Primary mucosa-associated lymphoid tissue lymphoma of the breast.

Mucosa-associated lymphoid tissue (MALT) lymphoma is an extranodal indolent lymphoma with histopatholigic features similar to those of marginal zone B-cell lymphomas. Primary breast MALT lymphomas were first described by Lamovec and Jancar as a low-grade B-cell lymphoma in 1987. Herein, a case is presented of a patient with primary MALT lymphoma of the breast. Issues in diagnosis and breast-conservation treatment, as it pertains to primary MALT lymphoma of the breast, will be discussed.

The Academy of Master Clinicians: Recognition of Clinical Excellence Within an Academic Medical Center.

PROBLEM: Academic health centers face increasing challenges in pursuing and maintaining clinical excellence in their tripartite mission. At Penn Medicine, an institution-wide strategic planning process was initiated in 2012. Among the recommendations that arose from that process was to enhance the recognition of Penn Medicine's most outstanding clinicians. The Academy of Master Clinicians (AoMC) was founded in 2013. APPROACH: The ad hoc committee charged with the development and implementation of the AoMC provided a mission statement, eligibility criteria, and a process for nomination and selection of AoMC members. This process was inclusive, extending to all entities of Penn Medicine. Various forms of institutional service were incorporated into the expectations for membership. OUTCOMES: To date, 53 clinicians have been selected for membership in the AoMC. Members meet monthly to focus on significant institutional issues. Initiatives are identified for member leadership and participation. Members are engaged in activities and programs for medical students, residents, and faculty, focusing on areas such as career advising, faculty development, physician burnout, and practice operations. The executive vice president (EVP)/dean has commented that the AoMC is "highly visible and impactful." NEXT STEPS: A yearly report on outcomes and impact of the AoMC is provided to the EVP and chief executive officer. In addition, at the end of each academic year, the members of the AoMC determine two to three new initiatives on which to work to formulate issues and potential actions.

Drug-metabolizing enzyme polymorphisms predict clinical outcome in a node-positive breast cancer cohort.

PURPOSE: Adjuvant chemotherapy cures only a subset of women with nonmetastatic breast cancer. Genotypes in drug-metabolizing enzymes, including functional polymorphisms in cytochrome P450 (CYP) and glutathione S-transferases (GST), may predict treatment-related outcomes. PATIENTS AND METHODS: We examined CYP3A4*1B, CYP3A5*3, and deletions in GST mu (GSTM1) and theta (GSTT1), as well as a priori-defined combinations of polymorphisms in these genes. Using a cohort of 90 node-positive breast cancer patients who received anthracycline-based adjuvant chemotherapy followed by high-dose multiagent chemotherapy with stem-cell rescue, we estimated the effect of genotype and other known prognostic factors on disease-free survival (DFS) and overall survival (OS). RESULTS: Patients who carried homozygous CYP3A4*1B and CYP3A5*3 variants and did not carry homozygous deletions in both GSTM1 and GSTT1 (denoted low-drug genotype group) had a 4.9-fold poorer DFS (P = .021) and a four-fold poorer OS (P = .031) compared with individuals who did not carry any CYP3A4*1B or CYP3A5*3 variants but had deletions in both GSTT1 and GSTM1 (denoted high-drug genotype group). After adjustment for other significant prognostic factors, the low-drug genotype group retained a significantly poorer DFS (hazard ratio [HR] = 4.9; 95% CI, 1.7 to 14.6; P = .004) and OS (HR = 4.8; 95% CI, 1.8 to 12.9; P = .002) compared with the high- and intermediate-drug combined genotype group. In the multivariate model, having low-drug genotype group status had a greater impact on clinical outcome than estrogen receptor status. CONCLUSION: Combined genotypes at CYP3A4, CYP3A5, GSTM1, and GSTT1 influence the probability of treatment failure after high-dose adjuvant chemotherapy for node-positive breast cancer.

Randomized comparison of ABVD and MOPP/ABV hybrid for the treatment of advanced Hodgkin's disease: report of an intergroup trial.

PURPOSE: In a series of trials, doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) and mechlorethamine, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, and vinblastine (MOPP/ABV) have been identified as effective treatments for Hodgkin's disease. We compared these regimens as initial chemotherapy for Hodgkin's disease. PATIENTS AND METHODS: Adult patients (N = 856) with advanced Hodgkin's disease were randomly assigned to treatment with ABVD or MOPP/ABV. The major end points were failure-free and overall survival, life-threatening acute toxicities, and serious long-term toxicities, including cardiomyopathy, pulmonary toxicity, myelodysplastic syndromes (MDS), and secondary malignancies. RESULTS: The rates of complete remission (76% v 80%, P =.16), failure-free survival at 5 years (63% v 66%, P =.42), and overall survival at 5 years (82% v 81%, P =.82) were similar for ABVD and MOPP/ABV, respectively. Clinically significant acute pulmonary and hematologic toxicity were more common with MOPP/ABV (P =.060 and.001, respectively). There was no difference in cardiac toxicity. There were 24 deaths attributed to initial treatment: nine with ABVD and 15 with MOPP/ABV (P =.057). There have been 18 second malignancies associated with ABVD and 28 associated with MOPP/ABV (P =.13). Thirteen patients have developed MDS or acute leukemia: 11 were initially treated with MOPP/ABV, and two were initially treated with ABVD but subsequently received MOPP-containing regimens and radiotherapy before developing leukemia (P =.011). CONCLUSION: ABVD and the MOPP/ABV hybrid are effective therapies for Hodgkin's disease. MOPP/ABV is associated with a greater incidence of acute toxicity, MDS, and leukemia. ABVD should be considered the standard regimen for treatment of advanced Hodgkin's disease.

Chemotherapy with or without radiotherapy in limited-stage diffuse aggressive non-Hodgkin's lymphoma: Eastern Cooperative Oncology Group study 1484.

PURPOSE: To compare low-dose (30 Gy) radiotherapy (RT) with observation (OBS) in limited-stage aggressive lymphoma patients achieving complete remission (CR) after chemotherapy, and to measure conversion from partial response (PR) to CR with high-dose (40 Gy) RT. PATIENTS AND METHODS: From 1984 to 1992, stage I (with risk factors) and II adults with diffuse aggressive lymphoma in CR after eight cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) were randomly assigned to 30 Gy involved-field RT or OBS. PR patients received 40 Gy RT. RESULTS: Among 172 CR patients, the 6-year disease-free survival (DFS) was 73% for low-dose RT versus 56% for OBS (two-sided P = .05). Failure-free survival (two-sided P = .06), and time to progression (two-sided P = .06) also favored RT. Intent-to-treat analyses yielded similar results. No survival differences were observed. Three RT versus 15 OBS patients relapsed in initial disease sites. At 6 years, failure-free survival was 63% in PR patients; conversion to CR did not significantly influence clinical outcome. CONCLUSION: For patients in CR after CHOP, low-dose RT prolonged DFS and provided local control, but no survival benefit was observed. The majority of PR patients were event-free at 6 years despite residual radiographic abnormalities. Future efforts should be directed toward improved imaging and more effective systemic therapies.

Ethnic disparities in adjuvant chemotherapy for breast cancer are not caused by excess toxicity in black patients.

BACKGROUND: Black patients with breast cancer may be at greater risk for chemotherapy-related hematologic toxicity than white patients because of lower baseline blood cell counts. We hypothesize that these baseline differences could lead to excess hematologic toxicity and greater modification of chemotherapy dosing in black patients and that this may contribute to the poorer survival observed in black patients with breast cancer compared with white patients with breast cancer. PATIENTS AND METHODS: We performed a retrospective cohort study of black and white patients with breast cancer treated with adjuvant chemotherapy at an academic medical center over an 18-month period. Clinical chart review and pharmacy records were used to collect data on the following: modification of chemotherapy dose or administration; hematologic toxicity; blood cell counts before, during, and after therapy; occurrence of febrile neutropenia; use of prophylactic antibiotics; and use of granulocyte colony-stimulating factor in order to determine whether ethnicity was an independent predictor of these outcomes. RESULTS: Among 23 black patients and 98 white patients with breast cancer treated with adjuvant chemotherapy, modification of chemotherapy administration occurred in 56 patients (46%). Modification was more common among black patients (65.2% vs. 41.8%; relative risk [RR], 1.56; P = 0.04). Black patients were more likely to receive reduced cumulative doses of adjuvant chemotherapy (RR, 2.49; P = 0.03). CONCLUSION: Our findings suggest that hematologic tolerability of adjuvant chemotherapy is similar in black and white patients. Strategies aimed at improving psychosocial barriers to adjuvant therapy and at reducing surgical complications in black patients may improve overall breast cancer outcomes in this group.

Ten-year outcome after combined modality therapy for inflammatory breast cancer.

PURPOSE: To evaluate the long-term outcome of combined modality therapy for inflammatory breast cancer. METHODS AND MATERIALS: The data from 54 women treated between 1983 and 1996 for inflammatory breast cancer were analyzed. Patients with metastatic disease or disease progression on induction chemotherapy were excluded. Induction chemotherapy was given to 52 patients. Mastectomy was performed in 52 patients. Radiotherapy was delivered to the breast or chest wall and regional lymph nodes in all patients. The median follow-up for all patients was 5.1 years. RESULTS: The 5- and 10-year overall survival rate was 56% and 35%, respectively; the corresponding relapse-free survival rates were 49% and 34%. Patients with a pathologic complete response after chemotherapy with or without preoperative radiotherapy had better 5- and 10-year overall survival rates (65% and 46%, respectively) and 5- and 10-year relapse-free survival rates (59% and 50%, respectively) compared with patients without a pathologic complete response. Those patients had a 5- and 10-year relapse-free survival rate of 45% and 27%, respectively. Locoregional failure at 5 and 10 years was 8% and 19%, respectively. CONCLUSION: The outcomes for patients completing multimodality therapy compare favorably with published data; however, the exclusion of patients with progression during induction chemotherapy may account in part for these results. The pathologic complete response rate was found to be an important prognostic factor. Selected patients with inflammatory breast cancer have the potential for long-term survival.

Fifteen-year results of breast-conserving surgery and definitive irradiation for Stage I and II breast carcinoma: the University of Pennsylvania experience.

PURPOSE: To determine the 15-year outcomes for women with early stage breast cancer after breast conservation therapy. METHODS AND MATERIALS: Between 1977 and 1990, 937 women with Stage I and II breast carcinoma (55% T1N0, 16% T2N0, 18% T1N1, and 11% T2N1) underwent lumpectomy, axillary lymphadenectomy, and definitive irradiation. The median patient age was 52 years. Of the 937 patients, 375 (40%) received adjuvant chemotherapy and/or hormonal therapy, including 249 (92%) of the 270 women with pathologically positive nodes. The median follow-up was 10.1 years. RESULTS: For the overall group, the 15-year overall survival rate was 71%, and the rate of freedom from distant metastases was 76%. The 15-year local failure rate was 19%. The 15-year contralateral breast cancer rate was 12%. The most common first events were distant failure (13%), local failure (10%), contralateral breast cancer (7%), and second malignant neoplasms (6%). The local failure rate at 10 years for favorable subsets of tumors characterized by mammographic detection, resection with negative margins, treatment with chemotherapy, and treatment with hormones was 8%, 10%, 10%, and 7%, respectively. Local failures were most commonly observed within (true recurrence), or just outside (marginal miss), the primary tumor bed (66%, 85 of 128). The rate of true recurrence or marginal miss at 5, 10, and 15 years was 5%, 10%, and 12%, respectively. CONCLUSION: These high rates of survival and local control confirm that breast conservation therapy yields favorable results in women with early breast cancer into the second decade after treatment.

Phase II randomized trial of cisplatin and WR-2721 versus cisplatin alone for metastatic melanoma: an Eastern Cooperative Oncology Group Study (E1686).

This study was designed to evaluate the toxicity and efficacy of cisplatin and WR-2721 in contrast to cisplatin alone for the therapy of measurable metastatic melanoma. Ninety-four patients with metastatic melanoma were randomized to receive either cisplatin at a dose of 150 mg/m2 and WR-2721 at a dose of 910 mg/m2, or cisplatin alone at a dose of 120 mg/m2. WR-2721 did not mitigate the toxic effects of cisplatin, and toxicity was increased in the WR-2721 plus cisplatin arm compared with cisplatin alone. For patients receiving cisplatin alone, the response rate was 16.3%; for those receiving cisplatin plus WR-2721, the response rate was 23.3%. The duration of response was 7.3 months. Median survival in the intent-to-treat analysis was 7.58 months. The study was terminated after accrual of 94 patients, with inadequate power to define an effect of WR-2721 on the duration of response and survival. In conclusion, cisplatin with WR-2721 showed an improved response rate over cisplatin alone. The lack of improved duration of response or impact on survival may be the result of the limited improvement of efficacy with the higher dosage of cisplatin in conjunction with WR-2721, or the limited number of patients accrued to this study. These factors, coupled with the failure of the combination to diminish toxicity, dampen enthusiasm for this combination.

Radiation therapy compared with chemotherapy for consolidation of chemotherapy-induced remission of advanced Hodgkin lymphoma: a study by the Eastern Co-operative Oncology Group (E1476) with >20 years follow-up.

MOPP-Bleo (nitrogen mustard, vincristine, procarbazine, prednisone and bleomycin) induction therapy was given to 253 evaluable patients with Hodgkin lymphoma, stages IIIB, III(s), or IV. Complete response (CR) occurred in 145 patients (57%) and partial response (PR) in 93 (37%). Of those 238 responders, 178 were randomized to consolidation therapy, and 164 were eligible and analyzable, including 114 CRs [55 patients randomized to ABVD and 59 to radiation therapy (RT)] and 50 partial responders (PRs) (25 each randomized to ABVD and RT). Among the 50 patients with PR, 34 (68%) converted to CR (16 with ABVD and 18 with RT). Therefore, of 253 patients, 182(72%) achieved CR and 56 (22%), PR. Median follow-up for all patients is 22.3 years and the estimated overall survival (OS) rate at 20 years is 48%. Of the 148 eligible, analyzable patients with CR, the estimated proportion remaining in CR at 20 years is 62%. OS at 20 years was significantly greater for patients receiving ABVD consolidation (66%) when compared with those who received RT consolidation (43%) (p = 0.002). Treatment toxicity was acceptable. After MOPP-Bleo induction for advanced Hodgkin lymphoma, ABVD provides better consolidation than local RT.

Older age predicts a decline in adjuvant chemotherapy recommendations for patients with breast carcinoma: evidence from a tertiary care cohort of chemotherapy-eligible patients.

BACKGROUND: The appropriate use of adjuvant chemotherapy for elderly women with breast carcinoma remains controversial. Efficacy data in women age >/= 70 years are scarce, resulting in a lack of clear guidelines for patients in this age group. Although several studies have demonstrated decreasing use of chemotherapy with age, none specifically examined its use in an elderly cohort of patients who were deemed eligible for such therapy based on consensus guidelines, simultaneously examining the impact of comorbidity and previous history of malignant disease on these recommendations. METHODS: The authors examined adjuvant chemotherapy use among chemotherapy-eligible patients age > or = 50 years who were evaluated in a tertiary care cancer center. Associations between patient age and 1) physician recommendation for adjuvant chemotherapy, 2) recommended treatment regimen, and 3) patient acceptance of the treatment plan recommended were examined, adjusting for the impact of aggressive tumor characteristics, medical comorbidity, previous history of malignant disease, and features of the treatment setting. RESULTS: Of the 208 chemotherapy-eligible patients who were studied, 74% overall were recommended chemotherapy. Chemotherapy was recommended to 92% of women age 50-59 years compared with 77% of women age 60-69 years and 23% of women age > or = 70 years. Increasing age was associated strongly with a decreasing likelihood of receiving a recommendation in favor of chemotherapy. After adjusting for estrogen receptor status, previous history of malignant disease, comorbidity score, and prognostic group, the odds of receiving a recommendation in favor of chemotherapy fell by 22% per year or 91% per 10-year interval, and the rate of decline did not change significantly at age > or = 70 years. We found no age-related differences in either the drug regimens recommended or patient acceptance rates for adjuvant therapy. CONCLUSIONS: Age was associated strongly and independently with physician recommendation for adjuvant chemotherapy among a group of older women who were eligible specifically for such therapy. Medical comorbidity and a history of previous malignant disease did not alter this correlation significantly, although the latter was a significant predictor of chemotherapy use. Further studies clearly are needed to determine the underlying reasons for this strong age effect and to explore strategies that will optimize the utilization of this potentially curative therapy in the elderly.

Natural killer-like T-cell lymphoma of the small intestine with a distinct immunophenotype and lack of association with gluten-sensitive enteropathy.

We report the case of a large natural killer (NK)-like T-cell lymphoma that involved the ileum and displayed a distinct immunophenotype and complex karyotype. The patient exhibited no evidence of gluten-sensitive enteropathy (celiac disease) or any other type of enteropathy as determined by clinical history, endoscopy, and serology for immunoglobulin A (IgA) antiendomysial and IgG antigliadin antibodies. Molecular studies demonstrated a clonal T-cell receptor gamma chain gene rearrangement. Immunophenotype analysis showed expression of intestinal epithelium-homing receptor CD103, CD7, cytoplasmic CD3 epsilon, CD56, and CD16 but no other T- or NK-cell markers. Cytogenetic analysis of the malignant cells revealed multiple chromosomal abnormalities indicative of a biologically advanced, high-grade lymphoma. A novel subset of normal intestinal intraepithelial lymphocytes, bearing a similar phenotype, has been described; moreover, this subset diminishes, rather than expands, in gluten-sensitive enteropathy. This case supports the notion that lymphomas involving the small intestine represent a heterogeneous group of lymphomas with diverse pathogenetic mechanisms.