Usefulness of the triple test score for palpable breast masses; discussion 1012-3.

HYPOTHESIS: The triple test score (TTS) is useful and accurate for evaluating palpable breast masses. DESIGN: Diagnostic test study. SETTING: University hospital multidisciplinary breast clinic. PATIENTS: Four hundred seventy-nine women with 484 palpable breast lesions evaluated by TTS from 1991 through July 2000. MAIN OUTCOME MEASURES: Physical examination, mammography, and fine-needle aspiration were each assigned a score of 1, 2, or 3 for benign, suspicious, or malignant results; the TTS is the sum of these scores. The TTS has a minimum score of 3 (concordant benign) and a maximum score of 9 (concordant malignant). The TTS was correlated with subsequent histopathologic analysis or follow-up. INTERVENTIONS: The TTS was prospectively calculated for each mass. Lesions with a TTS greater than or equal to 5 were excised for histologic confirmation, whereas lesions with scores less than or equal to 4 were either excised (n = 60) or followed clinically (n = 255). RESULTS: All lesions with TTS less than or equal to 4 were benign on clinical follow-up, including 8 for which the fine-needle aspiration was the suspicious component. Of the 60 biopsied lesions, 51 were normal breast tissue, 4 showed fibrocystic change, 1 was a papilloma, and 4 were atypical hyperplasia. All lesions with a TTS greater than or equal to 6 (n = 130) were confirmed to be malignant on biopsy. Thus, a TTS less than or equal to 4 has a specificity of 100% and a TTS greater than or equal to 6 has a sensitivity of 100%. Of the 39 lesions (8%) with scores of 5, 19 (49%) were malignant, and 20 (51%) were benign. CONCLUSIONS: The TTS reliably guides evaluation and treatment of palpable breast masses. Masses scoring 3 or 4 are always benign. Masses with scores greater than or equal to 6 are malignant and should be treated accordingly. Confirmatory biopsy is required only for the 8% of the masses that receive a TTS of 5.

Induction of anti-mammary cancer immunity by engaging the OX-40 receptor in vivo.

The OX-40 receptor (OX-40R) is a member of the tumor necrosis factor receptor (TNF-R) superfamily that is expressed on activated CD4+ T cells. The OX-40R is a costimulatory molecule that induces CD4+ T cell activation when engaged by its ligand (OX-40 L; found on antigen presenting cells). In human and murine tumors, we have shown upregulation of the OX-40R on CD4+ T cells from tumor-infiltrating lymphocytes (TIL) and tumor-draining lymph node cells (TDLNC) but not on systemic CD4+ T cells, such as peripheral blood lymphocytes (PBL) or splenocytes. In order to examine potentially heightened anti-tumor immunity through enhanced costimulation when engaging OX-40R in vivo, we inoculated mice with a murine mammary cancer cell line (SM1) and then treated with a soluble form of the OX-40 L. Mice injected with a lethal inoculum of SM1 cells were given two intraperitoneal injections (days 3 and 7 post-inoculation) of 100 microg soluble OX-40 L. Seven of 28 treated mice survived the lethal tumor inoculum, as compared to one of 28 control mice, demonstrating a significant survival benefit with treatment (p = 0.0136, log rank analysis). Mice that did not develop tumor by day 90 were rechallenged; all remained tumor-free. Mice were also injected with a second mammary tumor line (4T1) and treated with OX-40L:Ig with similar therapeutic results. Activation of OX-40R+ CD4+ T cells during mammary cancer priming stimulated an antitumor immune response resulting in enhanced survival and protective anti-tumor immunity. These results should have practical applications for treatment modalities for patients with breast cancer.

Usefulness of preoperative lymphoscintigraphy for the identification of sentinel lymph nodes in melanoma.

BACKGROUND: The exact role of lymphoscintigraphy (LS) in the evaluation of sentinel lymph nodes (SLNs) in melanoma is controversial. METHODS: We reviewed our experience with preoperative LS for the determination of the lymph node drainage pattern of clinically node negative primary melanomas, with attention to the rate of ambiguous drainage and the effect of previous wide local excision (WLE). RESULTS: The scans of 87 patients who underwent LS at our institution for evaluation of their primary melanomas from 1995 to the present were reviewed. Fourteen of the primary tumor sites were in the head and neck region, 41 were truncal, and 32 were in the extremities. The average tumor thickness was 2.6 mm. Nine of 14 (64%) head/neck lesions and 12 of 41 (29%) truncal lesions displayed ambiguous drainage, as compared with only 2 of 32 (6%) extremity lesions (P <0.05). Forty-one of the 87 patients (47%) had undergone previous WLE of their primary lesion prior to their LS. The number of draining basins for the WLE and the non-WLE groups were not significantly different, and at least one SLN was found for all WLE cases. CONCLUSIONS: Preoperative LS is important for the treatment planning of SLN biopsy for head/neck and truncal melanomas, but adds little additional information for extremity lesions. Lymph node drainage scans and subsequent SLN biopsies are not contraindicated in the presence of a prior WLE.

Lymph nodes in the human female breast: a review of their detection and significance.

Our experience led us to test the hypothesis that lymph nodes are not uncommon within the substance of the human female breast mound. The following specimen types and sources were used to survey the presence of intramammary lymph nodes in the human female breast mound: (1) cadaver breasts; (2) community hospital breast specimens; and (3) university and VA hospital specimens. We found true lymph nodes within and associated with breast specific tissue (ie, tissue that includes duct and gland structures), thereby validating the hypothesis posed. We discuss the significance of these findings in terms of our dominant patient care paradigm (the Triple Test-physical examination, imaging, and fine-needle aspiration [FNA]) and the choice of patient care management options. We conclude the following: lymph nodes occur in any quadrant of the breast mound; recognizing the possibility of intramammary lymph nodes is important when choosing between patient management options; intramammary lymph nodes can be sampled by FNA; intramammary lymph nodes can contain various disease processes; and in the Oregon Health Sciences University Multidisciplinary Breast Clinic, these intramammary lymph nodes are commonly identified by imaging methods and are more likely to be sampled by FNA than either by core or excisional biopsy.

Prevention of local recurrence after surgical debulking of nodal and subcutaneous melanoma deposits by hypofractionated radiation.

BACKGROUND: Local recurrence (LR) after surgical debulking of nodal or subcutaneous melanoma deposits defeats the purpose of operation and may worsen prognosis if the procedure was performed for stage III disease. To decrease LR rates in this setting, we extended the previously described role of hypofractionated radiation for melanoma deposits of the neck to all situations where the patient was felt to be at high risk for postoperative relapse after resection of bulky disease. METHODS: Hypofractionated external beam radiation was administered in 6-Gy doses for 5 fractions (total dose 30 Gy, given over a median of 15 elapsed days) to 42 resected melanoma deposit sites in 41 patients. RESULTS: Stages of the 41 patients at the time of treatment were: 22 stage III and 19 stage IV. All patients had complete gross resection of disease at the radiation site before radiation. Mean time between operation and initiation of radiation was 4 weeks. The 42 sites of treatment included 27 neck, 9 axilla, 3 groin, and 3 subcutaneous deposits. There were no treatment-related deaths; side effects were minimal and self-limited. Transient erythema, desquamation, fibrosis, telangiectasias, and mucositis, parotiditis, and xerostomia (for head and neck radiation) were reported, but no patient required interruption of therapy for these events. Of the 42 treated sites, only 2 recurred in the treatment field (one neck, one axilla) during the mean follow-up time of 22.4 months, for a treatment failure rate of 4.8%. This represents improved local control compared with patients treated with surgery alone at our institution and with published recurrence rates. CONCLUSIONS: The addition of hypofractionated radiation therapy after resection of nodal and subcutaneous melanoma deposits at a variety of sites is a rapid and well-tolerated method of providing excellent local control.

Office-based wire-guided open breast biopsy under local anesthesia is accurate and cost effective.

BACKGROUND: Mammographic abnormalities found to be malignant by stereotactic biopsy still require a wire-guided biopsy (WGB) in most cases. We have previously described a simplified method of WGB that allows the procedure to be done with a minimum of dissection and under local anesthesia in the office setting. We hypothesized that this procedure can be used to produce cost-effective, office-based breast preservation therapy (BPT). METHODS: We reviewed our recent experience with this WGB method to determine applicability and accuracy in the office setting. A cost-effectiveness analysis was also performed to determine potential charge reductions when this method is used to avoid operating room (OR) usage for either lumpectomy or lumpectomy plus sentinel lymph node biopsy (SLNB). RESULTS: Of the 164 biopsies reviewed, 114 (70%) were performed in the office setting under local anesthesia and 50 (30%) were performed in the OR. The most common reasons for choosing the OR setting included performance of biopsy during an unrelated procedure requiring the OR (16 cases), patient preference (12), deep lesions (6), and the inability of the patient to cooperate with local anesthesia (5). The complication rates were similar between the two settings (7% for office-based and 4% for OR; P = 0.697), and in neither setting were any lesions missed. A cost-effectiveness analysis using our Current Procedure Terminology (CPT)-based charges revealed a potential per-case charge reduction of $4,632 for office-based lumpectomy and $4306 for office-based lumpectomy/SLNB, using our method of WGB and local anesthesia, compared with the OR setting. CONCLUSIONS: Office-based WGB using our previously described method is accurate and can be applied to at least 70% of patients. Based on the favorable results of our cost analysis and rising support for SLNB, we anticipate increased utilization of the clinic setting and local anesthesia for BPT in the future.

Engagement of the OX-40 receptor in vivo enhances antitumor immunity.

The OX-40 receptor (OX-40R), a member of the TNFR family, is primarily expressed on activated CD4+ T lymphocytes. Engagement of the OX-40R, with either OX-40 ligand (OX-40L) or an Ab agonist, delivers a strong costimulatory signal to effector T cells. OX-40R+ T cells isolated from inflammatory lesions in the CNS of animals with experimental autoimmune encephalomyelitis are the cells that respond to autoantigen (myelin basic protein) in vivo. We identified OX-40R+ T cells within primary tumors and tumor-invaded lymph nodes of patients with cancer and hypothesized that they are the tumor-Ag-specific T cells. Therefore, we investigated whether engagement of the OX-40R in vivo during tumor priming would enhance a tumor-specific T cell response. Injection of OX-40L:Ig or anti-OX-40R in vivo during tumor priming resulted in a significant improvement in the percentage of tumor-free survivors (20-55%) in four different murine tumors derived from four separate tissues. This anti-OX-40R effect was dose dependent and accentuated tumor-specific T cell memory. The data suggest that engagement of the OX-40R in vivo augments tumor-specific priming by stimulating/expanding the natural repertoire of the host's tumor-specific CD4+ T cells. The identification of OX-40R+ T cells clustered around human tumor cells in vivo suggests that engagement of the OX-40R may be a practical approach for expanding tumor-reactive T cells and thereby a method to improve tumor immunotherapy in patients with cancer.

Assessing the need for Clinical Breast Examination (CBE) training: the Oregon experience.

BACKGROUND: Despite the widely held perception that CBE training has high priority among the continuing medical education (CME) needs of breast health care providers, there is actually little published information to support this notion. METHODS: The authors conducted a statewide needs assessment mail survey of providers regarding a number of potential CME needs, including CBE training. RESULTS: Of the 4,179 surveys from the single mailing, 1,427 were returned (34% response rate). Six categories of provider types responded; 51% were physicians and 23% were nurse practitioners. Fifty-nine percent of the respondents were female; 96% felt that routine CBE was an important or very important part of providing breast care. Although 79% of all respondents performed CBE at least weekly and 41% performed more than ten CBEs/week, 80% were interested in receiving some form of CME regarding CBE, and 79% of those who performed CBE at least weekly were interested in receiving skill-based CBE training. CONCLUSIONS: Despite the respondent bias inherent in survey studies, it can be concluded that there is indeed a CME need for CBE training, even among providers who perform CBE frequently. Based on these findings the authors are implementing a statewide CME program of CBE training.

Clinical experiences of medical students in Oregon with dying patients.

BACKGROUND: In Oregon only 31% of patients now die in acute care hospitals. This transformation carries profound implications for undergraduate medical education. METHODS: Students graduating from Oregon Health Sciences University between 1996 and 1998 were surveyed regarding their direct clinical involvement in the care of dying patients. RESULTS: Students had cared for substantial numbers of dying patients, and nearly all had participated in important advance planning discussions. However, student involvement had diminished markedly towards the latter stages of dying. Forty-five percent of the students had cared for two or fewer patients who died while still in the hospital. Even when patients died in the hospital, the students had rarely been present at the bedside at the time of patient death. Forty-two percent of the students had graduated having never witnessed a patient death. CONCLUSIONS: The findings highlight the need to create opportunities for students to care for dying patients in settings outside the acute care hospital.

Teaching medical students to give bad news: does formal instruction help?

BACKGROUND: In 1994, the Oregon Health Sciences University instituted an integrated course (Principles of Clinical Medicine; PCM) of classroom and outpatient clinic experience designed to give first- and second-year medical students a head start in clinical skills. During their third year, the students have been periodically evaluated by objective structured clinical examinations (OSCEs). Part of the OSCE assesses the student's skills in giving bad news by means of role playing. Assessment criteria fall into those measuring knowledge and those evaluating humanistic skills. METHODS: To evaluate whether formal instruction in giving bad news leads to an improvement in a medical student's skills, the bad-news portions of the OSCE scores of third-year medical students taught by the old curriculum (OC) were compared with those of third-year students who had taken PCM. RESULTS: While bad news knowledge scores did not differ significantly between the two groups of students, the average bad-news humanistic score was significantly better for the PCM group (85% vs 79%; p = 0.05). There was no significant difference in average scores for either knowledge or humanistic skills between male and female students in the PCM group. The benefit of PCM regarding delivering bad news was also reflected by a survey of attending physicians who had taught students under both the old and the new curricula. The majority of those surveyed scored students' skills in related areas better after PCM. CONCLUSION: Formal instruction in the first two years of medical school improved students' humanistic skills as they relate to the delivery of bad news.

Examining the immune response in sentinel lymph nodes of mice and men.

Recently, it was recognized that an immune response develops along one of two major pathways. One leads to a destructive immune response (type 1), while the alternative leads to a nondestructive immune response (type 2). Our studies in animal models suggest that therapeutic vaccines induce a tumor-specific type 1 immune response while ineffective vaccines induce a type 2 response. These results have led us to examine the immune response in sentinel lymph nodes draining tumor vaccines of patients entered onto clinical trials for melanoma, breast and renal cell cancer.

Submandibular gland carcinoma ex pleomorphic adenoma. Report of a case with cytologic features and diagnostic pitfalls.

BACKGROUND: Carcinoma ex pleomorphic adenoma is a rare neoplasm of the salivary gland. This lesion, also known as malignant mixed tumor, occurs when a malignant tumor arises in the epithelial component of a pleomorphic adenoma. Reports of fine needle aspiration biopsy (FNAB) diagnosis of malignant mixed tumors are rare and have been limited to cases arising in the parotid. Cytologic features and diagnostic pitfalls of this uncommon neoplasm are presented. CASE: A 75-year-old male presented with a nontender submandibular mass. The lesion had been present 12 months, with a recent increase in size. FNAB was performed, and the smears revealed a mixture of benign and malignant areas. The benign portion of the smears showed findings typical of pleomorphic adenoma. The malignant area showed large cells occurring singly and in groups. The malignant cells contained pleomorphic nuclei with irregular nuclear membranes and prominent macronucleoli; cytologically, they resembled cells from a poorly differentiated adenocarcinoma. CONCLUSION: We present the first case of carcinoma ex pleomorphic adenoma of the submandibular gland correctly diagnosed by FNAB. This rare salivary gland malignancy can be accurately diagnosed on FNAB if strict criteria are applied.

Accurate evaluation of palpable breast masses by the triple test score.

BACKGROUND: We previously reported that the triple test (physical examination, mammography, and fine needle aspiration) for palpable breast masses yields 100% diagnostic accuracy when all 3 components are concordant (all benign or all malignant). However, 40% of cases are nonconcordant and require open biopsy. OBJECTIVE: To evaluate our experience with the triple test to develop a method to further limit the need for surgical biopsy. DESIGN: Diagnostic test study. SETTING: University hospital multidisciplinary breast clinic. PATIENTS: Two hundred fifty-nine patients with 261 palpable breast masses studied between 1991 and 1997. INTERVENTION: The triple test was prospectively applied to each breast mass. Each component of the triple test was assigned 1, 2, or 3 points for a benign, suspicious, or malignant result, respectively, yielding a total triple test score (TTS). MAIN OUTCOME MEASURES: The TTS was correlated with subsequent histopathologic examination results. RESULTS: Eighty-eight masses had a TTS of more than 6 points; all had malignant histopathologic characteristics. One hundred fifty-two masses had a TTS of 4 points or lower; all were benign. In both groups, diagnostic accuracy and predictive value were 100%, with P<.001. Twenty-one masses had a TTS of 5 points; of these, 13 (62%) were benign and 8 (38%) were malignant. CONCLUSIONS: The TTS reliably guides evaluation and treatment of palpable breast masses. Masses that score 6 points or higher are malignant and should undergo definitive therapy; masses that score 4 points or lower are benign and may be clinically followed up. Only those masses that score 5 points (8% of our database) require open biopsy.

Relationships between operative approaches and outcomes in esophageal cancer.

BACKGROUND: Controversy exists whether patients with esophageal carcinoma are best managed with Ivor-Lewis (IL) or transhiatal (TH) esophagectomy. The TH approach is presumed to be superior with respect to operative time, leak rates, morbidity/mortality, and length of stay (LOS), but may represent an inferior cancer operation compared with formal IL. Accordingly, we reviewed the results of our esophageal resections to compare these outcome parameters for each operative approach. METHODS: We performed a retrospective review of all esophagectomies performed at Oregon Health Sciences University and Portland Veterans Affairs Medical Center between 1987 and 1996. Survival was determined by the Kaplan-Meier method, and comparisons between the IL and TH groups were made with Student's t test, Fisher's exact test, and log-rank analysis. RESULTS: Seventy-eight patients were identified. Forty patients had IL and 38 had TH. Fifty-eight patients had adenocarcinoma, 19 had squamous cell, and 1 had an unknown histology. Mean operative time was 389 minutes for IL versus 275 minutes for TH (P = 0.0001). Leak rates were 7.5% for IL and 13% for TH (P = 0.21). There were no significant differences between IL and TH with respect to other types of complications, operative deaths, blood loss, need for transfusion, LOS, stricture rates, or need for dilatation. Overall mean survival was 12 months. Mean survival rates were 8 months for IL and 12 for TH (P = NS), and were also equivalent when compared by histology and stage for stage. CONCLUSIONS: We conclude that IL and TH are comparable operations with equivalent survival rates. The TH approach did not decrease the incidence of complications, transfusions, leaks, strictures, or subsequent dilatations. Although TH requires less operating room time, this does not translate into a decrease in LOS. Either approach appears to be acceptable depending on surgeons' preferences and appropriate patient selection.

Presence of the T-cell activation marker OX-40 on tumor infiltrating lymphocytes and draining lymph node cells from patients with melanoma and head and neck cancers.

BACKGROUND: The OX-40 antigen is a cell surface glycoprotein in the tumor necrosis factor receptor family that is expressed primarily on activated CD4+ T cells. Selective target organ expression of the OX-40 receptor on autoantigen specific T cells has been found in autoimmune disease. In order to evaluate whether OX-40 is expressed on T cells from patients with nodal-draining carcinomas, OX-40 expression was assessed in tumor infiltrating lymphocytes (TILs), draining lymph node cells (DLNCs), and/or peripheral blood lymphocytes (PBLs) of 13 patients with head and neck squamous cell carcinomas and 9 patients with melanomas. METHODS: Cell phenotype was determined by fluorescence cell analysis using a monoclonal antibody to human OX-40, and CD4+ T cell lymphokine production was determined by reverse transcriptase-polymerase chain reaction (RT-PCR). RESULTS: Expression of the OX-40 receptor was found in as many as 31% of the TILs and as many as 28% of the DLNCs tested. Conversely, no OX-40 expression was found in PBLs. In addition, CD4+ T cells isolated from DLNCs (but not from TILs or PBLs) secreted a Th1 pattern of cytokines (IL-2, gamma interferon). Co-culture of autologous CD4+ TILs with an MHC class II+ melanoma cell line transfected with OX-40 ligand cDNA resulted in T cell proliferation and in vitro tumor regression. CONCLUSIONS: These findings suggest that OX-40+ CD4+ T cells isolated from tumors and their adjacent draining nodes may represent a tumor-specific population of activated T cells capable of mediating tumor reactivity. These cells may play an exploitable role in future trials of immunotherapy.

Diagnosis of palpable breast lesions in younger women by the modified triple test is accurate and cost-effective.

OBJECTIVE: To study the accuracy and cost of diagnosing palpable breast lesions in younger patients using a modified triple test (MTT: physical examination, ultrasonography instead of mammography, and fine-needle aspiration). DESIGN: Diagnostic test study and cost-effectiveness estimate. SETTING: Multidisciplinary university breast clinic. PATIENTS: Fifty-five women below the recommended age of screening mammography (mean age, 33 years) with unilateral, palpable breast lesions. INTERVENTION: Each lesion was tested by all 3 elements of MTT, and each element was interpreted as benign, suspicious, or malignant. MAIN OUTCOME MEASURES: Patients with MTTs in which all elements were concordant (in agreement) and benign were evaluated clinically (mean follow-up, 11 months). Patients in whom the results of fine-needle aspiration were scored as suspicious or malignant underwent open confirmatory biopsy. RESULTS: Forty-eight patients had concordant benign MTTs, including 14 patients with breast cysts. No cancers developed at the index sites during follow-up, including 5 biopsies done at the patients' request (negative predictive value and specificity, 100%). Fine-needle aspiration and physical examination were more accurate than ultrasonography in the 7 cases in which MTT was nonconcordant. Compared with the criterion standard (physical examination and open biopsy), use of MTT under the conditions of this study could avoid open biopsies in almost all cases, with average savings in charges of up to $623 per case. CONCLUSION: Use of MTT for the diagnosis of unilateral, palpable breast lesions in younger women yields high diagnostic accuracy without the need for routine open biopsy, resulting in an overall reduction in patient charges.

Synchronous non-small cell lung cancers.

INTRODUCTION: The few series of synchronous lung cancers have included small cell and carcinoid tumors. We wished to determine the prognosis for patients with synchronous non-small cell lung cancer (NSCLC). METHODS: A database of 3034 lung cancer patients was reviewed for synchronous NSCLC. Survival was determined by Kaplan-Meier method and compared by log-rank analysis. RESULTS: There were 27 patients (0.8%). Fourteen were completely resected (CR) and had a 5-year survival rate of 45% The 5-year survival rate for patients whose highest stage tumor was stage I or II was 38%, versus 0% for patients whose highest tumor stage of III (P = 0.01). The 5-year survival rate for patients with two stage I tumors was 41% versus 0% for patients with 2 stage III tumors (P = 0.03). The 5-year survival rate for patients treated with wedge resections was similar to that for patients treated with lobectomies or pneumonectomy (L/P). CONCLUSIONS: We conclude that the prognosis for patients with synchronous NSCLC may not be dismal if both tumors are resectable and stage I or II. Wedge resections are an alternative for those who cannot tolerate L/P.