Immunization of high-risk breast cancer patients with clustered sTn-KLH conjugate plus the immunologic adjuvant QS-21.

PURPOSE: To determine the clinical toxicities and antibody response against sTn and tumor cells expressing sTn following immunization of high-risk breast cancer patients with clustered sTn-KLH [sTn(c)-KLH] conjugate plus QS-21. EXPERIMENTAL DESIGN: Twenty-seven patients with no evidence of disease and with a history of either stage IV no evidence of disease, rising tumor markers, stage II (>or=4 positive axillary nodes), or stage III disease received a total of five injections each during weeks 1, 2, 3, 7, and 19. Immunizations consisted of sTn(c)-KLH conjugate containing 30, 10, 3, or 1 microg sTn(c) plus 100 microg QS-21. Induction of IgM and IgG antibodies against synthetic sTn(c) and natural sTn on ovine submaxillary mucin were measured before and after therapy. Fluorescence-activated cell sorting analyses assessed reactivity of antibodies to LSC and MCF-7 tumor cells. RESULTS: The most common toxicities were transient local skin reactions at the injection site and mild flu-like symptoms. All patients developed significant IgM and IgG antibody titers against sTn(c). Antibody titers against ovine submaxillary mucin were usually of lower titers. IgM reactivity with LSC tumor cells was observed in 21 patients and with MCF-7 cells in 13 patients. There was minimal IgG reactivity with LSC cells. CONCLUSION: Immunization with sTn(c)-KLH conjugate plus QS-21 is well tolerated and immunogenic in high-risk breast cancer patients. Future trials will incorporate sTn(c) as a component of a multiple antigen vaccine.

Increased progesterone receptor expression in benign epithelium of BRCA1-related breast cancers.

The study of pathologically normal breast epithelium of BRCA mutation carriers may yield insights into the early natural history of breast tumorigenesis. Hormone receptor expression was assessed in 24 cases of invasive breast cancer associated with a mutation in BRCA1 (n = 15) or BRCA2 (n = 9) and in 39 sporadic cases matched for patient age and tumor hormone receptor status. Expression of progesterone receptor was significantly (P = 0.0003) more common in normal breast epithelium adjacent to invasive breast carcinoma in BRCA1-linked cases compared with sporadic cases. The wild-type BRCA allele was retained in normal epithelium of all cases tested. We conclude that deregulation of progesterone receptor expression, as a result of BRCA1 haploinsufficiency, may represent an early event in BRCA1-linked breast tumorigenesis.

Clinical trial designs for rare diseases: studies developed and discussed by the International Rare Cancers Initiative.

BACKGROUND: The past three decades have seen rapid improvements in the diagnosis and treatment of most cancers and the most important contributor has been research. Progress in rare cancers has been slower, not least because of the challenges of undertaking research. SETTINGS: The International Rare Cancers Initiative (IRCI) is a partnership which aims to stimulate and facilitate the development of international clinical trials for patients with rare cancers. It is focused on interventional--usually randomized--clinical trials with the clear goal of improving outcomes for patients. The key challenges are organisational and methodological. A multi-disciplinary workshop to review the methods used in ICRI portfolio trials was held in Amsterdam in September 2013. Other as-yet unrealised methods were also discussed. RESULTS: The IRCI trials are each presented to exemplify possible approaches to designing credible trials in rare cancers. Researchers may consider these for use in future trials and understand the choices made for each design. INTERPRETATION: Trials can be designed using a wide array of possibilities. There is no 'one size fits all' solution. In order to make progress in the rare diseases, decisions to change practice will have to be based on less direct evidence from clinical trials than in more common diseases.

Rituximab, methotrexate, procarbazine, and vincristine followed by consolidation reduced-dose whole-brain radiotherapy and cytarabine in newly diagnosed primary CNS lymphoma: final results and long-term outcome.

PURPOSE: A multicenter phase II study was conducted to assess the efficacy of rituximab, methotrexate, procarbazine, and vincristine (R-MPV) followed by consolidation reduced-dose whole-brain radiotherapy (rdWBRT) and cytarabine in primary CNS lymphoma. PATIENTS AND METHODS: Patients received induction chemotherapy with R-MPV (five to seven cycles); those achieving a complete response (CR) received rdWBRT (23.4 Gy), and otherwise, standard WBRT was offered (45 Gy). Consolidation cytarabine was given after the radiotherapy. The primary end point was 2-year progression-free survival (PFS) in patients receiving rdWBRT. Exploratory end points included prospective neuropsychological evaluation, analysis of magnetic resonance imaging (MRI) white matter changes using the Fazekas scale, and evaluation of the apparent diffusion coefficient (ADC) as a prognostic factor. RESULTS: Fifty-two patients were enrolled, with median age of 60 years (range, 30 to 79 years) and median Karnofsky performance score of 70 (range, 50 to 100). Thirty-one patients (60%) achieved a CR after R-MPV and received rdWBRT. The 2-year PFS for this group was 77%; median PFS was 7.7 years. Median overall survival (OS) was not reached (median follow-up for survivors, 5.9 years); 3-year OS was 87%. The overall (N = 52) median PFS was 3.3 years, and median OS was 6.6 years. Cognitive assessment showed improvement in executive function (P < .01) and verbal memory (P < .05) after chemotherapy, and follow-up scores remained relatively stable across the various domains (n = 12). All examined MRIs (n = 28) displayed a Fazekas score of ≤ 3, and no patient developed scores of 4 to 5; differences in ADC values did not predict response (P = .15), PFS (P = .27), or OS (P = .33). CONCLUSION: R-MPV combined with consolidation rdWBRT and cytarabine is associated with high response rates, long-term disease control, and minimal neurotoxicity.

Subdural hematoma in patients with cancer.

BACKGROUND: Subdural hematoma (SDH) in patients with cancer is poorly described, and its frequency and causes may have changed with recent oncologic advances. OBJECTIVE: We conducted an analysis of the clinical and radiographic features, etiologies, treatments, and outcomes of patients with SDHs and cancer. METHODS: We retrospectively identified patients at Memorial Sloan-Kettering Cancer Center with a diagnosis of SDH and cancer from January 2000 to December 2007. We analyzed clinical and radiographic data; multivariate Cox regression was performed to associate tumor type and etiology with survival outcome. RESULTS: There were 90 patients; 66 had acute or subacute SDHs, 9 chronic SDHs, 11 subdural hygromas, and 4 SDHs of unclear chronicity. Gliomas (16%), leukemias (14%), and prostate cancers (14%) were the most frequent malignancies. The most common single etiologies were coagulopathy (27%) and trauma (11%). SDHs with multiple etiologies occurred in 25 patients (28%) with the combination of coagulopathy and trauma occurring in 15. Sixty patients (67%) were either completely or partially independent after SDH, and 1-year survival was 43% (95% confidence interval: 32.1-52.9). Overall survival correlated with etiology (P < .0001) and whether the malignancy was in remission (P = .005). Trauma was associated with the best overall survival compared with coagulopathy. CONCLUSION: Leukemia and prostate cancer are the most common systemic cancers associated with SDH, and gliomas may predispose to SDH more often than previously recognized. Coagulopathy is common and associated with the worst outcome, but many patients experience good functional outcome and survival.

Sentinel lymph node biopsy for patients with cutaneous desmoplastic melanoma.

BACKGROUND: Although desmoplastic melanoma (DM) often presents at a locally advanced stage, nodal metastases are rare. We describe our experience with lymphatic mapping and sentinel lymph node biopsy (SLNB) in patients with DM to characterize the biological behavior of these tumors. METHODS: Twenty-seven patients with cutaneous DM underwent wide excision and attempted SLNB between 1996 and 2001. All pathology was reviewed by a single dermatopathologist (KB). Clinical and histological features were recorded. RESULTS: There were 20 male and 7 female patients. The median age was 64 years (range, 35-83 years). The head and neck was the most commonly involved anatomical region (n = 14). The median Breslow thickness was 2.2 mm. Twenty-four patients underwent successful SLNB. No patient had a positive sentinel node. At a median follow-up of 27 months, five patients recurred (four systemic and one local); all five had undergone successful SLNB. Two of these patients died of disease, two are alive with disease, and one remains alive and disease free. No patient experienced failure in a regional nodal basin. CONCLUSIONS: DM is a biologically distinct form of melanoma, with a very low incidence of regional lymph node metastases, either at presentation or in long-term follow-up. This biology should be considered when designing rational treatment strategies for these patients.