An exploratory study of sunitinib plus paclitaxel as first-line treatment for patients with advanced breast cancer.

BACKGROUND: Sunitinib has shown single-agent activity in patients with previously treated metastatic breast cancer (MBC). We investigated the safety of the combination of sunitinib and paclitaxel in an exploratory study of patients with locally advanced or MBC. METHODS: Patients received oral sunitinib 25 mg/day (with escalation to 37.5 mg/day as tolerated) on a continuous daily dosing schedule and paclitaxel 90 mg/m(2) on days 1, 8, and 15 of each 28-day cycle. Study endpoints included safety (primary endpoint), pharmacokinetics, and antitumor activity. RESULTS: Twenty-two patients were enrolled. The most frequent adverse events (AEs) were fatigue/asthenia (77%), dysgeusia (68%), and diarrhea (64%). Grade 3 AEs included neutropenia (43%), fatigue/asthenia (27%), neuropathy (18%), and diarrhea (14%). No drug-drug interaction was observed on the basis of pharmacokinetic analysis. Of 18 patients with measurable disease at baseline, 7 (38.9%) achieved objective responses (including 2 complete and 5 partial responses). Clinical responses were observed in three of nine patients with triple-negative receptor status (estrogen receptor negative, progesterone receptor negative, and human epidermal growth factor receptor-2 negative). CONCLUSIONS: These data indicate that sunitinib and paclitaxel in combination are well tolerated in patients with locally advanced or MBC. No drug-drug interaction was detected and there was preliminary evidence of antitumor activity.

Autoradiographic imaging of rat sarcoma in different anatomical sites using 2-[14C]deoxyglucose.

As sarcomas are known to have accelerated glycolysis, we used the radiolabeled glucose analogue 2-deoxy-d-[U-14C]glucose in autoradiographic imaging studies of a methylcholanthrene-induced rat fibrosarcoma placed in an i.m. site, and in models of pulmonary and hepatic metastases. Fifty muCi of 2-deoxy-d-[U-14C]glucose were injected i.p. into groups of rats bearing tumors in these three sites; sacrifice of animals for imaging was carried out 45 min later. Excellent imaging of sarcoma tissue in all three anatomical sites was obtained, with high visual contrast compared to the normal tissue background. Using densitometry of autoradiographs, tumor/tissue ratios were 7.1 for i.m. tumors, 3.8 for pulmonary metastases, and 2.8 for hepatic metastases. Autoradiographic imaging of sarcomas may be obtained based upon avidity of neoplastic tissue for the glucose analogue 2-deoxy-d-[U-14C] glucose. Such imaging is not dependent upon anatomical site and reproducibly images rat sarcomas in muscle, lung, and liver.

Metabolic imaging of human extremity musculoskeletal tumors by PET.

The measurement of glucose utilization rate (GUR) by positron emission tomography (PET) using 18F-2-fluoro-2-deoxy-D-glucose (FDG) is a valuable method to assess the grade of malignancy of brain tumors. We have designed a feasibility trial to determine whether PET could be used to image and predict the grade of malignancy of human extremity musculoskeletal tumors. Five patients with extremity tumors (four soft-tissue tumors and one osteogenic tumor) were studied. Peak and mean apparent GURs were determined in the tumor region. All tumors were subsequently resected and graded in a standard fashion using the NCI grading system. Peak apparent GURs ranged from 3.3 mg/100 g/min to 15.2 mg/100 g/min, with the highest values found in the high grade tumors. Although the number of patients studied was small, a good correspondence was shown between GURs and histopathologic grading. Our results indicate that PET can be used to image and evaluate the metabolic activity of human musculoskeletal tumors.

Medicolegal analysis of errors in diagnosis and treatment of surgical endocrine disease.

BACKGROUND: The medicolegal impact of adverse events in surgical endocrine disease has not been described previously. This study was undertaken to determine the causes, costs, and outcomes of endocrine malpractice litigation. METHODS: Jury verdict reports from the U.S. civil court system from 1985 through 1991 were reviewed. Sixty-two malpractice cases were identified from 21 states. RESULTS: The 62 cases were classified into three categories, totaling 63 adverse events: (1) complications (n = 34, 54%) from thyroid (n = 32, 51%) or parathyroid (n = 2, 3%) surgery; (2) delayed diagnosis (n = 22, 35%) of thyroid cancer (n = 11, 18%), adrenal tumors (n = 9, 14%), and hyperparathyroidism (n = 2, 3%); and (3) medical morbidity (n = 7, 11%) from radioactive iodine (n = 5, 8%) or from propylthiouracil (n = 2, 3%). Surgical injuries, mostly recurrent nerve injuries by general surgeons, accounted for the greatest number of cases and the highest cost of litigation. CONCLUSIONS: Medical malpractice involving endocrine disease results in expensive litigation, a result of serious harm. Technical misadventures account for most cases, followed closely by delays in diagnosis. These data may aid design of risk prevention strategies in endocrine disease.

Inhibition of established rat fibrosarcoma growth by the glucose antagonist 2-deoxy-D-glucose.

Sarcoma cells exhibit higher rates of glycolysis than normal tissues and may be dependent on glucose utilization for growth. Accordingly, we tested the ability of the glucose antimetabolite 2-deoxy-D-glucose (2-DG) to inhibit the growth of an established methylcholanthrene-induced rat fibrosarcoma in three groups of F344 rats with increasing subcutaneous inoculations of tumor (2 X 10(6) cells, 1 X 10(7) cells, and 1 mm tumor fragments). Rats were randomized to receive 2-DG or saline solution at doses of 0.75 gm/kg, 1.5 gm/kg, or 1.75 gm/kg, beginning 3 days after tumor implantation and continuing for 10 days. Tumors were removed and weighed on day 14. We measured tissue [14C]-2-DG levels in tumor, brain, liver, and muscle after intraperitoneal injection of radiolabeled 2-DG. In these same tissues we determined the activity of glucose-6-phosphatase (G-6-Pase), an enzyme which dephosphorylates the intracellular glycolytic inhibitor 2-DG-6-phosphate, thus reversing the antitumor effect of 2-DG. All groups treated with 2-DG had a significant reduction in tumor weight of 50% to 70% when compared with saline solution-treated controls. Toxicity was substantial at the highest dose of 2-DG, but minimal toxicity was noted at intermediate and low doses. Tumor had the greatest uptake of [14C]-2-DG, with low levels of G-6-Pase leading to prolonged retention and highest tissue levels of radiolabeled 2-DG. Use of 2-DG inhibits established sarcoma growth because it is rapidly transported into tumors, cannot be metabolized after phosphorylation, and is dephosphorylated and released slowly from tumor cells. Rat sarcoma growth is dependent on glucose utilization and can be effectively inhibited by glucose antagonism.

Comparative analysis of complications from I-131 radioablation for well-differentiated thyroid cancer.

BACKGROUND: The decision to extend thyroidectomy to the opposite lobe during resection of well-differentiated thyroid cancer should include an analysis of complications of I-131 radioablation directly related to the thyroid remnant. If significant, then contralateral resection would be indicated. To clarify this issue we studied the incidence of complications of I-131 radioablation in 63 cases of well-differentiated thyroid cancer. METHODS: Retrospective reviews of operative notes, pathology reports, office records, and physician interviews were made. We analyzed operations, complications, and radiation dosing. RESULTS: Procedures included unilateral thyroidectomy, 10 (15.9%); subtotal thyroidectomy, seven (11.1%); near-total thyroidectomy, 25 (39.7%); and total thyroidectomy, 21 (33.3%). The average ablative dose was 101 mCi (range, 30 to 208 mCi). Nineteen percent (12 of 63) of patients had complications including radiation thyroiditis (eight), chronic sialoadenitis (one), odynophagia (one), facial edema (one), and shingles (one). Near-total or total thyroidectomy resulted in significantly fewer complications compared with lesser resections (8.7% versus 47.1%, p < 0.005). CONCLUSIONS: The incidence of complications of I-131 radioablation after thyroidectomy for well-differentiated thyroid cancer is related to the extent of thyroidectomy performed. We recommend contralateral thyroid resection (resulting in a near-total or total thyroidectomy) in patients likely to receive postoperative I-131 radioablation.

The effect of a new branched chain--enriched amino acid solution on postoperative catabolism.

Branched-chain amino acids (BCAAs) may regulate muscle amino acid flux. Metabolic studies of both experimental animals and humans utilizing comparatively large amounts of BCAAs infused with hypocaloric glucose have shown that catabolism and proteolysis can be blunted. These studies suggested that the nitrogen-sparing properties of amino acid solutions used in postoperative trauma or sepsis might be improved by increasing the amount of BCAAs. This hypothesis was tested on ten patients undergoing operations of moderate severity utilizing a peripheral amino acid mixture with a branched-chain:non-branched-chain ratio of 45:55% given in 5% dextrose. The patients received 1.7 gm of protein equivalent/kg of ideal body weight in 5% dextrose-crystalloid solution with a concentration of 3.5% amino acids for the first 5 postoperative days. Nitrogen balance, 3-methylhistidine excretion, blood chemistries, and plasma amino acid profile tests were done daily. The results showed that nitrogen equilibrium was maintained for 5 postoperative days without any untoward effects on patients, their surgical wounds, or hepatic function. Plasma amino acids showed no significant changes from baseline with the exception of elevations of the BCAAs. We conclude that this 45% BCAA-enriched solution may be safely administered to patients with postoperative traumatic injury and results in nitrogen equilibrium over a 5-day period.

Causes of breast cancer malpractice litigation. A 20-year civil court review.

To determine objectively the patient and physician factors that lead to breast cancer malpractice litigation, a review was undertaken of all cases tried in the US federal and state civil court system over a 20-year period from 1971 through 1990. Forty-five cases were identified and all involved a delayed diagnosis of breast cancer (the mean delay was 15 months). The patients were young (mean age, 40 years). Of 45 cases studied, the majority of patients (37 [82%]) found a painless mass by self-examination of the breast. Only 22 patients (49%) had further workup, mostly by mammography (20 [44%]). The results of 16 mammograms (80%) were read as normal. Obstetricians and gynecologists were involved in the greatest number of cases (21 [50%]), followed by family practitioners and internists (17 [41%]), general surgeons (12 [28%]), and radiologists (4 [10%]).

Medicolegal analysis of the delayed diagnosis of cancer in 338 cases in the United States.

OBJECTIVE: To define the frequency, clinical characteristics, and legal outcomes of the delayed diagnosis of cancer leading to negligence litigation. DESIGN: Retrospective review of 338 jury verdict reports from 42 states in the United States. SETTING: State and federal civil court decisions, as reported to litigation survey services, in a 5-year interval from 1985 to 1990. RESULTS: Of 338 cancers divided into 13 major organ sites, breast (38%, n = 127), gastrointestinal (15%, n = 51), lung (15%, n = 50), and head and neck cancers (10%, n = 33) accounted for 80% (270/338) of lawsuits. The average diagnostic delay for 212 cases was 17 months. The median age of patients with delays was 15 years younger than the age of patients presenting with cancer in the general population. For cancers in nine major organ sites, the ratio of mortality for patients filing lawsuits to that for patients with cancer in the general population averaged 3.4:1. The total known indemnity payout was $140.2 million, with an average payout per case of $64,600. At 1 to 3 months of diagnostic delay, jury verdicts largely favored the defense (seven of 11 [65%] defense verdicts); after 6 months of delay, jury verdicts were almost evenly divided between defense verdicts, plaintiff verdicts, and out-of-court settlements. CONCLUSIONS: The delayed diagnosis of cancer leading to negligence litigation is associated with significant indemnity payments, often involves middle-aged patients far younger than the expected age in the general cancer population, and is defensible only in the minority after 6 months of diagnostic delay.

Malpractice litigation involving laparoscopic cholecystectomy. Cost, cause, and consequences.

OBJECTIVE: To analyze 44 cases of malpractice litigation involving laparoscopic cholecystectomy for cost, cause, and consequences of civil court actions. DESIGN: Survey of national jury verdict reporting services, covering 20 states during the 39-month interval from January 1, 1993, to April 30, 1996. The 44 laparoscopic cholecystectomies were performed during the 40-month interval from February 1, 1989, to June 30, 1992. MAIN OUTCOME MEASURES: Types of injuries leading to litigation, morbidity and mortality from injuries, trial verdicts, and cost of liability payments. RESULTS: The 44 injuries composed 4 main categories of injuries: (1) bile duct, n = 27, 61%; (2) bowel, n = 7, 16%; (3) major vascular, n = 4, 9%; and (4) other, n = 6, 14%. Bowel injuries involved trocar or cautery injury; vascular injuries all involved trocars. There were 7 deaths (16%) overall from either septic peritonitis resulting from bowel injury (4 patients [57%]) or bile peritonitis involving spills or cystic duct leaks (3 patients [43%]). No deaths resulted from injury to main bile ducts. Of the 44 cases, 21 (48%) settled out of court (mean payment, $469,711). Of the remaining 23 cases proceeding to trial, 19 (83%) were defended successfully while 4 (17%) concluded with plaintiff jury verdicts (mean payment, $188,772). CONCLUSIONS: Frequent settlements of cases involving laparoscopic cholecystectomy injuries that are litigated have resulted in a selection of cases of increased defensibility at trial. The high mortality rate from bowel injuries is a new medicolegal finding in laparoscopic cholecystectomies, as expensive to settle (mean payment, $438,000) as laparoscopic cholecystectomy bile duct injury (mean payment, $507,000).

Tactile imaging of breast masses: first clinical report.

HYPOTHESIS: Tactile imaging can accurately document the palpable extent of breast masses. DESIGN: Prospective nonrandomized interventional trial, comparing mass size estimates from preoperative physical examination, ultrasound, and tactile imaging with postoperative measurements of the resected masses. SETTING: A community ambulatory surgical center and a university hospital tertiary care center. PATIENTS: Twenty-three women undergoing surgical excision of breast masses. All subjects had a single, palpable, dominant mass, 0.5 to 3 cm in diameter. INTERVENTION: Prior to surgery, the size of each mass was estimated from tactile imaging using an array of pressure sensors that is stroked over the mass. Size was also estimated by ultrasound and physical examination. Immediately following resection of the mass, it was bisected, and the palpable extent was measured with a caliper. MAIN OUTCOME MEASURE: Maximum mass diameter estimates from ultrasound, physical examination, and tactile imaging, compared with the resected measurement. RESULTS: Tactile imaging estimates were repeatable (7.5% mean SD for multiple estimates of the same mass) and show good agreement with the resected measurements. Mean absolute error was 13%, and linear regression with zero intercept had a slope of 0.94, r(2) = 0.51. Physical examination and ultrasound estimates had respective mean absolute errors of 46% and 34%, regression slopes of 1.27 and 0.89, and r(2) = 0.28 and 0.37. CONCLUSIONS: Tactile imaging can provide accurate and reproducible estimates of the size of breast masses. This capability can enhance cancer surveillance for patients with benign masses (eg, due to scarring or fibrocystic changes) because previous work suggests that reliable detection of a difference in mass size by physical examination requires a 40% change in diameter. In contrast, this study suggests tactile imaging requires only a 15% change (95% confidence interval).

Lymphoscintigraphic anatomy of sentinel lymphatic channels after subareolar injection of Technetium 99m sulfur colloid.

BACKGROUND: Injection of Technetium 99m sulfur colloid (Tc-99m-SC) into the subareolar lymphatic plexus provides a rapid and reliable method of identifying breast sentinel lymph nodes and their lymphatic connections to the areola, termed sentinel lymphatic channels (SLCs). The objective of this study was to define the anatomic origin, number, and direction of the SLC in relation to the areola after subareolar injection of Tc-99m-SC. STUDY DESIGN: Using a hand-held goniometer, the exit angle (theta(e)) and direction from the vertical (to the patient's right or left) of SLCs were determined in 87 successful preoperative lymphoscintigrams (46 left breast and 41 right breast). RESULTS: One major lymphatic trunk was identified in 91% of cases (n = 79), and two lymphatic trunks were identified in 9% of cases (n = 8). Overall, 24% (n = 21) of major lymphatic trunks exited the areola vertically (theta(e) = 0 degrees), 33% (n = 29) exited the areola with theta(e) = right or left 1 to 30 degrees, and 32% (n = 28) exited with a theta(e) = right or left 31 to 60 degrees. In total, 90% (n = 78) of SLCs exited the areola with a theta(e) = right or left 0 to 60 degrees, equivalent to 10 to 12 o'clock in the right breast, and 12 to 2 o'clock in the left breast. CONCLUSIONS: Radial angular measurements of SLCs from preoperative lymphoscintigrams performed by SA injection confirm that the origin of the majority of SLCs is within the upper, outer edge of the areola, and that all SLCs ultimatelytraverse the upper, outer quadrant of the breast and terminate on axillary sentinel nodes.

Sentinel lymph node mapping in breast cancer using subareolar injection of blue dye.

BACKGROUND: Lymphatic mapping in breast cancer performed solely by intraparenchymal injections of blue dye remains an accepted method of identifying sentinel nodes, largely because of its simplicity. As currently practiced, the technique is associated with a marked learning curve, variable identification rates of sentinel nodes, and high false-negative rates. The purpose of this study is to improve dye-only lymphatic mapping of the breast by using an alternative site for injection of blue dye: the subareolar lymphatic plexus. STUDY DESIGN: In the 10 months between August 1998 and May 1999, 40 women with operable breast cancer in stages I and II underwent lymphatic mapping and sentinel node biopsy performed solely by subareolar injections of blue dye, followed by complete axillary node dissection. The technique involved the injection of 5 mL of 1% isosulfan blue into the subareolar plexus, which consists of breast tissue located immediately beneath the areola. No peritumoral injections of blue dye were performed. The ability of subareolar dye injections to identify sentinel nodes and accurately predict the pathologic status of the axilla was determined and compared with published results for dye-only lymphatic mapping using intraparenchymal injections. RESULTS: The identification rate of sentinel nodes was 98% (in 39 of 40 patients). Axillary basins harboring positive lymph nodes were found in 15 of these 39 patients (38.5%). Sentinel nodes correctly predicted the status of these 15 positive axillary basins in 100% of the patients. There were no false-negative sentinel node biopsies, indicating a false-negative rate of 0 (in 0 of 15). The overall accuracy, sensitivity, and specificity were 100%. CONCLUSIONS: Compared with other series of dye-directed lymphatic mapping, the present study of dye-only injections into the subareolar plexus demonstrates a high sentinel node identification rate, absent false-negative rate, and rapid learning curve. On the basis of these findings, we propose that injections into the subareolar lymphatic plexus are the optimal way to perform dye-only lymphatic mapping of the breast.

Preoperative lymphoscintigraphy during lymphatic mapping for breast cancer: improved sentinel node imaging using subareolar injection of technetium 99m sulfur colloid.

BACKGROUND: Preoperative lymphoscintigraphy has been recommended to confirm the successful uptake and direction of migration of radiotracer into sentinel nodes during lymphatic mapping for breast cancer. In addition, preoperative lymphatic mapping may provide a visually useful aid to the relative location of sentinel nodes within a nodal basin. One common method of breast lymphoscintigraphy involves injections of unfiltered technetium 99m sulfur colloid (Tc-99m-SC) directly into parenchymal tissues surrounding a tumor or biopsy cavity (IP injection). Because of the many imaging failures and prolonged imaging times of IP lymphoscintigraphy, the procedure has fallen into disfavor by oncologic surgeons. The purpose of this study is to document the increased success rate of preoperative breast lymphoscintigraphy using a new anatomic site of injection, the subareolar lymphatic plexus (SA injection). STUDY DESIGN: In the 12 months between December 1, 1998, and December 29, 1999, 42 women with stage I and II breast cancer underwent preoperative lymphoscintigraphy by either the IP (n = 12, December 1998 to May 1999) or SA (n = 30, May 1999 to December 1999) route of injection. Both groups were injected with 1 mCi (37 MBq) of unfiltered Tc-99m-SC followed immediately by external gamma-camera imaging. The success rate for preoperative sentinel node imaging and the total imaging time were recorded in both groups. RESULTS: The success rate of identifying a sentinel node by SA lymphoscintigraphy was 90% (n = 27 of 30 patients), compared with 50% (n = 6 of 12 patients) for IP lymphoscintigraphy (p = 0.009). The imaging time in the SA injection group was 34 +/- 16 minutes, which was 59% shorter than the imaging time in the IP injection group of 82 +/- 48 minutes (p < 0.001). No uptake into internal mammary nodes was seen in either group. CONCLUSIONS: Moving the site of injection ofunfiltered Tc-99m-SC to the subareolar lymphatic plexus (SA injection) increased the success rate of preoperative lymphoscintigraphy to 90%, compared with 50% using IP injections. Preoperative SA lymphoscintigraphy resulted in the rapid visualization of axillary sentinel nodes within 30 minutes of SA injection, enabling a visual determination of the approximate number of sentinel nodes and their relative locations within the axilla. We conclude SA injection of unfiltered Tc-99m-SC is superior to IP injections when performing preoperative breast lymphoscintigraphy and is a visually useful aid to lymphatic mapping for breast cancer.

Medicolegal analysis of bile duct injury during open cholecystectomy and abdominal surgery.

To understand the medicolegal impact of bile duct injury, we analyzed 68 cases of biliary injury resulting from open cholecystectomy and abdominal surgery. Cases were litigated within the US civil justice system between 1970 and 1991. Operations resulting in bile duct complications included cholecystectomy for cholelithiasis in 49 patients (72%), common bile duct exploration in 5 patients (7%), and other abdominal operations in 7 patients (10%); 7 operations were of unknown type. The average delay in recognition of injury was 16 days (range 3 to 42). The mortality rate was 18% (12 of 68). Median jury verdict awards in successfully litigated cases were twice that of out-of-court settlements ($500,000 versus $250,000, P = 0.01). Bile duct injury after open cholecystectomy and abdominal surgery has a high mortality rate when diagnosed late, and is expensive to litigate. This review may be useful in defining the medicolegal outcome of similar injuries from laparoscopic cholecystectomy.

Use of a branched chain amino acid enriched solution in patients under metabolic stress.

The metabolic response to stress results in proteolysis, increased gluconeogenesis, and negative nitrogen balance. Infusion of BCAA has been shown experimentally to decrease protein degradation and stimulate protein synthesis. Such infusion may modify the response of patients to metabolic stress. An amino acid solution containing 45 percent BCAA as a component of central vein parenteral nutrition was infused into 20 moderately to severely stressed postoperative patients in a prospective, nonrandomized fashion. Infusion was begun within 24 hours postoperatively and continued for 7 to 14 days. Patients received 1.6 g protein equivalents per kg body weight daily and 30 kcal/kg body weight daily. Nutritional indexes as measured by albumin and transferrin values were maintained during the study period. Nitrogen balance became increasingly positive over the period of infusion without an increase in the urinary excretion of 3-methylhistidine. There were no serious clinical or biochemical side effects of the BCAA infusion, although a statistically significant increase in alkaline phosphatase was observed. These results suggest that central vein parenteral nutrition utilizing a 45 percent BCAA enriched solution can promote nitrogen retention without serious side effects in moderately to severely stressed patients.

Albumin turnover in sarcoma-bearing rats in relation to cancer anorexia.

Hypoalbuminemia, a frequent finding in cancer patients, can be demonstrated in the tumor-bearing rat. In actuality, the circulating amount of albumin is maintained in tumor-bearing rats, although total body water and plasma volume are increased. The fractional degradation rate of newly synthesized albumin labelled by the injection of carbon-14-carbonate was significantly increased in tumor-bearing rats (half-life 55 hours) as compared with control rats (half-life 85 hours). These findings indicate maintained synthesis of albumin in the tumor-bearing rats, a finding consistent with an increased ratio of specific activity in albumin to that in plasma urea after the injection of carbon-14-carbonate. Hypoalbuminemia in cancer seems to be the net result of an increased turnover rate of albumin and dilution of the maintained albumin mass. Despite the presence of cancer anorexia, the flux of substrates from the degradation of peripheral tissues is sufficient to supply the liver and, in turn, to enable an increased protein synthesis with maintenance of the synthetic rate of albumin.

Medicolegal perspectives on laparoscopic bile duct injuries.

Information from medical litigation serves as an important educational tool for surgeons. We believe that clinicians should be actively involved in a medico-legal analysis of bile duct injuries because it is the clinical expert witness who is called on to educate the lay jury regarding the standards of care in laparoscopic surgery. Ultimately, the strengths or weaknesses of the experts' arguments, as interpreted by the injury, determine the legal outcome of malpractice claims. Although the civil justice system proscribes the method by which litigation is adjudicated, it does not dictate the medical standards serving as benchmarks for treatment. Indeed, clinicians themselves dictate standards of medical care in surgical injuries accompanied by litigation. For this reason, clinicians are justified in their intense interest in the medicolegal aspects of these cases. At the same time, the reader is forewarned that this review focuses on medical factors of bile duct injury and on ideas that are empirically derived from analysis of past negligence litigation. As befits the role of an interested clinician only, no attempt is made to be advisory or complete on matters of case law.

The delayed diagnosis of breast cancer: medicolegal implications and risk prevention for surgeons.

The delayed diagnosis of breast cancer is a leading source of error in clinical practice, and an important cause of medical malpractice claims for surgeons and other clinicians. If clinical situations frequently leading to the delayed diagnosis of breast cancer could be predicted, misdiagnosis could be avoided more easily. Therefore, a policy of risk prevention should focus on understanding which group of patients fall into a high-risk profile for diagnostic errors, and why physicians commonly commit errors when evaluating these specific patients. Drawing on multiple sources of medical malpractice information, a profile of high-risk for misdiagnosis was created and analyzed. We have identified a "Triad of Error" for misdiagnosed breast cancer, involving (1) young patients, with (2) self-discovered breast masses, and (3) negative mammograms. The "Triad of Error" accounts for the majority of cases of misdiagnosed breast cancer. An understanding by surgeons and other clinicians of the clinical, biological, and technical basis for the "Triad of Error", and how these factors interact to produce misdiagnoses, should lead to more rapid diagnosis of breast cancer, and fewer medical liability claims. The surgeon plays a central role in preventing the delayed diagnosis of breast cancer by interrupting this cycle of diagnostic error, through the use of tissue sampling techniques that rapidly establish a definitive diagnosis of breast abnormalities.

Cancer cachexia.

Cancer cachexia describes a syndrome of progressive weight loss, anorexia, and persistent erosion of host body cell mass in response to a malignant growth. Although often associated with preterminal patients bearing disseminated disease, cachexia may be present in the early stages of tumor growth before any signs or symptoms of malignancy. A decline in food intake relative to energy expenditure (which may be increased, normal, or decreased) is the fundamental physiologic derangement leading to cancer-associated weight loss. In addition, abnormalities of host carbohydrate, protein, and fat metabolism lead to continued mobilization and ineffective repletion of host tissue, despite adequate nutritional support. Mediators of cancer anorexia and associated abnormalities are unknown. Cachectin/TNF or other host-derived cytokines (produced as a defense against malignancy) have been implicated as signal molecules in cachexia, based upon similar metabolic derangements produced by these cytokines in other chronic wasting illnesses. Nutritional support is effective in maintaining body weight of cachectic cancer patients, but ineffective in maintaining lean body mass. Although in one study parenteral nutritional support has improved operative morbidity and mortality in cancer patients, it has not yet improved response to chemotherapy or radiation therapy. Because of metabolic derangements seen in cancer cachexia, effective nutritional treatment regimens will probably require manipulation of host intermediary metabolism in addition to feeding. Insulin therapy or exercise are two such methods which appear to preserve host composition by preferential feeding of the host at the expense of the tumor. Future studies which more clearly define the role of signal molecules in producing cancer cachexia syndrome may lead to new treatment strategies, possibly involving modulation of the effects of such molecules on host metabolism.