Patients' understanding of how genotype variation affects benefits of tamoxifen therapy for breast cancer.

BACKGROUND: CYP2D6 is a critical enzyme in the metabolism of tamoxifen and potentially a key determinant in breast cancer outcomes. Our study examined patients' beliefs about how the CYP2D6 genotype would affect their prognoses. METHODS: Women enrolled in a pharmacogenomic clinical trial and on tamoxifen for prevention or treatment of breast cancer underwent CYP2D6 genotyping (EM = extensive, IM = intermediate, PM = poor metabolizing alleles). The informed consent said that the purpose of the trial was to examine effects of dose adjustment based on genotype, but that clinical benefits were uncertain. Our embedded sub-study surveyed 320 patients prior to receiving their genotypes. We experimentally manipulated 6 vignettes to describe hypothetical tamoxifen treatment (no or yes) and hypothetical genotype (EM, IM or PM). For each vignette, women gave their perceived recurrence risk (RR; 0-100%). RESULTS: Women believed that genotype would not affect their RR if they did not take tamoxifen (p = 0.06). However, women believed that if prescribed tamoxifen, genotype would affect their RR (22% if EM, 30% if IM and 40% if PM, p < 0.001). CONCLUSION: Women believed that extensive tamoxifen metabolizers had better prognoses, despite study materials stating uncertainty about any benefit. The rapidly changing nature of genomic science calls for caution when communicating clinical utility.

Using electronic health records to help coordinate care.

The use of electronic health records that can securely transmit patient data among physicians will help coordinate the care of 60 million Americans with multiple chronic conditions. This article summarizes the different organizations in the United States that are developing this technology. It discusses some of the problems encountered and the current initiatives to resolve them. The article concludes with three recommendations for enhancing care coordination: (1) a common health record, such as the Continuity of Care Record, to facilitate the exchange of clinical information among health providers; (2) regional governance structures to encourage the exchange of clinical data; and (3) payment by purchasers of care, both public and private, to physicians for using electronic health records.

Vulvar melanoma: a retrospective analysis and literature review.

OBJECTIVE: This review focuses on current directions in the staging and treatment of melanoma of the vulva. METHODS: All women treated for invasive melanoma of the vulva at the University of Virginia Health Sciences Center from 1980 through 2000 were identified through a retrospective review of the records of the Division of Gynecologic Oncology. Their treatments and outcomes were then analyzed and presented. RESULTS: Over the 20-year study period, 14 cases of melanoma of the vulva were identified. Of the 14 patients treated with curative intent, 6 developed recurrences following the completion of primary therapy, and all are dead from their disease. The mean duration from completion of therapy to recurrence was 7.5 months; the mean survival following recurrence was 17 months. CONCLUSION: One-centimeter skin margins appear adequate for vulvar melanomas <1 mm thick, and 2-cm margins appear adequate for intermediate-thickness melanomas (1-4 mm). In all cases it is necessary to include at least a 1-cm-deep margin extending through the subcutaneous fat to the muscular fascia below. Elective node dissection seems to offer no additional advantage in superficial lesions <0.76 mm thick, and its role in deeper lesions is still uncertain.

Inconsistencies in the treatment of football neck injuries.

There are clearly inconsistencies in treatment techniques offered by EMS providers to football athletes with potential severe neck injuries. It is unclear if current teaching methods or cirriculums play a role in these inconsistencies. Standardized cirriculum and practical skills would ensure consistent treatment of potential catastrophic neck injuries in football athletes. This study also suggest the need of formal protocols for treating these injuries. Many times there may be non-EMS providers involved in the care of the athletes. Communication of the protocols to all "team" members is vitally important. We ALL (EMS, athletic trainers, coaches, and physicians) need to be on the "same page" when treating such an injury. The result of a knowledgeable team may mean the difference between an athlete being a liability on society versus a productive member of society.

Identical or overlapping sequences in the primary structure of human alpha(2)-macroglobulin are responsible for the binding of nerve growth factor-beta, platelet-derived growth factor-BB, and transforming growth factor-beta.

alpha(2)-Macroglobulin (alpha(2)M) functions as a proteinase inhibitor and as a carrier of diverse growth factors. In this study, we localized binding sites for platelet-derived growth factor-BB (PDGF-BB) and nerve growth factor-beta (NGF-beta) to a linear sequence in the 180-kDa human alpha(2)M subunit which includes amino acids 591-774. A glutathione S-transferase fusion protein containing amino acids 591-774 (FP3) bound PDGF-BB and NGF-beta in ligand blotting assays whereas five other fusion proteins, which collectively include amino acids 99-590 and 775-1451 did not. The K(D) values for PDGF-BB and NGF-beta binding to immobilized FP3 were 300 +/- 40 and 180 +/- 30 nM, respectively; these values were comparable with those determined using methylamine-modified alpha(2)M, suggesting that higher-order alpha(2)M structure is not necessary for PDGF-BB and NGF-beta binding. PDGF-BB and NGF-beta blocked the binding of transforming growth factor-beta1 (TGF-beta1) to FP3. Furthermore, murinoglobulin, which is the only known member of the alpha-macroglobulin family that does not bind TGF-beta, also failed to bind PDGF-BB and NGF-beta. These results support the hypothesis that either a single linear sequence in human alpha(2)M or overlapping sequences are responsible for the binding of TGF-beta, PDGF-BB, and NGF-beta, even though there is minimal sequence identity between these three growth factors. FP3 blocked the binding of PDGF-BB to a purified chimeric protein, in which the extracellular domain of the PDGF beta receptor was fused to the IgG(1) Fc domain, and to PDGF receptors on NIH 3T3 cells. Thus, FP3 may inhibit the activity of PDGF-BB.

Primary breast carcinoma of the vulva: a case report and literature review.

BACKGROUND: In 1872, Hartung was the first to describe the case of a fully formed mammary gland arising in the left labium majora of a 30-year-old woman. Since Hartung's initial report, 38 additional cases of ectopic vulvar breast tissue have been described. This case report describes the rare occurrence of primary mammary adenocarcinoma arising within the vulva. CASE: A 64-year-old G4P4 white female presented with a 4-year history of a 2 x 1 cm firm, indurated, raised lesion of the left lateral mons. A wide local excision with ipsilateral inguinofemoral lymphadenectomy was performed. Given histological findings characteristic of both invasive ductal carcinoma and invasive lobular carcinoma, in conjunction with the presence of estrogen and progesterone receptors within the tumor, a diagnosis of infiltrating adenocarcinoma arising within ectopic breast tissue was made. CONCLUSIONS: Thirty-nine reported cases of ectopic breast tissue arising within the vulva have been reported in the world literature. Though the diagnosis of primary breast carcinoma arising within the vulva is based primarily upon histologic pattern, estrogen and progesterone receptor positivity provide supporting evidence. Given the rarity of this condition, guidelines for therapy are unavailable; we therefore suggest looking to the current management of breast cancer in order to establish a sensible approach.

Endometrial stromal sarcoma of the vulva arising in extraovarian endometriosis: a case report and literature review.

BACKGROUND: Extraovarian malignant transformation of endometriosis is a rare event; 52 cases have been reported. We describe the first published account in the world literature of an endometrial stromal sarcoma (ESS) arising in the vulva from a focus of endometriosis. CASE: A 34-year-old G4 P3 morbidly obese white female was seen with a 1-year history of a palpable lesion arising within the superior aspect of the left labium majus. Radical left hemivulvectomy with clitorectomy was performed. The histopathologic findings were consistent with ESS arising from endometriosis associated with the extrapelvic portion of the round ligament within the canal of Nuck. Twenty months later metatastatic ESS developed in the upper lobe of the right lung and the patient underwent wedge resection. Nine months later she developed a recurrent pulmonary nodule at the site of the previous wedge resection and underwent successful right pulmonary lobectomy. The patient was last seen in October 1995 and had no evidence of disease at that time. CONCLUSIONS: Since approximately 0.7-1.0% of patients with endometriosis have lesions that will ultimately undergo malignant transformation, consideration should be given to bilateral oophorectomy at the time of abdominal surgery in patients with significant endometriosis.

A phase II study of irinotecan (CPT-11) in patients with advanced squamous cell carcinoma of the cervix.

BACKGROUND: This study was conducted to determine the efficacy and safety of irinotecan (CPT-11) as second-line therapy in patients with advanced cervical carcinoma. METHODS: Sixteen patients with platinum-resistant squamous cell carcinoma were treated with CPT-11 as second-line therapy. CPT-11 was administered in repeated 6-week cycles comprised of the administration of CPT-11 once weekly for 4 weeks, followed by a 2-week rest. The starting dose of CPT-11 was 125 mg/M2 given intravenously over 90 minutes; subsequent doses were adjusted based on individual patient tolerance. RESULTS: The median age of the patients was 43 years (range, 27-69 years). Three patients had a baseline Eastern Cooperative Oncology Group performance score (PS) of 0, 8 had a PS of 1, and 5 had a PS of 2. All patients had received cisplatin-based chemotherapy and 13 of 16 patients (81.3%) had been treated with prior pelvic/abdominal radiation therapy. Fourteen patients were evaluable for response. There were no objective responses although subjective decreases in symptoms were observed in some patients. Grade 3 to 4 toxicities included diarrhea in three patients, nausea and emesis in one patient, leukopenia in six patients, and neutropenia in five patients. Eighteen of 25 cycles required dose reductions leading to a median dose intensity of only 59.4 mg/M2/week, which was 71% of the planned dose of 83.3 mg/M2/week. CONCLUSIONS: The amount of CPT-11 actually delivered to the patients under the conditions of this pilot study failed to result in an antitumor response. However, the marked subjective improvement of symptoms observed in this study and the significant activity reported by other investigators justify future studies of CPT-11 in patients with cervical carcinoma.

Malignant melanoma of the vagina and locoregional control: radical surgery revisited.

BACKGROUND: Anecdotal reports and retrospective case reviews suggest improved locoregional control, and possibly overall survival, with radical surgical extirpation as the primary management of vaginal melanoma. This study seeks to reevaluate, through case presentation and literature review, the usefulness of radical pelvic surgical procedures in the management of vaginal melanoma. CASE: Seven cases of primary vaginal melanoma were seen at the University of Virginia Hospital from 1966 to 1996; each was compared in terms of primary management, disease-free interval, sites of relapse, and overall survival. All patients who died of their disease relapsed locally prior to their death, with the exception of two patients who underwent wide local excision (WLE) followed by postoperative high-dose fractionation teletherapy. CONCLUSIONS: The use of WLE followed by high-dose fractionation teletherapy in the primary management of vaginal melanoma appears to provide excellent locoregional control, without the attendant morbidity and physical disfigurement associated with more radical surgical resection. The results reported here, as well as other published reports, suggest that locoregional control may be obtained with even large melanomas with radiotherapy when administered in high individual fractions (greater than 400 cGy/fx). This type of response is consistent with the higher response rate seen with cutaneous melanomas when large individual fractions are compared to conventional fractionation. Because of the extremely poor survival with vaginal melanoma regardless of primary therapy, novel therapeutic strategies, including further investigation into the use of high-dose fractionation irradiation, are urgently needed.

The association of human papillomavirus type 16 E6 and E7 antibodies with stage of cervical cancer.

OBJECTIVE: Previous investigators have reported higher HPV type 16 antibody positivity among cervical cancer patients than among healthy women. The objective of this study was to determine the association of HPV 16 antibody levels with the stage of cervical cancer. METHODS: Pretreatment tumor biopsies and sera were obtained from 137 newly diagnosed cervical cancer patients residing in Mexico. Using peptide ELISA and radioimmunoprecipitation assay (RIPA), HPV 16 E6- and E7-specific antibodies were measured. RESULTS: By ELISA, elevated antibody titers to HPV 16 E6 and E7 were detected in 16.8 and 32.8% of the women, respectively. While sera positivity did not differ by disease stage, the mean absorbance in the E7-positive sera was 0.42, 0.62, 0.91, and 0.81 for stages I to IV, respectively. Using RIPA, anti-E6 and E7 positivity was demonstrated in 46.7 and 38.7% of the females, respectively. Although no difference across disease stage was detected for E6, increasing proportions of positivity to E7 with stage of disease was detected. The rates for increasing disease stage were 0.14, 0.37, 0.40, and 0.67. Sera from the 6-month postradiation follow-up examinations of a small group of patients demonstrated a statistically significant decrease in antibody positivity from pretreatment positivity to HPV 16 E6 (n = 14; P = 0.01) and HPV 16 E7 (n = 20; P = 0.0001) using ELISA. CONCLUSIONS: These data suggest that HPV 16 E7 antibody positivity may be associated with stage of cervical cancer. Such immune parameters may be applicable to disease staging, monitoring of recurrence and, perhaps, diagnosis. Further investigation into the relationship of HPV 16 E6 and E7 antibodies with stage of cervical cancer and response to therapy is warranted.

Effects of stress management on clinical outcomes in rheumatoid arthritis.

OBJECTIVE: To examine the effects of stress-management training on clinical outcomes in persons with rheumatoid arthritis (RA). METHODS: Patients with RA (n = 141) were randomly assigned to 1 of 3 groups: a stress management group, an attention control group, or a standard care control group. The stress management and the attention control groups received a 10-week intervention followed by an additional 15-month maintenance phase. RESULTS: The stress management group showed statistically significant improvements on measures of helplessness, self-efficacy, coping, pain, and health status. Selected beneficial effects were still detectable at the 15-month followup evaluation. CONCLUSION: The data indicated that stress management interventions are capable of producing important clinical benefits for persons with RA.

Primary intraocular lens implantation in the setting of penetrating ocular trauma.

PURPOSE: To evaluate the clinical outcome of patients who underwent lensectomy and intraocular lens (IOL) implantation at the time of primary repair of a penetrating ocular injury. METHODS: A review of 14 patients who sustained cataracts and lens rupture in the setting of a corneal laceration to determine anatomic and visual outcome, in addition to complications related to the primary IOL. RESULTS: The IOL remained anatomically stable in all 14 patients with no complications encountered at implantation or after surgery. Final visual acuity in 9 of the 14 patients was 20/40 or better. Six patients underwent pars plana vitrectomy for removal of an intraocular foreign body. CONCLUSION: Intraocular lens implantation at the time of lensectomy and primary repair of a corneal laceration allows good visual rehabilitation with restoration of binocular function and serves as an alternative to contact lens correction in select patients.

The effect of folate and cobalamin on osteoarthritic hands.

OBJECTIVE: Historically diet and arthritis have been cause/effect associated but the idea is controversial with little evidence that specific diet components are effective treatment. This controlled, double-blinded, crossover study reports the effect of folate and cobalamin supplements in 26 humans diagnosed for an average 5.7 years with idiopathic osteoarthritis of the hands who had been medicated by prescribed nonsteroidal anti-inflammatory drugs (NSAID). METHODS: Subjects entered the study after a 10-day washout period from use of all anti-arthritis drugs, vitamins, and minerals. They were randomly allocated to consume daily 6400 micrograms folate or 6400 micrograms folate plus 20 micrograms cobalamin or lactose placebo each for 2 months within self-selected diets. Pain was to be medicated by acetaminophen as needed, and at the end of each phase they returned for assessment and dispensing of the next treatment. Serum folate and cobalamin, red blood cell folate, blood smears, diet records, standard rheumatology assessment and hand grip measurements were reviewed and statistically analyzed. RESULTS: For all subjects mean right and left hand grip values were higher with combined cobalamin-folate ingestion than with other "vitamin" supplements and were equivalent to NSAID use. Number of tender hand joints were greater with use of NSAID than with use of cobalamin-folate. Side effects with the vitamin combination were none; side effects of NSAID are many, and the cost of vitamins and acetaminophen also is lower. CONCLUSION: The limited number of subjects in this study demonstrates that ingestion of a prescribed cobalamin-folate supplement and acetaminophen as needed resulted in positive outcomes.

Association of immunoglobulin Km and Gm allotypes with specific antinuclear antibodies and disease susceptibility among connective tissue disease patients.

The distribution of the immunoglobulin Km(1) and Gm phenotypes was examined in patients with connective tissue diseases, including systemic lupus erythematosus, mixed connective tissue disease, and scleroderma, whose sera were characterized for antibodies against nuclear antigens and polypeptides of U small nuclear ribonucleoproteins. We found a strong association between Km(1) phenotype and susceptibility to systemic lupus erythematosus (P less than 0.00001, relative risk = 17). We also found a positive association between the Km(1) phenotype and the presence of anti-double-stranded DNA antibodies. The presence of certain immunoglobulin genes or gene families may have a role in susceptibility to the development of autoantibodies and/or of connective tissue disease.

Psychological symptoms in primary fibromyalgia syndrome: relationship to pain, life stress, and sleep disturbance.

Twenty-five subjects with primary fibromyalgia syndrome and 22 subjects with rheumatoid arthritis were compared on measures of psychological distress, pain, health status, life stress, sleep disturbance, and coping strategies. Higher levels of psychological distress were found in the primary fibromyalgia syndrome group, but the degree of life stress was shown to be a significant covariate.

Pathologic features of muscle in systemic lupus erythematosus: a biopsy series with comparative clinical and immunopathologic observations.

Clinical evidence of skeletal muscle involvement is frequent in systemic lupus erythematosus (SLE). In order to characterize the manifestations of SLE in skeletal muscle, a biopsy series on 19 patients with SLE was studied in terms of the histologic, histochemical, and direct immunofluorescent features of skeletal muscle. The results were correlated with clinical and laboratory data. The histologic spectrum included inflammatory myopathy, vasculitis, perifascicular atrophy, and neurogenic atrophy. Histochemical examination revealed type I fiber predominance in 44 per cent of patients and selective type II fiber atrophy in 33 per cent. Direct immunofluorescent examination of skeletal muscle biopsy specimens revealed immunoglobulin and complement deposition in vessel walls, in sarcolemmal basement-membrane areas, and within non-necrotic muscle fibers. The histologic, histochemical, and immunochemical findings are correlated with the findings in other organ systems.