suggested to play important roles in estrogen-induced breast carcinogenesis. In the present study, we investigated changes in breast morphology and oxidative stress following estrogen exposure. Female ACI rats were treated with 17beta-estradiol (E(2), 3 mg, s.c.) for either 7, 15, 120 or 240 days. Animals were euthanized, tissues were excised, and portions of the tissues were either fixed in 10% buffered formalin or snap-frozen in liquid nitrogen. Paraffin-embedded tissues were examined for histopathologic changes. Proliferative changes appeared in the breast after 7 days of E(2) exposure. Atypical ductal proliferation and significant reduction in stromal fat were observed following 120 days of E(2) exposure. Both in situ and invasive carcinomas were observed in the majority of the mammary glands from rats treated with E(2) for 240 days. Palpable breast tumors were observed in 82% of E(2)-treated rats after 228 days, with the first palpable tumor appearing after 128 days. No morphological changes were observed in the livers, kidneys, lungs or brains of rats treated with E(2) for 240 days compared to controls. Furthermore, 8-isoprostane (8-isoPGF(2alpha)) levels as well as the activities of antioxidant enzymes, such as glutathione peroxidase, superoxide dismutase and catalase, were quantified in the breast tissues of rats treated with E(2) for 7, 15, 120 and 240 days and compared to activity levels in age-matched controls. 8-isoPGF(2alpha) levels displayed time-dependent increases upon E(2) treatment and were significantly higher than control levels at the 15, 120 and 240 day time-points. 8-isoPGF(2alpha) observed in E(2)-induced mammary tumors were significantly higher than levels found in control mammary tissue from age-matched animals. Similarly, alterations in glutathione peroxidase and superoxide dismutase activities were detected in both mammary and tumor tissue from E(2)-treated rats. Taken together, our data reveal that proliferative changes in the breast tissue of ACI rats are associated with increases in 8-isoPGF(2alpha) formation as well as changes in the activities of antioxidant enzymes. These oxidative changes appear to be a function of E(2) exposure and occur prior to tumor development.

Aggressive presentation of breast implant-associated ALK-1 negative anaplastic large cell lymphoma with bilateral axillary lymph node involvement

We recently encountered a unique case of breast silicone implant-associated ALK-1 negative anaplastic large cell lymphoma (ALCL) in a female with a remote history of breast carcinoma, which presented as a sinusoidal infiltrate in an axillary lymph node (LN) and had a highly complex karyotype. A 68-year-old female had undergone right breast lumpectomy followed by right modified radical mastectomy with axillary LN dissection in 1991 for infiltrating moderately differentiated ductal carcinoma. No lymphovascular invasion or LN involvement was identified. She received six cycles of chemotherapy and 5 years of tamoxifen. In January of 1992, the patient underwent right breast reconstruction with a silicone implant. Sixteen years later the patient developed right axillary lymphadenopathy. Her past medical history was significant only for the prior breast carcinoma and biliary cirrhosis. She had no history of non-Hodgkin or Hodgkin lymphoma. Right axillary LN biopsy showed a large cell neoplasm infiltrating and expanding the sinuses (Figure1A). An exhaustive staining panel led to the diagnosis of an ALK-1 negative ALCL (Figure1B). A staging bone marrow biopsy showed no evidence of lymphoma. A subsequent FDG-PET/CT scan showed a hypermetabolic focus (maximum SUV 7.4) posterior to the breast implant. The grossly intact implant was removed with capsulectomy. Histologic review of the fibrotic capsular tissue showed an infiltrate of large neoplastic cells as seen previously (Figure 2A), which had the following phenotype (Figure 2B): CD457/þ, CD30þ, CD15þ, EMAþ, MUM1þ, CD2þ and CD4þ. These cells did not express CD3, CD5, CD7, CD8, ALK-1, CD56, CD20, PAX5, CD79a, OCT2, CD138, p53, or cytotoxic T-cell granule constituents (TIA-1, granzyme-B and perforin). In situ hybridisation for EBV mRNA was negative. The proliferation rate, as assessed with a stain for Ki-67, was 490%. Cytogenetic analysis revealed highly complex clonal chromosome abnormalities, penta-ploidy range metaphases and homogenously staining regions (hsr’s): 116–123,55N4,XX,71, add(1)(p36.3),i(1)(q10),hsr(1)(q21q25),þ2,þ362, þ6,hsr(7)(q32q35)62,i(8)(q10),þ9,þ10, inv(11) (p15.1q22.1)63,add(12)(q24.1),713,714,715,i (17)(q10),þ19,720,þ1*8mar[cp13]/46,XX,inv(11) (p15.1q22.1)[7]. FISH analysis using T-cell receptor alpha/delta break-apart, ALK break-apart and D7S486/CEP7 probes showed no evidence of rearrangement or deletion. PCR analysis showed clonal T-cell receptor beta gene rearrangement. Four months after initial diagnosis, the patient developed left-sided (contralateral) axillary lymphadenopathy, and a LN biopsy again disclosed sinusoidal infiltrates of ALCL. After completion of six

Incidence and Clinical Significance of Lymph Node Metastasis Detected by Cytokeratin Immunohistochemical Staining in Ductal Carcinoma In Situ

BackgroundThis study explored the long-term prognosis of patients with ductal carcinoma-in-situ (DCIS) and lymph node metastasis detected by cytokeratin immunohistochemical stains (CK-IHC).MethodsUsing the Columbia University breast cancer database, we identified all DCIS patients who had eight or more axillary nodes dissected and free of metastasis. Five-micrometer sections from all paraffin blocks containing lymph node tissue were stained with an anticytokeratin antibody cocktail (AE1/AE3 and KL1). The results of the CK-IHC and updated database were anonymized and merged. Survival of CK-IHC–positive and –negative patients was compared by using Kaplan-Meier curves and log-rank tests.ResultsCK-IHC was performed on 301 DCIS patients, who had an average of 16.7 axillary nodes dissected. Eighteen (6%) of 301 patients tested positive by CK-IHC. Seventy patients with bilateral breast cancer and 2 patients without any follow-up data were excluded, for a final study population of 229 patients. Among the 216 patients with negative CK-IHC, 18 patients died, compared with 1 of 13 patients with positive CK-IHC. The median follow-up for the study group was 127 months. Kaplan-Meier overall and breast cancer–specific survival estimates were similar for CK-IHC–positive and –negative patients (P = .81 and P = .73, respectively).ConclusionsCK-IHC increases the incidence of positive nodes by 6% in DCIS patients. A positive node by CK-IHC does not seem to affect survival in these patients. These results raise concerns regarding the clinical significance of positive nodes by CK-IHC in DCIS patients.

Resection and Debridement of Chest-Wall Tumors and General Aspects of Reconstruction

The main criterion for adequate local control of a chest-wall malignancy remains wide excision. With the available techniques of skeletal and soft-tissue reconstruction, even large lesions can be resected with safe margins. The primary purpose is to achieve a curative resection, although a significant number of symptomatic patients can benefit from palliative resection provided by such procedures. A key element in the success in treating chest-wall tumors is a multidisciplinary approach by all participating physicians, namely the thoracic surgeon, the plastic and reconstructive surgeon, the radiotherapist, and the medical oncologist.

A New Agent, Blue and Radioactive, for Sentinel Node Detection

Background: Although with some disadvantages, combining radiotracer and isosulfan blue facilitates the detection of sentinel lymph nodes. This study was designed to evaluate the use of 99mTc-labeled phthalocyanine tetrasulfonate (99mTc-PCTS) as a single agent for simultaneous blue staining and radiotracer localization of the sentinel lymph node.Methods: Twelve rabbits were injected into the dermis and subcutaneously in the distal hind limb with 1 mL of blue 99mTc-PCTS (.5 mCi). The popliteal and inguinal fossae were explored between 15 minutes and 24 hours after injection for blue and/or radioactive tissue. Popliteal and inguinal fossae and other lymph nodes and organs were harvested for determination of the concentration of radioactivity and for histology.Results: Within minutes of 99mTc-PCTS injection, the lymphatic channels were easily identified by the blue color. At 10 minutes, the radioactive count over the popliteal fossa was significantly higher than over other areas. At exploration, a blue and radioactive popliteal node was identified in all animals; inguinal nodes were neither blue nor radioactive. At death, the radioactivity in the popliteal node was 1000 times higher than in other nodes or organs. Although fainter, the blue color in the popliteal node was still visible at 6 weeks. Histological sections of popliteal node identified the dye in the cytoplasmic compartment of the cells.Conclusions: Technetium-99m PCTS is a single agent that identifies sentinel lymph nodes by color and radioactivity and is retained for an extended period of time without migrating to other tissues.

Why should the first be last? “seasonal” variations in the National Board of Medical Examiners (NBME) Subject Examination Program for medical students in surgery

We recently noticed that many of the students whom past experience had proved good performers did not do as well on the early (July) NBME Surgery examination as expected. Moreover, students with weaker records did better than expected in the later (April) tests. Because the raw scores of the NBME examinations are important for students’ course grades and residency placement, we decided to quantitatively analyze the observed trend to determine if some correction of “seasonal” scores might be necessary. If the raw surgical subject scores vary seasonally, the ability to accurately compare students taking the examination at different rotations is undercut. Medical students are educated and evaluated in a wide variety of styles and settings. Recognizing this, medical schools have increasingly relied on more objective, standardized criteria to aid in the grading and ranking of medical students upon the completion of surgical clerkships. To this end, the NBME has prepared and offers a subject examination (sometimes called a “shelf” examination) for use by medical schools to aid in the evaluation of medical students. Some schools require threshold scores on the NBME subject examination in order for students to pass their given clerkships. Subject examination scores are variably used as a major component in the determination of final student grade in the surgery clerkship. In many schools, the raw scores on the NBME subject examination serve as a prerequisite for achieving clerkship honors. Clerkship honors, in turn, are required by many of the “better” residency programs for consideration for an interview and possible appointment. Thus, the NBME subject examination can play a substantial role in evaluation of surgical clinical clerks and potential residents. Although no comprehensive study has been done on this topic, Ripkey et al have mentioned that medical students sitting for subject examinations in Medicine and Surgery later in the examination season tended to have higher scores relative to their peers who were tested earlier in the examination season. The NBME already acknowledges “seasonal” variations for the subject examination in Medicine. The NBME states in its Spring 2001 Subject Examination Newsletter that, “it is common knowledge that scores in certain clinical exams are progressively higher for students of equivalent ability who take the relevant rotation later in the academic year. This is particularly true for Medicine, where the nature of the subject enables substantive contributions to the score from knowledge accumulated over a variety of rotations. Beginning July 2001, national norms will be provided each quarter as well as the entire year.” The NBME, however, does not account for “seasonal” variations in any of its other subject examinations, such as Surgery, where we thought the greatest degree of “seasonal” variation existed. Our study considers the need for a reexamination of the method by which the raw scores of the Surgery subject examination are interpreted by the NBME and program directors.

Surgical options as quality of care indicators in breast cancer

Breast conservation (BCT) was accepted as a surgical option after rigorous evaluation in six international prospective randomized trials. The 1991 NIH consensus conference on the treatment of early breast cancer concluded: ‘‘Breast conservation treatment is an appropriate method of primary therapy for the majority of women with stage I and II breast cancer and is preferable because it provides survival rates equivalent to those of total mastectomy and axillary dissection while preserving the breast.’’ Two of six international trials reported their 20-year follow up confirming equal long-term survival and local control with mastectomy (MAST) or BCT [1,2]. The incidence of ipsilateral new primaries however was higher in the breast conservation arm. Unfortunately, none of the six international trials had included any quality of life (QOL) measures when comparing MAST to BCT. In this issue, Pockaj and colleagues extensively review the medical literature to identify QOL outcomes and the factors that influence these outcomes in women undergoing various breast cancer surgical procedures. The authors appropriately define the limitations or shortcomings of research on QOL after breast cancer Surgery; these shortcomings include the difference of tools and instruments across studies, the sensitivity of these tools across phases of care, the power of the studies to detect changes, the lack of comorbidity data, and the measures to account for base line status. Clearly, the diagnosis and treatment of cancer in general and particularly of breast cancer affects QOL in many ways. Chemotherapy and hormonal treatment have a major short-term impact on the quality of life of women such as nausea, vomiting, fatigue, loss of hair and weight gain etc. Adjuvant therapy also carries a long-term impact on QOL such as early menopause or worsening of menopausal symptoms that will have a direct impact on sexuality. It would be naı̈ve to expect that a difference in surgical procedure would alleviate the side effects of adjuvant therapy or improve the general aspect of QOL including the fear of death from cancer. Pockaj and colleagues’ review of the literature did not demonstrate a better overall QOL with BCT when compared to MAST, an expected observation! As an organ however, the breast is a gender identifier and its loss may have a significant impact on the feminine body image and the feeling of wholeness. Hence, the main QOL impact of preserving the breast after breast cancer surgery would be to improve body image (attractiveness, appearance, feeling of wholeness, cosmetic result), and perhaps alleviate the insecurities in intimate relations. Pockaj and colleagues’ review did confirm the expected improvement in body image in patients who underwent BCT when compared to MAST. In the first reported meta-analysis in Pockaj’s review, Moyer did find that patients who underwent BCT had an improved psychological, marital-sexual and social adjustment, as well as superior body image or self-image when compared to those who underwent MAST. In the second meta-analysis listed in Pockaj’s paper, four out five studies that focused on surgical outcomes identified an improved body image in the BCT group. In the more recent surgical QOL studies, the trial by Engel et al. from Germany Pockaj and colleagues summed up the results by stating ‘‘MAST patients scored consistently worse in variables associated with body image (attractiveness, appearance feeling whole, cosmetic result, scar and insecurity)’’. In another large prospective randomized trial by Ganz et al. that was referenced by Pockaj, patients who had MAST had a worse physical functioning than patients with BCT. Again, Pockaj summarized a well-designed study of 152 matched BCT and MAST group conducted by Janni et al. by stating: ‘‘Women in the MAST group were less satisfied with their cosmetic result and more likely to feel that their physical appearance had critically changed, more likely to feel emotional stress in personal interactions thought to be caused by the type of surgical treatment, and more likely to choose a different surgical treatment if they could do it over again.’’ Pockaj also reviewed the largest recent study by Roland and stated: ‘‘Women who underwent BCT had overall better body selfimage than did women who underwent MAST or Mastectomy with reconstruction (MþR). Women who underwent MAST or MþR reported that the surgery had a negative impact on their sexuality, with women who underwent MþR reporting the most impact. Women who underwent MAST with or without reconstruction experienced more physical symptoms and discomfort around the surgical site than did women who underwent BCT.’’ As in many solid tumors, when facing breast cancer, patients and surgeons are focused on three issues: survival, local control and quality of life. BCT achieves similar survival, equal local control of the primary, and an improvement in body image and insecurities in intimate relations. Furthermore, BCT carries a lower complications rate and a shorter operative time [3] than MAST. As the Medical community is defining quality of care measures in breast cancer surgery, it is very obvious that the rate of BCT ought to be one of the major quality indicators. Breast reconstruction however, is an issue of debate. It would be intuitive that patients who undergo reconstruction after MAST would have a better body image than those who do not. But this assumption, as stated in Pockaj’s review, has not been established yet from the