Metabolism of low-density lipoproteins by cultured hepatocytes from normal and homozygous familial hypercholesterolemic subjects.

The profoundly elevated concentrations of low-density lipoproteins (LDL) present in homozygous familial hypercholesterolemia lead to symptomatic cardiovascular disease and death by early adulthood. Studies conducted in nonhepatic tissues demonstrated defective cellular recognition and metabolism of LDL in these patients. Since mammalian liver removes at least half of the LDL in the circulation, the metabolism of LDL by cultured hepatocytes isolated from familial hypercholesterolemic homozygotes was compared to hepatocytes from normal individuals. Fibroblast studies demonstrated that the familial hypercholesterolemic subjects studied were LDL receptor-negative (less than 1% normal receptor activity) and LDL receptor-defective (18% normal receptor activity). Cholesterol-depleted hepatocytes from normal subjects bound and internalized 125I-labeled LDL (Bmax = 2.2 micrograms LDL/mg cell protein). Preincubation of normal hepatocytes with 200 micrograms/ml LDL reduced binding and internalization by approx. 40%. In contrast, 125I-labeled LDL binding and internalization by receptor-negative familial hypercholesterolemic hepatocytes was unaffected by cholesterol loading and considerably lower than normal. This residual LDL uptake could not be ascribed to fluid phase endocytosis as determined by [14C]sucrose uptake. The residual LDL binding by familial hypercholesterolemia hepatocytes led to a small increase in hepatocyte cholesterol content which was relatively ineffective in reducing hepatocyte 3-hydroxy-3-methylglutaryl-CoA reductase activity. Receptor-defective familial hypercholesterolemia hepatocytes retained some degree of regulatable 125I-labeled LDL uptake, but LDL uptake did not lead to normal hepatocyte cholesterol content or 3-hydroxy-3-methylglutaryl-CoA reductase activity. These combined results indicate that the LDL receptor abnormality present in familial hypercholesterolemia fibroblasts reflects deranged hepatocyte LDL recognition and metabolism. In addition, a low-affinity, nonsaturable uptake process for LDL is present in human liver which does not efficiently modulate hepatocyte cholesterol content or synthesis.

Postmastectomy radiotherapy: clinical practice guidelines of the American Society of Clinical Oncology.

OBJECTIVE: To determine indications for the use of postmastectomy radiotherapy (PMRT) for patients with invasive breast cancer with involved axillary lymph nodes or locally advanced disease who receive systemic therapy. These guidelines are intended for use in the care of patients outside of clinical trials. POTENTIAL INTERVENTION: The benefits and risks of PMRT in such patients, as well as subgroups of these patients, were considered. The details of the PMRT technique were also evaluated. OUTCOMES: The outcomes considered included freedom from local-regional recurrence, survival (disease-free and overall), and long-term toxicity. EVIDENCE: An expert multidisciplinary panel reviewed pertinent information from the published literature through July 2000; certain investigators were contacted for more recent and, in some cases, unpublished information. A computerized search was performed of MEDLINE data; directed searches based on the bibliographies of primary articles were also performed. VALUES: Levels of evidence and guideline grades were assigned by the Panel using standard criteria. A "recommendation" was made when level I or II evidence was available and there was consensus as to its meaning. A "suggestion" was made based on level III, IV, or V evidence and there was consensus as to its meaning. Areas of clinical importance were pointed out where guidelines could not be formulated due to insufficient evidence or lack of consensus. RECOMMENDATIONS: The recommendations, suggestions, and expert opinions of the Panel are described in this article. VALIDATION: Seven outside reviewers, the American Society of Clinical Oncology (ASCO) Health Services Research Committee members, and the ASCO Board of Directors reviewed this document.

Pathologic findings in nonpalpable invasive breast cancer.

Previous studies have shown that patients with nonpalpable invasive breast cancer have a favorable prognosis. These studies, however, have not analyzed pathologic features of mammographically detected tumors according to tumor size. We describe the histopathologic features of 77 nonpalpable invasive breast cancers, comparing neoplasms less than or equal to 1 cm with larger clinically occult tumors. Forty-seven lesions (61%) were less than or equal to 1 cm (group A) and 30 (39%) were greater than 1 cm (group B). In group A, there were 30 infiltrating ductal carcinomas (IDC); seven infiltrating lobular carcinomas (ILC); and two cases each of mixed ILC and IDC, mixed tubular carcinoma and ILC, and infiltrating cribriform carcinoma. There was one case each of mucinous carcinoma, apocrine carcinoma, tubular carcinoma, and mixed mucinous and IDC. In group B, there were 23 (77%) IDC, five (17%) ILC, and two mixed IDC and ILC. Tumors in group B were more frequently grade 3 (22% versus 7%), but this was not statistically significant (p = 0.21). There were no important differences in the frequency, subtypes and location of carcinoma in situ, or other histopathologic parameters evaluated in the biopsy specimens. Mastectomy specimens with axillary lymph node dissections were available for review in 64 cases (83%). Group B patients had a higher rate of residual invasive carcinoma (31% versus 13%) and lymph node metastases (31% versus 16%), but these differences were not statistically significant. Residual carcinoma in situ was more frequent in group B (54%) compared with group A (26%) (p = .036). Of seven group B cases with negative biopsy margins, residual invasive carcinoma was present in five (71%). We conclude that small nonpalpable invasive breast cancers differ from larger nonpalpable tumors primarily in size. The finding of negative biopsy margins should not be construed as conclusive evidence for the absence of residual infiltrating disease.

Apolipoprotein B synthesis in humans: liver synthesizes only apolipoprotein B-100.

Apolipoprotein (apo) B-100 and B-48 are prominent apolipoproteins in VLDL, IDL, and chylomicrons. Organ cultures of normal adult human liver were established to ascertain the form of apo B synthesized by hepatocytes in humans. Human liver was minced and incubated in 15 mL methionine-free RPMI-1640 medium with 10% dialyzed fetal calf serum plus 250 microCi 35S-methionine for eight hours at 37 degrees C. Lipoproteins secreted by the liver were isolated by ultracentrifugation and the content of newly synthesized apo B determined by quantitation of radioactivity in the apoB-100 and apoB-48 bands after separation by 3% NaDodSO4 gel electrophoresis. In the eight-hour period, 2.5% to 3.2% of added 35S-methionine was secreted in TCA-precipitable protein of which 0.34% was apo B. Ninety-nine percent of the apo B in VLDL, IDL, and LDL was in the apo B-100 electrophoretic band. No significant radioactivity was detected in the apo B-48 electrophoretic band. Eighty-nine percent of the total radioactivity of apo B-100 was in VLDL with 3% and 8% in IDL and LDL, respectively. These results establish that adult human liver in organ culture synthesizes apo B-100 but not apo B-48.

Paget's disease of the breast: a 33-year experience.

BACKGROUND: Paget's disease (PD) of the breast is an uncommon condition traditionally treated with mastectomy. To assess the natural history and treatment options in PD we have reviewed the experience at the Roswell Park Cancer Institute (RPCI). STUDY DESIGN: The medical records of patients treated for PD at RPCI between 1963 and 1996 were reviewed. RESULTS: Eighty patients were treated in the period reviewed. The median follow up was 61 months. Sixty-eight of 80 patients had nipple changes consistent with PD including 30 who had an associated breast mass (group 1), and 38 who had no associated mass (group 2). Of the 68 patients with clinical PD, 58 (85%) were treated with mastectomy while the remainder were treated with some form of breast conserving therapy. Breast cancer (BC) was found in 56 of 68 patients (82%) with clinical PD, including 28 of 30 patients (93%) in group 1 and 28 of 38 patients (74%) in group 2. Breast cancer was centrally located (within 2 cm of the areolar margin) in 61% of patients, including 71% in group 1 and 50% in group 2. Of the 28 patients with an associated BC in group 1, 21 (75%) had invasive cancer, 6 (21%) had ductal carcinoma in situ (DCIS), and 16 (57%) had pathologic axillary nodes. Of the 28 patients with an associated BC in group 2, 10 (36%) had invasive cancer, 18 (64%) had DCIS, and 6 (21%) had positive axillary nodes. The median survival was significantly shorter for group 1 (42 months) than for group 2 (126 months; p = 0.007). CONCLUSION: Most patients with PD have an associated BC (82%) that was centrally located (61%). In those patients without an associated mass, a significant number (26% in this series) may not have an underlying BC and may be overtreated with mastectomy. On the other hand, a significant number of patients with PD and no associated breast mass will be found to have a peripherally located tumor (29% in this series). These non-central BC masses could potentially be missed by a wide local excision that includes the areolar complex.

The evaluation of palpable breast masses: common pitfalls and management guidelines.

The management of a palpable breast mass starts with identification of the lesion and a suspicion of malignancy. While seemingly simple, the initial evaluation can significantly impact upon treatment options and outcomes. The management of two patients recently referred to this Institution highlights common pitfalls and technical considerations in the diagnosis and treatment of palpable breast masses. The case histories of two patients referred after open breast biopsy were examined. The English language medical literature was searched manually and by Medline for publications related to the evaluation of palpable breast masses. Imaging, diagnostic techniques and technical considerations in the management of palpable lesions were reviewed. The initial use of carefully selected diagnostic and therapeutic measures is critical in optimizing outcomes measured in improved quality of life and survival. Inappropriate choices at this first stage can have extremely negative consequences. The early evaluation of two patients highlighted these considerations. Management pitfalls included serial examination of a suspicious lesion, failure to obtain a mammogram prior to excisional biopsy and unnecessary testing. Technical problems included piecemeal excision of the tumor with positive margins, use of a drain, closure of deep tissues with dimpling of the breast, and incision placement in a location that subsequently necessitated mastectomy. Careful adherence to the clinical and operative principles of breast cancer management optimizes outcomes in the evaluation of palpable breast masses.

Incorporation of laparoscopy into a surgical endoscopy training program.

The impact of introducing laparoscopy as part of the overall gastrointestinal endoscopy case load performed by residents was reviewed. During 1990, there was a significant increase (56.9%) in the number of flexible diagnostic endoscopic procedures performed compared with 1989. When the total number of laparoscopic procedures was considered, the increase was 117%. Residents participated in the "surgeon's" position in 59% of the therapeutic laparoscopic procedures and as either surgeon or "first assistant" in 86% of all therapeutic laparoscopic procedures and 94% of all diagnostic laparoscopic procedures. Complication rates for diagnostic laparoscopic procedures were low in 1989 (0.03%) and 1990 (0.2%). Complication rates for therapeutic laparoscopic procedures were also low (4%). There was no difference in the complication rate for cases in which residents were in the surgeon's position (4%) versus cases in which they were not (4%). Introduction of laparoscopic procedures into a surgical residency program can be done safely, especially in cases in which an established program in endoscopy exists.

Laparoscopic versus traditional appendectomy for suspected appendicitis.

We compared the results of concurrently performed laparoscopic versus open appendectomy as treatments for suspected acute appendicitis. The 68 laparoscopic procedures resulted in 62 appendectomies, 47 by the laparoscopic (LA) technique and 15 by the open (LO) technique. Another 54 patients underwent open appendectomy (OA). Significantly more females underwent laparoscopy (LA and LO: 52% versus OA: 33%, p = 0.047). Operative duration was shortest for OA (81 +/- 3 minutes), which was shorter than for LO (108 +/- 7 minutes), but not different than LA (86 +/- 6 minutes). The postoperative length of stay was not different for LA (3.5 +/- 0.5 days) compared with OA (5.9 +/- 1.6 days) or LO (4.8 +/- 1.3 days). One death occurred in the OA group. Wound complication rates were not significantly different for LA (4.3%) compared with OA (9.4%) and LO (13.3%). Overall complication rates were lower for LA (10.6%) and OA (18.9%) compared with LO (46.7%, p < 0.01). Median hospital cost for LO ($10,425) was higher (p < 0.02) than for either LA ($5,899) or OA ($5,220). When appendicitis was not present, definitive confirmation of pathology was achieved in 9 of 18 patients undergoing LA versus 4 of 14 patients having OA (p = not significant). We conclude that when laparoscopy and laparoscopic appendectomy can be performed, the procedure is safe and produces results comparable with those of open appendectomy without significant overall cost differences.

Breast cancer practice guidelines: evaluation and quality improvement.

The utility of practice guidelines in breast cancer management remains unproved. This paper examines the scope and goals of published guidelines and their utility in the process of breast cancer treatment quality improvement. Although existing breast cancer guidelines vary widely in scope and intent, they provide a framework for meaningful quality-of-care evaluation. Among the few comprehensive breast cancer guideline programs are those developed by the Ontario Cancer Treatment Practice Guidelines Initiative, the Revlon/UCLA Breast Center, the Association of Community Cancer Centers (ACCC), the Society of Surgical Oncology (SSO), and the National Comprehensive Cancer Network (NCCN). Ultimately, guidelines will prove useful only if they are utilized as part of a comprehensive program to improve quality, cost-effectiveness, and outcomes. To accomplish this, they must include mechanisms for revision and evaluation. The evaluation of guideline utility in quality improvement, particularly in breast cancer care, is a complex long-term process, which should include input from practitioners, institutions, payors, and government.

NCCN Practice Guidelines for Breast Cancer.

The therapeutic options for patients with noninvasive or invasive breast cancer are complex and varied. In many situations, the patient and physician have the responsibility to jointly explore and ultimately select the most appropriate option from among the available alternatives. With rare exception, the evaluation, treatment, and follow-up recommendations contained within these guidelines were based largely on the results of past and present clinical trials. However, there is not a single clinical situation in which the treatment of breast cancer has been optimized with respect to either maximizing cure or minimizing toxicity and disfigurement. Therefore, patient and physician participation in prospective clinical trials allows patients not only to receive state-of-the-art cancer treatment but also to contribute to the improvement of treatment of future patients.

In-situ ablation of breast cancer.

Recent trends in the management of early breast cancer have moved toward breast conservation, without a loss in disease-free intervals or overall survival. The in situ ablation of breast tumors without the need for lumpectomy is the next logical extension of this trend. Advances in stereotactic guided localization, ultrasound and magnetic resonance imaging (MRI) technology has markedly improved our ability to visualize, biopsy and possibly treat breast tumors. With these technologies, probes for delivery of energy for ablating tumors and for monitoring the effect can be placed precisely within breast tumors. Several methods are available to destroy tumors in situ, based on thermal destruction of tumor with either heat or cold. Cryoablation is performed using a liquid-nitrogen cooled needle. Heating techniques include delivery of the heat through probes placed in the lesion to conduct radiofrequency irradiation or laser light energy. Two techniques, focused ultrasound and focused microwave thermotherapy, are truly non-invasive in that they do not involve any skin puncture. In addition to the incentive of eliminating lumpectomy from the treatment paradigm for early stage breast cancer, and the potential cosmetic advantages, in situ ablation may also provide an immunological benefit by providing a source of antigens for the development of a systemic anti-tumor immune response. The augmentation of this response may provide an advantage to in situ ablation in terms of recurrence and survival rates.

Breast cancer imaging.

The role of the surgeon in the diagnosis and management of breast cancer continues to evolve as office based diagnostic procedures gain more prominence. This article outlines the basic clinical and technical aspects of mammography and ultrasound. The evaluation and management of several challenging breast problems are discussed.

Is MUGA scan necessary in patients with low-risk breast cancer before doxorubicin-based adjuvant therapy? Multiple gated acquisition.

Doxorubicin-based chemotherapy in the adjuvant treatment of breast cancer has become standard. Use of doxorubicin is limited by cardiac dysfunction; however, the incidence is dramatically reduced by limiting the dose to less than 550 mg/m(2). Although the cumulative dose in breast cancer is typically 240 mg/m(2), multiple gated acquisition (MUGA) scans are still recommended for determining cardiac functional status in these patients. To examine the need for this practice, we reviewed 296 patients who underwent surgery for breast cancer at Roswell Park Cancer Institute between July 1997 and December 1998. Fifty-nine of 95 (62%) patients receiving doxorubicin-based regimens, and 3 of 39 (7%) receiving nondoxorubicin regimens had pretreatment MUGA scans. The MUGA scans showed normal results in 58 patients and low-normal in 4 (6.5%), with no wall motion abnormalities encountered. There were no cases where doxorubicin was not used because of an abnormal MUGA scan. There were no cardiac complications in the 59 women who received doxorubicin-based chemotherapy. MUGA will screen out few, if any, women under consideration for doxorubicin-based adjuvant therapy; the decision to avoid doxorubicin can be made based on age and preexisting comorbidity. Guidelines recommending routine use of MUGA before the administration of doxorubicin for adjuvant therapy for breast cancer should be reconsidered.

High-dose oral and intravenous metoclopramide in doxorubicin/cyclophosphamide-induced emesis. A randomized double-blind study.

Emesis remains a major side effect of cancer chemotherapy. High-dose intravenous metoclopramide has proved to be effective antiemetic therapy for cisplatinum induced emesis. It has not been rigorously tested in nonplatinum chemotherapy. This double-blind, noncrossover, randomized trial compared high-dose oral and intravenous metoclopramide to standard oral prochlorperazine in emesis caused by doxorubicin [70 mg/m2 body surface area (BSA)] and cyclophosphamide (700 mg/m2 BSA). Prochlorperazine (10 mg/dose), oral metoclopramide, and intravenous metoclopramide (2 mg/kg/dose each) were given 30 min before chemotherapy and then every 4 h for 24 h. Ten patients were randomized to prochlorperazine therapy, 10 to oral metoclopramide, and 9 to i.v. metoclopramide. Median number of emeses for the first chemotherapy cycle was 3, 3, and 7 for prochlorperazine, oral, and i.v. metoclopramide, respectively. Statistical analysis showed no significant advantage of any regimen (p greater than 0.4). For patients who continued the antiemetic study, frequency of emesis increased with each successive cycle of chemotherapy. Six of 19 patients treated with metoclopramide developed dystonic reactions compared with zero of 10 on prochlorperazine. High plasma metoclopramide levels were achieved with both metoclopramide regimens and did not correlate with frequency of emesis. High-dose oral and i.v. metoclopramide in an every 4 h regimen did not show any advantage over standard antiemetic therapy for doxorubicin/cyclophosphamide-induced emesis and were associated with significant toxicity.

Sarcoma of the breast: implications of the extent of local therapy.

Although the majority of breast neoplasms will be of epithelial origin, tumors of the stromal elements of the breast may occur. A retrospective review of the medical records and tumor registry data of 25 patients with breast sarcoma treated at Roswell Park Cancer Institute from 1964 to 1995 was performed. There were 24 females and 1 male, with a median age of 55 years. Delay in seeking medical attention was common. Angiosarcoma was the most common histologic type of breast sarcoma (n = 10). Mastectomy was the predominant form of local therapy (21 patients). Overall survival was 61 per cent at 5 years and 36 per cent at 10 years. There was no difference in survival or local control rates for those patients treated with local excision when compared with patients treated with mastectomy. Sarcoma is an unusual form of breast tumor. Survival and local control are similar when comparing local excision and mastectomy. When local excision is performed, attention must be directed to achieving clear margins of resection. The benefit of adjuvant therapy remains undefined.

Effectiveness of multiple-level sectioning in detecting axillary nodal micrometastasis in breast cancer: a retrospective study with immunohistochemical analysis.

OBJECTIVE: To evaluate the effectiveness of original multiple-level sectioning in detecting axillary nodal micrometastasis in breast carcinoma. DESIGN: Retrospective analysis of 707 axillary nodes from 34 consecutive node-negative invasive breast cancers from the years 1989 and 1990. All but 2 cases were originally examined by multiple-level sectioning. The original histologic sections were reviewed. Additional sections were cut for hematoxylin-eosin staining and cytokeratin immunohistochemistry. RESULTS: A micrometastasis was found in only 1 case (1 node) on the original histologic section, which was 1 of the 2 cases not originally processed by multiple-level sectioning. Additional sections and cytokeratin immunostains were negative on all cases, including the false-negative case identified on original section. CONCLUSIONS: The finding of a micrometastasis in 1 case on the original, but not on any additional recuts or cytokeratin immunostains, indicates that the original multiple-level sectioning was very effective (0% false negatives). Immunohistochemistry provided no additional benefit in detecting micrometastases in cases already examined by multiple-level sectioning. Thorough histologic examination on properly prepared sections is probably the most efficient and cost-effective way to detect the vast majority of axillary nodal micrometastases.

Prognostic factors in breast cancer. College of American Pathologists Consensus Statement 1999.

BACKGROUND: Under the auspices of the College of American Pathologists, a multidisciplinary group of clinicians, pathologists, and statisticians considered prognostic and predictive factors in breast cancer and stratified them into categories reflecting the strength of published evidence. MATERIALS AND METHODS: Factors were ranked according to previously established College of American Pathologists categorical rankings: category I, factors proven to be of prognostic import and useful in clinical patient management; category II, factors that had been extensively studied biologically and clinically, but whose import remains to be validated in statistically robust studies; and category III, all other factors not sufficiently studied to demonstrate their prognostic value. Factors in categories I and II were considered with respect to variations in methods of analysis, interpretation of findings, reporting of data, and statistical evaluation. For each factor, detailed recommendations for improvement were made. Recommendations were based on the following aims: (1) increasing uniformity and completeness of pathologic evaluation of tumor specimens, (2) enhancing the quality of data collected about existing prognostic factors, and (3) improving patient care. RESULTS AND CONCLUSIONS: Factors ranked in category I included TNM staging information, histologic grade, histologic type, mitotic figure counts, and hormone receptor status. Category II factors included c-erbB-2 (Her2-neu), proliferation markers, lymphatic and vascular channel invasion, and p53. Factors in category III included DNA ploidy analysis, microvessel density, epidermal growth factor receptor, transforming growth factor-alpha, bcl-2, pS2, and cathepsin D. This report constitutes a detailed outline of the findings and recommendations of the consensus conference group, organized according to structural guidelines as defined.

Exposures in early life: associations with DNA promoter methylation in breast tumors.

There is evidence that epigenetic changes occur early in breast carcinogenesis. We hypothesized that early-life exposures associated with breast cancer would be associated with epigenetic alterations in breast tumors. In particular, we examined DNA methylation patterns in breast tumors in association with several early-life exposures in a population-based case-control study. Promoter methylation of E-cadherin, p16 and RAR-ß2 genes was assessed in archived tumor blocks from 803 cases with real-time methylation-specific PCR. Unconditional logistic regression was used for case-case comparisons of those with and without promoter methylation. We found no differences in the prevalence of DNA methylation of the individual genes by age at menarche, age at first live birth and weight at age 20. In case-case comparisons of premenopausal breast cancer, lower birth weight was associated with increased likelihood of E-cadherin promoter methylation (OR = 2.79, 95% CI, 1.15-6.82, for ⩽2.5 v. 2.6-2.9 kg); higher adult height with RAR-ß2 methylation (OR = 3.34, 95% CI, 1.19-9.39, for ⩾1.65 v. <1.60 m); and not having been breastfed with p16 methylation (OR = 2.75, 95% CI, 1.14-6.62). Among postmenopausal breast cancers, birth order was associated with increased likelihood of p16 promoter methylation. Being other than first in the birth order was inversely associated with likelihood of ⩾1 of the three genes being methylated for premenopausal breast cancers, but positively associated with methylation in postmenopausal women. These results suggest that there may be alterations in methylation associated with early-life exposures that persist into adulthood and affect breast cancer risk.

Laparoscopic cholecystectomy and unsuspected gallbladder carcinoma.

Gallbladder cancer is a relatively uncommon malignancy in the United States. Its presentation is similar to that of lithic disease of the gallbladder. Laparoscopic cholecystectomy has become the method of choice for removing the gallbladder in most benign conditions. Occasionally, unsuspected gallbladder carcinoma is encountered in association with laparoscopic cholecystectomy. Overall, gallbladder cancer portends a poor prognosis. However, in select cases, a favorable outcome can be expected and the less favorable predicted expected outcome can be improved. Management of patients with gallbladder cancer in different situations is discussed: gallbladder cancer noted postoperatively on final pathology, gallbladder cancer noted after removal of the gallbladder and opening of the specimen at the time of surgery, difficulty encountered at the time of dissection and resultant suspicion of gallbladder cancer, and diagnosis of extensive disease at initial placement of the laparoscope. The technique of extended cholecystectomy is outlined.

New for gallstones: video laparoscopy for cholecystectomy.

Laparoscopic cholecystectomy is a new technique for treatment of symptomatic cholelithiasis. Advantages of efficacy, reduced pain and shortened disability make this the preferred treatment. The procedure can be learned by surgeons versed in biliary surgery. Physicians not fully trained in biliary tract surgery should not perform LC because of the dangers of bile duct and arterial injuries, and because of the need for immediate open surgery in 5-10% of patients.