Long-term outcomes to neoadjuvant pembrolizumab based on pathological response for patients with resectable stage III/IV cutaneous melanoma.

BACKGROUND: While neoadjuvant immunotherapy for melanoma has shown promising results, the data have been limited by a relatively short follow-up time, with most studies reporting 2-year outcomes. The goal of this study was to determine long-term outcomes for stage III/IV melanoma patients treated with neoadjuvant and adjuvant programmed cell death receptor 1 (PD-1) inhibition. PATIENTS AND METHODS: This is a follow-up study of a previously published phase Ib clinical trial of 30 patients with resectable stage III/IV cutaneous melanoma who received one dose of 200 mg IV neoadjuvant pembrolizumab 3 weeks before surgical resection, followed by 1 year of adjuvant pembrolizumab. The primary outcomes were 5-year overall survival (OS), 5-year recurrence-free survival (RFS), and recurrence patterns. RESULTS: We report updated results at 5 years of follow-up with a median follow-up of 61.9 months. No deaths occurred in patients with a major pathological response (MPR, <10% viable tumor) or complete pathological response (pCR, no viable tumor) (n = 8), compared to a 5-year OS of 72.8% for the remainder of the cohort (P = 0.12). Two of eight patients with a pCR or MPR had a recurrence. Of the patients with >10% viable tumor remaining, 8 of 22 patients (36%) had a recurrence. Additionally, the median time to recurrence was 3.9 years for patients with ≤10% viable tumor and 0.6 years for patients with >10% viable tumor (P = 0.044). CONCLUSIONS: The 5-year results from this trial represent the longest follow-up of a single-agent neoadjuvant PD-1 trial to date. Response to neoadjuvant therapy continues to be an important prognosticator with regard to OS and RFS. Additionally, recurrences in patients with pCR occur later and are salvageable, with a 5-year OS of 100%. These results demonstrate the long-term efficacy of single-agent neoadjuvant/adjuvant PD-1 blockade in patients with a pCR and the importance of long-term follow-up for these patients. TRIAL REGISTRATION: Clinicaltrials.gov, NCT02434354.

Characteristics of pyrexia in BRAFV600E/K metastatic melanoma patients treated with combined dabrafenib and trametinib in a phase I/II clinical trial.

BACKGROUND: Pyrexia is a frequent adverse event with combined dabrafenib and trametinib therapy (CombiDT), but little is known of its clinical associations, etiology, or appropriate management. PATIENTS AND METHODS: All patients on the BRF133220 phase I/II trial of CombiDT treated at the standard dose (150/2) were included for assessment of pyrexia (n = 201). BRAF and MEK inhibitor-naïve patients (n = 117) were included for efficacy analyses. Pyrexia was defined as temperature ≥38°C (≥100.4(°)F) or related symptoms. RESULTS: Fifty-nine percent of patients developed pyrexia during treatment, 24% of which had pyrexia symptoms without a recorded elevation in body temperature. Pyrexia was grade 2+ in 60% of pyrexia patients. Median time to onset of first pyrexia was 19 days, with a median duration of 9 days. Pyrexia patients had a median of two pyrexia events, but 21% had three or more events. Various pyrexia management approaches were conducted in this study. A trend was observed between dabrafenib and hydroxy-dabrafenib exposure and pyrexia. No baseline clinical characteristics predicted pyrexia, and pyrexia was not statistically significantly associated with treatment outcome. CONCLUSIONS: Pyrexia is a frequent and recurrent toxicity with CombiDT treatment. No baseline features predict pyrexia, and it is not associated with clinical outcome. Dabrafenib and metabolite exposure may contribute to the etiology of pyrexia. The optimal secondary prophylaxis for pyrexia is best studied in a prospective trial.

Sorafenib in advanced melanoma: a Phase II randomised discontinuation trial analysis.

The effects of sorafenib--an oral multikinase inhibitor targeting the tumour and tumour vasculature--were evaluated in patients with advanced melanoma enrolled in a large multidisease Phase II randomised discontinuation trial (RDT). Enrolled patients received a 12-week run-in of sorafenib 400 mg twice daily (b.i.d.). Patients with changes in bi-dimensional tumour measurements <25% from baseline were then randomised to sorafenib or placebo for a further 12 weeks (ie to week 24). Patients with > or =25% tumour shrinkage after the run-in continued on open-label sorafenib, whereas those with > or =25% tumour growth discontinued treatment. This analysis focussed on secondary RDT end points: changes in bi-dimensional tumour measurements from baseline after 12 weeks and overall tumour responses (WHO criteria) at week 24, progression-free survival (PFS), safety and biomarkers (BRAF, KRAS and NRAS mutational status). Of 37 melanoma patients treated during the run-in phase, 34 were evaluable for response: one had > or =25% tumour shrinkage and remained on open-label sorafenib; six (16%) had <25% tumour growth and were randomised (placebo, n=3; sorafenib, n=3); and 27 had > or =25% tumour growth and discontinued. All three randomised sorafenib patients progressed by week 24; one remained on sorafenib for symptomatic relief. All three placebo patients progressed by week-24 and were re-started on sorafenib; one experienced disease re-stabilisation. Overall, the confirmed best responses for each of the 37 melanoma patients who received sorafenib were 19% stable disease (SD) (ie n=1 open-label; n=6 randomised), 62% (n=23) progressive disease (PD) and 19% (n=7) unevaluable. The overall median PFS was 11 weeks. The six randomised patients with SD had overall PFS values ranging from 16 to 34 weeks. The most common drug-related adverse events were dermatological (eg rash/desquamation, 51%; hand-foot skin reaction, 35%). There was no relationship between V600E BRAF status and disease stability. DNA was extracted from the biopsies of 17/22 patients. Six had V600E-positive tumours (n=4 had PD; n=1 had SD; n=1 unevaluable for response), and 11 had tumours containing wild-type BRAF (n=9 PD; n=1 SD; n=1 unevaluable for response). In conclusion, sorafenib is well tolerated but has little or no antitumour activity in advanced melanoma patients as a single agent at the dose evaluated (400 mg b.i.d.). Ongoing trials in advanced melanoma are evaluating sorafenib combination therapies.

A randomized phase II pilot trial of adjuvant marimastat in patients with early-stage breast cancer.

BACKGROUND: This pilot trial was performed to evaluate the safety, toxicity and pharmacokinetics of chronic therapy with the matrix metalloproteinase inhibitor marimastat in the adjuvant treatment of breast cancer. PATIENTS AND METHODS: Patients with high-risk node negative or node positive breast cancer received marimastat either 5 or 10 mg p.o. b.i.d. for 12 months. Marimastat was given either as a single agent following completion of adjuvant chemotherapy or concurrently with tamoxifen. RESULTS: Sixty-three patients were enrolled from June 1997 to May 1998. All patients have completed 12 months of treatment or have discontinued therapy due to toxicity, relapse or intercurrent illness. Moderate (WHO criteria) arthralgia/arthritis was reported by 34% of patients receiving 5 mg b.i.d. and 45% of patients receiving 10 mg b.i.d.; severe arthralgia/arthritis was reported by 6% and 23% of patients, respectively. Six patients (19%) receiving 5 mg b.i.d. and 11 (35%) receiving 10 mg b.i.d. discontinued marimastat therapy due to toxicity. Trough plasma levels were rarely within the target range for biological activity (40-200 ng/ml) with mean concentration for patients receiving: 5 mg b.i.d. = 7.5; 5 mg b.i.d. plus tamoxifen = 6.9; 10 mg b.i.d. = 11.9; 10 mg b.i.d. plus tamoxifen = 12.8. CONCLUSIONS: A randomized adjuvant trial with marimastat is not warranted as chronic administration cannot maintain plasma levels with the target range.

Review of the 2001 AJCC staging system for cutaneous malignant melanoma.

The American Joint Committee on Cancer (AJCC) staging system for melanoma has recently been revised and published. The previous staging system had not been substantially modified since the late 1980s. In a series of papers, the staging system for melanoma was critically analyzed, and many shortcomings were identified. Many well-established prognostic factors were not used in the staging system. This assessment has led to a substantially modified staging system for cutaneous melanoma in 2001 that is a considerable improvement over past staging systems, albeit more complex. The following modifications are the most important: 1) The primary determinant of tumor (T) staging is tumor thickness as measured in millimeters. The Clark level of invasion is now used only for defining T1 (< or = 1mm) melanomas; 2) The cutpoints for tumor thickness are less than or equal to 1 mm, 1 to 2 mm, 2 to 4 mm, and greater than 4 mm; 3) Ulceration has been added in describing the primary tumor; 4) Local recurrence, satellite disease, and in-transit metastases have similar prognosis and are now all classified together as regional stage III disease; 5) Size of lymph node as prognostic factor has been eliminated and replaced with the number of positive nodes; 6) The presence of an elevated serum lactic dehyrogenase level is used in the metastasis (M) category. This revised staging system more precisely defines prognosis and will improve the stratification of patients in future clinical trials.

Locally recurrent malignant melanoma characteristics and outcomes: a single-institution study.

Despite improvements in the identification and treatment of melanoma, local recurrence continues to challenge the success of current melanoma therapy. A retrospective analysis of 1,996 patients presenting from 1990 to 1997 at the Pigmented Lesion Group of the University of Pennsylvania was performed to assess clinical characteristics and outcomes of locally recurrent melanoma. The cases were analyzed by chart and pathological slide review. A control group was identified for statistical comparison. The incidence of locally recurrent melanoma during the study period was 2.2%. Lentigo maligna melanoma (LMM) accounted for 37% of the local recurrences. Increased tumor thickness and microsatellites were associated with "early" local recurrence and decreased survival from time of recurrence. Nineteen percent of the local recurrences occurred more than 5 years after the initial definitive treatment. The preponderance of locally recurrent LMM suggests the need for refinements in the techniques of margin identification and surgical excision of LMM. Tumors with increased thickness and microsatellites should receive particularly close attention. Lastly, with nearly 20% of the local recurrences occurring more than 5 years after the initial date of treatment, the authors suggest extending the follow-up time for all melanoma lesions beyond 5 years.

The impact of a multidisciplinary breast cancer center on recommendations for patient management: the University of Pennsylvania experience.

BACKGROUND: Advances in the diagnosis and treatment of breast carcinoma have led to a multidisciplinary approach to management for patients with breast carcinoma. To assess the effect of this approach, the authors performed an evaluation for a cohort of patients examined in a multidisciplinary breast cancer center. METHODS: An analysis was performed for the records of 75 consecutive women with 77 breast lesions examined in consultation in a multidisciplinary breast cancer center between January and June 1998. Each patient's case was evaluated by a panel consisting of a medical oncologist, surgical oncologist, radiation oncologist, pathologist, diagnostic radiologist, and, when indicated, plastic surgeon. A comprehensive history and physical examination was performed, and the relevant mammograms, pathology slides, and medical records were reviewed. Treatment recommendations made before this evaluation were compared with the consensus recommendations made by the panel. RESULTS: For the 75 patients, the multidisciplinary panel disagreed with the treatment recommendations from the outside physicians in 32 cases (43%), and agreed in 41 cases (55%). Two patients (3%) had no treatment recommendation before consultation. For the 32 patients with a disagreement, the treatment recommendations were breast-conservation treatment instead of mastectomy (n = 13; 41%) or reexcision (n = 2; 6%); further workup instead of immediate definitive treatment (n = 10; 31%); treatment based on major change in diagnosis on pathology review (n = 3; 9%); addition of postmastectomy radiation treatment (n = 3; 9%); or addition of hormonal therapy (n = 1; 3%). CONCLUSIONS: The multidisciplinary breast cancer evaluation program provided an integrated program in which individual patients were evaluated by a team of physicians and led to a change in treatment recommendation for 43% (32 of 75) of the patients examined. This multidisciplinary program provided important second opinions for many patients with breast carcinoma.

Early stage (I, II, III) melanoma.

Metastatic melanoma beyond the regional nodes (American Joint Committee on Cancer stage IV) is a highly lethal disease. Few affected individuals survive beyond 5 years despite aggressive treatment. Clearly, effective adjuvant therapies to prevent the development of stage IV disease in at-risk patients are worthwhile and acceptable to patients, even if they are associated with significant toxicities. Improvements in our understanding of the prognosis and staging of melanoma have allowed us to better categorize patients based on their risk of developing metastatic disease, permitting the development of logical strategies using adjuvant therapies with toxicity profiles that are appropriate based on the level of risk for recurrence. Adherence to the standards of care for the surgical management of melanoma patients with high-risk primary disease or regional disease will help optimize the benefit that can be derived from adjuvant therapy. Clinical trials remain critically important as we seek to improve the outcome for melanoma patients, but for high-risk melanoma patients outside the context of clinical trials, adjuvant therapy with high-dose interferon-alfa2b should be considered a standard treatment option.

Metastatic melanoma.

The overall survival for patients with metastatic melanoma ranges from 4.7 to 11 months, with a median survival of 8.5 months. Standard treatment for patients with metastatic melanoma has not been defined. The range of treatment options includes close observation, surgical resection of isolated metastases, therapy with dacarbazine, combination chemotherapy, and participation in clinical trials. Numerous chemotherapeutic agents have shown activity in the treatment of malignant melanoma. Dacarbazine (DTIC-Dome; Bayer Corporation, West Haven, CT) has a response rate of 15% to 20% and remains the reference agent for the treatment of metastatic disease. Additional agents with single-agent activity include cisplatin, (Platinol-AQ; Bristol-Myers Oncology, Princeton, NJ); carmustine (BiCNU; Bristol-Myers Oncology, Princeton, NJ); paclitaxel (Taxol; Bristol-Myers Squibb, Princeton, NJ); and docetaxel (Taxotere; Rhone-Poulenc Rorer Pharmaceuticals, Collegeville, PA). Temozolomide (Temodar; Schering-Plough, Kenilworth, NJ), which is essentially an oral form of dacarbazine but with greater central nervous system penetrance, is associated with a response rate of 20%. Combination chemotherapy with or without tamoxifen has been extensively evaluated in patients with metastatic melanoma. Although the initial results with the Dartmouth regimen (dacarbazine, cisplatin, carmustine, and tamoxifen) were associated with overall response rates of 50% to 55% in single-institution studies, results from larger multicenter studies reveal responses rates ranging from 10% to 20%. Based on the results of several clinical trials, there is no evidence that the addition of tamoxifen improves the response rate. Another combination regimen is cisplatin, vinblastine, and dacarbazine (CVD), which is associated with a 20% to 25% response rate. There has been widespread interest in developing immunotherapies against metastatic melanoma. Interferon (IFN)-alfa and interleukin (IL)-2 as single agents have produced response rates in the 15% to 20% range. Biochemotherapy, which is a combination of immunotherapy and cytotoxic chemotherapy, has been studied in patients with metastatic melanoma. Multiple phase II studies have demonstrated high response rates but unclear impact on overall survival. Therapy is associated with significant toxicity. Ongoing randomized clinical trials will clarify the role of biochemotherapy in patients with metastatic melanoma. Ongoing new approaches to treatment include the therapeutic use of vaccines alone or in combination with cytokines.

Incidence of sentinel node metastasis in patients with thin primary melanoma (< or = 1 mm) with vertical growth phase.

BACKGROUND: Patients with thin primary melanomas (< or = 1 mm) generally have an excellent prognosis. However, the presence of a vertical growth phase (VGP) adversely impacts the survival rate. We report on the rate of occurrence of nodal metastasis in patients with thin primary melanomas with a VGP who are offered sentinel lymph node (SLN) biopsy. METHODS: Among 235 patients with clinically localized cutaneous melanomas who underwent successful SLN biopsy, 71 had lesions 1 mm or smaller with a VGP. The SLN was localized by using blue dye and a radiotracer. If negative for tumor by using hematoxylin and eosin staining, the SLN was further examined by immunohistochemistry. RESULTS: The rate of occurrence of SLN metastasis was 15.2% in patients with melanomas deeper than 1 mm and 5.6% in patients with thin melanomas. Three patients with thin melanomas and a positive SLN had low-risk lesions, based on a highly accurate six-variable multivariate logistic regression model for predicting 8-year survival in stage I/II melanomas. The fourth patient had a low- to intermediate-risk lesion based on this model. At the time of the lymphadenectomy, one patient had two additional nodes with metastasis. CONCLUSIONS: VGP in a melanoma 1 mm or smaller seems to be a risk factor for nodal metastasis. The risk of nodal disease may not be accurately predicted by the use of a multivariate logistic regression model that incorporates thickness, mitotic rate, regression, tumor-infiltrating lymphocytes, sex, and anatomical site. Patients with thin lesions having VGP should be evaluated for SLN biopsy and trials of adjuvant therapy when stage III disease is found.

Phase I trial of TALL-104 cells in patients with refractory metastatic breast cancer.

The human cytotoxic T-cell line TALL-104 displays antitumor effects in animals with implanted and spontaneous malignancies. A Phase I trial was conducted to determine toxicity of TALL-104 cell therapy in women with metastatic refractory breast cancer. Fifteen patients with metastatic infiltrating ductal (n = 12), lobular (n = 2), or medullary (n = 1) carcinoma received escalating doses of lethally irradiated TALL-104 cells (three patients/group received 10(6), 3 x 10(6), 10(7), 3 x 10(7), and 10(8) cells/kg) for 5 consecutive days (induction course). Patients without progressive disease received monthly maintenance 2-day infusions at the same dose level. Mild grade I/II toxicity developed in 11 patients regardless of cell dose. One grade IV toxicity consequent to hepatic tumor necrosis occurred in a patient given 10(8) cells/kg, 3 weeks after the induction course. Nine patients progressed within 1 month from induction, and five patients had stable disease for 2-6 months. One patient (at 3 x 10(7)/kg) had improvement of liver metastases and ascites, and a second patient (at 10(6)/kg) experienced a dramatic relief in bone pain. Increases in blood natural killer cell activity and levels of IFN-gamma, interleukin-10, and activation markers (soluble interleukin-2 receptor and soluble intercellular adhesion molecule-1) were often seen. Only one patient developed anti-HLA class I antibody responses against TALL-104 cells; specific CTL activity developed in three patients during induction and in four patients during the maintenance boosts. In conclusion, TALL-104 cells were well tolerated by patients with metastatic breast cancer at the doses and regimen tested. The clinical responses observed in this preliminary trial demonstrate that further investigation of TALL-104 cell therapy is warranted.

Primary and metastatic diseases in malignant melanoma of the gastrointestinal tract.

In this review, the gastrointestinal (GI) manifestations of malignant melanoma including primary mucosal melanoma of the GI tract and metastatic melanoma to the GI tract are discussed. Although malignant melanoma most commonly arises in the skin, primary melanomas can also arise from the mucosal epithelial lining of the gastrointestinal tract. The vast majority of gastrointestinal melanoma is metastatic from a cutaneous primary; however, there is evidence that melanoma can arise de novo from within certain areas of the gastrointestinal system. The sporadic nature and small numbers of patients reported in the literature with mucosal melanomas have prevented a good understanding of the pathogenesis, natural history, and optimal treatment of this uncommon presentation of melanoma.

Phase III multicenter randomized trial of the Dartmouth regimen versus dacarbazine in patients with metastatic melanoma.

PURPOSE: Several single-institution phase II trials have reported that the Dartmouth regimen (dacarbazine, cisplatin, carmustine, and tamoxifen) can induce major tumor responses in 40% to 50% of stage IV melanoma patients. This study was designed to compare the overall survival time, rate of objective tumor response, and toxicity of the Dartmouth regimen with standard dacarbazine treatment in stage IV melanoma patients. PATIENTS AND METHODS: In this multicenter phase III trial, 240 patients with measurable stage IV melanoma were randomized to receive the Dartmouth regimen (dacarbazine 220 mg/m(2) and cisplatin 25 mg/m(2) days 1 to 3, carmustine 150 mg/m(2) day 1 every other cycle, and tamoxifen 10 mg orally bid) or dacarbazine 1, 000 mg/m(2). Treatment was repeated every 3 weeks. Patients were observed for tumor response, survival time, and toxicity. RESULTS: Median survival time from randomization was 7 months; 25% of the patients survived > or = 1 year. There was no difference in survival time between the two treatment arms when analyzed on an intent-to-treat basis or when only the 231 patients who were both eligible and had received treatment were considered. Tumor response was assessable in 226 patients. The response rate to dacarbazine was 10.2% compared with 18.5% for the Dartmouth regimen (P =.09). Bone marrow suppression, nausea/vomiting, and fatigue were significantly more common in the Dartmouth arm. CONCLUSION: There was no difference in survival time and only a small, statistically nonsignificant increase in tumor response for stage IV melanoma patients treated with the Dartmouth regimen compared with dacarbazine. Dacarbazine remains the reference standard treatment for stage IV melanoma.

American Society of Clinical Oncology clinical practice guidelines for the use of chemotherapy and radiotherapy protectants.

PURPOSE: Because toxicities associated with chemotherapy and radiotherapy can adversely affect short- and long-term patient quality of life, can limit the dose and duration of treatment, and may be life-threatening, specific agents designed to ameliorate or eliminate certain chemotherapy and radiotherapy toxicities have been developed. Variability in interpretation of the available data pertaining to the efficacy of the three United States Food and Drug Administration-approved agents that have potential chemotherapy- and radiotherapy-protectant activity-dexrazoxane, mesna, and amifostine-and questions about the role of these protectant agents in cancer care led to concern about the appropriate use of these agents. The American Society of Clinical Oncology sought to establish evidence-based, clinical practice guidelines for the use of dexrazoxane, mesna, and amifostine in patients who are not enrolled on clinical treatment trials. METHODS: A multidisciplinary Expert Panel reviewed the clinical data regarding the activity of dexrazoxane, mesna, and amifostine. A computerized literature search was performed using MEDLINE. In addition to reports collected by individual Panel members, all articles published in the English-speaking literature from June 1997 through December 1998 were collected for review by the Panel chairpersons, and appropriate articles were distributed to the entire Panel for review. Guidelines for use, levels of evidence, and grades of recommendation were reviewed and approved by the Panel. Outcomes considered in evaluating the benefit of a chemotherapy- or radiotherapy-protectant agent included amelioration of short- and long-term chemotherapy- or radiotherapy-related toxicities, risk of tumor protection by the agent, toxicity of the protectant agent itself, quality of life, and economic impact. To the extent that these data were available, the Panel placed the greatest value on lesser toxicity that did not carry a concomitant risk of tumor protection. RESULTS AND CONCLUSION: Mesna: (1) Mesna, dosed as detailed in these guidelines, is recommended to decrease the incidence of standard-dose ifosfamide-associated urothelial toxicity. (2) There is insufficient evidence on which to base a guideline for the use of mesna to prevent urothelial toxicity with ifosfamide doses that exceed 2.5 g/m(2)/d. (3) Either mesna or forced saline diuresis is recommended to decrease the incidence of urothelial toxicity associated with high-dose cyclophosphamide use in the stem-cell transplantation setting. Dexrazoxane: (1) The use of dexrazoxane is not routinely recommended for patients with metastatic breast cancer who receive initial doxorubicin-based chemotherapy. (2) The use of dexrazoxane may be considered for patients with metastatic breast cancer who have received a cumulative dosage of 300 mg/m(2) or greater of doxorubicin in the metastatic setting and who may benefit from continued doxorubicin-containing therapy. (3) The use of dexrazoxane in the adjuvant setting is not recommended outside of a clinical trial. (4) The use of dexrazoxane can be considered in adult patients who have received more than 300 mg/m(2) of doxorubicin-based therapy for tumors other than breast cancer, although caution should be used in settings in which doxorubicin-based therapy has been shown to improve survival because of concerns of tumor protection by dexrazoxane. (5) There is insufficient evidence to make a guideline for the use of dexrazoxane in the treatment of pediatric malignancies, with epirubicin-based regimens, or with high-dose anthracycline-containing regimens. Similarly, there is insufficient evidence on which to base a guideline for the use of dexrazoxane in patients with cardiac risk factors or underlying cardiac disease. (6) Patients receiving dexrazoxane should continue to be monitored for cardiac toxicity. Amifostine: (1) Amifostine may be considered for the reduction of nephrotoxicity in patients receiving cisplatin-based chemoth

Autologous stem-cell transplant after conventional dose adjuvant chemotherapy for high-risk breast cancer: impact on the delivery of local-regional radiation therapy.

BACKGROUND: High-dose chemotherapy with autologous stem-cell transplantation is used increasingly in the treatment of poor-prognosis primary breast cancer. Because these patients may be cured with standard multimodality therapy, it is important to address both the efficacy of transplantation, and its effect on the delivery of standard treatments including local radiation therapy. PATIENTS AND METHODS: Patients with high risk primary breast cancer were treated with high-dose cyclophosphamide and thiotepa and stem-cell transplant following surgery and conventional-dose adjuvant chemotherapy. Outcome, including sites of failure and delivery of local radiation therapy, was assessed for 103 patients. RESULTS: Overall and disease-free survival rates at 18 months were 83% (+/- 4%) and 77% (+/- 4%) respectively. Twenty patients (19.4%) received radiation therapy prior to transplant. Of the remaining 83, 77 received radiation therapy after transplant. Overall, 5 (19.2%) of 26 first sites of recurrence were local alone. For patients receiving radiation prior to transplant, 3 of 7 (43%, 95% CI: 6%-80%) sites of first recurrence were local, while 2 of 19 (10.5%, 95% CI: 0%-24.5%) sites of first recurrence were local alone in patients receiving post-transplant radiation or no radiation. CONCLUSION: Transplantation does not appear to significantly compromise the delivery or outcome of local radiation therapy for primary breast cancer.

Breast MR imaging in patients with axillary node metastases and unknown primary malignancy.

PURPOSE: To assess the usefulness of magnetic resonance (MR) imaging of the breast in patients with malignant axillary adenopathy and unknown primary malignancy. MATERIALS AND METHODS: Between October 1993 and December 1997, 38 women with malignant axillary adenopathy and negative mammographic and physical examination findings underwent contrast material-enhanced MR imaging. Sixteen patients were excluded due to axillary tail cancer (n = 7), lack of follow-up (n = 4), second primary malignancy (n = 3), or chemotherapy before MR imaging (n = 2). The study population comprised the remaining 22 patients. Histopathologic findings were available in 20 patients; follow-up MR imaging findings were available in two patients. RESULTS: MR imaging depicted a primary breast cancer in 19 patients (86%; identified at excisional biopsy or mastectomy in 17, resolved on follow-up MR images during treatment in two). MR imaging depicted 4-30-mm cancers (mean, 17 mm), which correlated closely with histopathologic size. Two patients (9%) had false-negative findings: (a) One had a 2-mm invasive ductal carcinoma, and (b) one had 17- and 20-mm invasive ductal carcinomas. Of the 19 patients, 11 underwent mastectomy, seven underwent breast-conservation therapy, and one did not undergo a surgical procedure. CONCLUSION: MR imaging is very sensitive for the detection of mammographically and clinically occult breast cancer in patients with malignant axillary adenopathy. In these patients, MR imaging offers potential not only for cancer detection but also for staging the cancer within the breast, which may be useful for treatment planning.

Progression-related expression of beta3 integrin in melanomas and nevi.

The expression of the beta3 integrin subunit was investigated in 130 fixed, paraffin-embedded specimens of human melanomas and nevi using two different monoclonal antibodies. Expression was not observed in melanocytes and was absent or low in most nevi. In primary melanomas, expression was absent or low in the nontumorigenic radial growth phase, which includes the classes of in situ and microinvasive melanomas. In contrast, expression was high in the tumorigenic or vertical growth phase compartment of many primary melanomas and in most metastatic melanomas. Expression patterns were similar with the two antibodies, SSA6 and SAP, and was membrane-related as well as cytoplasmically expressed. In those nevi that reacted focally, the reactivity tended to occur in the dermal component of neurotized nevi, and in Spitz nevi, where the reactivity was stronger and more diffuse. A few dysplastic nevi showed focal reactivity of the junctional component. These results are consistent with tumor progression-related expression of the beta3 integrin, which is expressed in melanocytic tumors as the alphavbeta3 integrin, having affinity for matrix molecules, including vitronectin and fibronectin. In all melanomas, and in the subset of tumorigenic vertical growth phase melanomas, expression increased with thickness (P < .01). For this reason, and because ligation of this integrin has been shown in vitro to have several properties that may be related to the malignant phenotype, it is likely that expression of this marker may have prognostic value. However, because of its consistent and strong expression in Spitz nevi, the diagnostic utility of this marker will likely be limited.