OC-02 - Risk of arterial thromboembolism in patients with breast cancer.

INTRODUCTION: Breast cancer is the most common cancer in women and clearly increases the risk of venous thromboembolism. However, its association with arterial thromboembolism is less well defined. AIM: To determine the short-term cumulative incidence and relative hazard of arterial thromboembolism in elderly patients with incident breast cancer. MATERIALS AND METHODS: Using the Surveillance Epidemiology and End Results-Medicare linked database, which includes approximately 28% of all patients diagnosed with cancer in the United States, we identified patients with a new primary diagnosis of breast cancer from 2002 through 2011. These patients were individually matched by age, sex, race, registry, and medical comorbidities to a group of Medicare enrollees without cancer, and each pair was followed through 2012. Validated diagnosis codes were used to identify a primary composite outcome of arterial thromboembolism defined as any ischemic stroke or myocardial infarction. Secondary outcomes included ischemic stroke alone and myocardial infarction alone. Cumulative incidence rates were calculated using competing risk survival statistics. The Gray test was used to compare rates between groups. The proportional hazard assumption was violated for the entirety of patient follow-up; therefore, Cox proportional hazard analysis was performed at discrete time points when the assumption was generally met. RESULTS: We identified 96,666 pairs of breast cancer patients and matched controls. Median age was 75 years and few cancers were advanced at diagnosis (12% stages 3/4). The 3-month cumulative incidence of arterial thromboembolism was 2.1% (95% confidence interval [CI] 2.0-2.2%) in cancer patients compared to 1.4% (95% CI 1.3-1.5%) in controls (hazard ratio [HR] 1.5, 95% CI 1.4-1.6, p<0.01). The short-term risk of each secondary outcome was heightened in the breast cancer group, although the relative hazard for myocardial infarction was higher than for ischemic stroke. The 3-month cumulative incidence of ischemic stroke was 1.3% (95% CI 1.2-1.4%) in cancer patients compared to 1.0% (95% CI 0.9-1.1%) in controls (HR 1.3, 95% CI 1.2-1.4, p<0.01), and the 3-month cumulative incidence of myocardial infarction was 0.9% (95% CI 0.8-0.9%) in cancer patients compared to 0.4% (0.4-0.5%) in controls (HR 2.0, 95% CI 1.8-2.3, p<0.01). Excess risks attenuated over time and were no longer present beyond 1 year. CONCLUSIONS: Patients with incident breast cancer face an increased short-term risk of ischemic stroke and myocardial infarction.

Seizure prophylaxis and melanoma brain metastases.

Melanoma has a high propensity to metastasize to the brain. In patients with brain metastases (BM) survival is limited, neurologic morbidity is high, with seizure incidence reported up to 67%. Current guidelines recommend against antiepileptic drug prophylaxis (AED PPX) in patients without a history of seizure. We reviewed our experience with melanoma BM to determine the efficacy of AED PPX in the era of second generation AED and to delineate risk factors associated with development of seizures. We reviewed records of all patients treated at Memorial Sloan-Kettering Cancer Center with melanoma and BM between May 2006 and October 2008. Seizure risk was studied relative to BM characteristics at diagnosis and AED PPX. We identified 109 patients. Median age was 61 years (range 29-91); 56% had no neurologic symptoms at diagnosis. On neuroimaging, 94% (102/109) had cortical lesions, 60% (65/109) had more than one supratentorial lesion, 54% (59/109) had hemorrhage. Seizure led to diagnosis of BM in 13% (14/109); 20% (22/109) developed seizures later. On univariate analysis among patients without a seizure at diagnosis, AED-PPX was significantly associated with decreased risk of seizure (P = 0.03) with 3-month seizure rate of 0% compared to 17% without AED-PPX. Hemorrhage (P < 0.001) and multiple supratentorial metastases (P = 0.03) were associated with increased seizure risk. Melanoma patients with multiple supratentorial BM and hemorrhage may have an increased risk of seizure. AED PPX may be effective in selected patients, and should be addressed in a randomized controlled trial.

Use of high technology imaging for surveillance of early stage breast cancer.

Guidelines do not support utilization of high technology radiologic imaging (HTRI) for surveillance after curative treatment for early stage breast cancer. Surveillance, Epidemiology, and End Results (SEER)-Medicare linked data were used to identify 25,555 women diagnosed with stage I-II breast cancer between 1998 and 2003 who survived ≥ 48 months from diagnosis without evidence of second primary or recurrent cancer in this interval. HTRI utilization (computerized tomography scanning (CT), bone scan (BS), breast magnetic resonance imaging, and positron emission tomography scans) was measured in months 13-48 post-diagnosis. Cases were individually matched to 75,669 female Medicare enrollees without cancer. Factors associated with HTRI utilization were evaluated. Forty percent of women with stage I-II breast cancer and 25% of controls had ≥ 1 HTRI during the surveillance interval (P < 0.001). High utilization rates were observed for CT (30%) and BSs (19%). The proportion of women who had a CT during the surveillance period increased in both cancer survivors and controls. Among breast cancer cases age <80, higher comorbidity index, stage II disease, and more recent diagnosis were independently associated with receipt of HTRI. Paralleling patterns observed in controls, HTRI utilization for surveillance following diagnosis of early stage breast cancer has steadily increased among Medicare beneficiaries. Strategies to foster judicious utilization of HTRI should be a priority.

Histology and outcomes of newly detected lung lesions in melanoma patients.

BACKGROUND: Melanoma frequently metastasizes to the lung. Improved radiologic techniques may decrease the need for biopsy of such lesions. The aim of this study was to examine factors predictive of a positive biopsy of melanoma. METHODS: Using the Memorial Sloan-Kettering Cancer Center melanoma database, all patients with melanoma who had undergone biopsy of a suspicious new lung lesion from 1996 to 2009 were identified. Age, date of diagnosis, histology, and stage were obtained. Chart review was carried out to obtain medical history, smoking status, radiological appearance, and histology of lung lesions biopsied. RESULTS: Two hundred and twenty-nine patients were identified; median age was 63 years; 48% were never smokers; 27% had a prior nonmelanoma cancer; 88% of lung nodules were malignant: 69% melanoma, 19% other cancers. Among 113 patients undergoing positron emission tomography (PET), proportions of benign, melanoma, and nonmelanoma 2-[fluorine-18]fluoro-2-deoxy-D-glucose-avid nodules did not differ (P = 0.53). On multivariable analysis, >stage I melanoma, negative smoking history, multiple lung nodules, and no prior nonmelanoma cancer were significantly associated with a melanoma biopsy result rather than other cancer. CONCLUSIONS: In this study, 31% of lung lesions were not melanoma. In the subset undergoing PET, this did not differentiate between benign and malignant lesions. Biopsy is mandated in melanoma patients with new lung nodules.

Leptomeningeal metastases in the MRI era.

BACKGROUND: Diagnosis of leptomeningeal metastasis (LM) has become increasingly frequent. The diagnostic gold standard has been CSF cytology, but MRI is now used routinely for diagnosis. Diagnosis and prognosis of LM has not been studied in the MRI era. METHODS: Patients with LM from 2002 through 2004 were identified through a neurology database, as well as by reviewing all abnormal CSF cytologies from a pathology database. Diagnosis was made by malignant cytology or imaging; suspicious cases treated as LM were also included. RESULTS: A total of 187 patients with LM were analyzed in this retrospective review. Of these, 150 had solid and 37 had hematopoietic malignancies. Median age was 56.4 years, and median Karnofsky performance status (KPS) was 70. The most common types of solid tumor were breast (65 patients), lung (47), gastrointestinal (11), and melanoma (9). Of the hematopoietic tumors, 21 were lymphoma and 15 were leukemia. Fifty-three percent of patients were diagnosed by imaging, 23% by cytology, and 24% by both. Treatment included radiation therapy in 55%, intrathecal chemotherapy in 29%, and systemic chemotherapy in 18%; 21% received supportive care alone. Median overall survival was 2.4 (95% confidence interval 1.9-3.1) months. Median survival for patients with hematopoietic tumors was 4.7 months and for solid tumors was 2.3 months (p = 0.0006). In multivariate analysis, initial KPS and tumor type (solid vs hematopoietic) were significant predictors of survival. CONCLUSIONS: Despite enhanced diagnosis with MRI, prognosis remains poor in leptomeningeal metastasis. Those with hematopoietic tumors continue to fare better than those with solid tumors.

Intracerebral and subarachnoid hemorrhage in patients with cancer.

OBJECTIVE: To analyze the risk factors, presentation, etiologies, and outcomes of adult cancer patients with intracranial hemorrhage (IH). METHODS: We analyzed 208 patients retrospectively with the diagnosis of IH from the Memorial Sloan-Kettering neurology database from January 2000 through December 2007. Charts were examined for clinical and radiographic data. Survival was calculated using the Kaplan-Meier method. Survival between groups was compared via the log-rank test. Logistic regression models were used to assess for prognostic indicators of 30- and 90-day mortality. RESULTS: There were 181 intracerebral and 46 subarachnoid hemorrhages. Sixty-eight percent of patients had solid tumors, 16% had primary brain tumors, and 16% had hematopoietic tumors. Hemiparesis and headache were the most common symptoms. Intratumoral hemorrhage (61%) and coagulopathy (46%) accounted for the majority of hemorrhages, whereas hypertension (5%) was rare. Median survival was 3 months (95% confidence interval [CI] 2-4), and 30-day mortality was 31%. However, nearly one-half of patients were completely or partially independent at the time of discharge. Patients with primary brain tumors had the longest median survival (5.9 months, 95% CI 2.9-11.8, p = 0.05). Independent predictors of 30-day mortality were not having a primary brain tumor, impaired consciousness, multiple foci of hemorrhage, hydrocephalus, no ventriculostomy, and treatment of increased intracranial pressure. CONCLUSIONS: Intracranial hemorrhage in patients with cancer is often due to unique mechanisms. Prognosis is poor, but comparable to intracranial hemorrhage in the general population. Aggressive care is recommended despite high mortality, because many patients have good functional outcomes.

Retrospective comparison of the effects of filgrastim and pegfilgrastim on the pace of engraftment in auto-SCT patients.

The high doses of chemotherapy used for the preparatory regimens before autologous blood or marrow stem cell transplantation leave patients at risk for neutropenic complications. The administration of filgrastim post transplant reduces the time to neutrophil recovery and therefore has become a standard practice at many institutions. In 2006, we implemented a practice change from filgrastim to pegfilgrastim. We present data on 164 consecutive patients (82 patients who received filgrastim compared with 82 patients who received pegfilgrastim) who received an auto-SCT between January 2006 and November 2007. Patients who received pegfilgrastim had faster engraftment (9.6 days compared with 10.9 days, P<0.0001), a lower incidence of febrile neutropenia (59% compared with 78%, P=0.015), as well as shorter hospital stay, fewer days of treatment with i.v. antibiotics (6.3 days compared with 9.6 days, P=0.006), and fewer radiographic tests, which translated to an estimated total cost savings of over $8000 per patient. Overall, there were no differences in toxicity with these two agents. We conclude that a single dose of pegfilgrastim is a safe and efficacious alternative to daily injections of filgrastim and can be a cost-effective approach in auto-SCT patients.

Phase II trial of neoadjuvant temozolomide in resectable melanoma patients.

BACKGROUND: We treated melanoma patients with temozolomide (TMZ) in the neoadjuvant setting and collected cryopreserved tumor samples before and after treatment. The primary objective was to determine whether the response proportion was higher than previously reported in widely metastatic patients. A secondary objective was to test the feasibility of obtaining adequate tissue before and after treatment for genetic testing. MATERIALS AND METHODS: Chemotherapy-naive melanoma patients who were candidates for surgical resection were eligible. TMZ was administered orally at 75 mg/m(2)/day for 6 weeks of every 8-week cycle. Cycles were repeated until complete response (CR), progression, or stable disease (SD) for two cycles. RESULTS: Of 19 assessable patients, 2 had CRs and 1 had partial response. Four patients had SD; 12 progressed. Tumor O-6-methylguanine-DNA methyltransferase (MGMT) promoter was unmethylated in all nine patients analyzed including from the two CR patients. Pretreatment tumor microarray results were obtained in 16 of 19 patients. CONCLUSIONS: The response proportion to TMZ in the neoadjuvant setting was 16%, not different than in the metastatic setting. Responses were seen even in tumors with a methylated MGMT promoter. Pretreatment cryopreserved tumor adequate for microarray analysis could be obtained in most, but not all, patients. Post-treatment tumor was unavailable in complete responders.

Pharmacokinetics and tolerability of exemestane in combination with raloxifene in postmenopausal women with a history of breast cancer.

PURPOSE: Raloxifene is a second-generation selective estrogen receptor modulator that reduces the incidence of breast cancer in postmenopausal women. Exemestane, a steroidal aromatase inhibitor, decreases contralateral new breast cancers in postmenopausal women when taken in the adjuvant setting. Preclinical evidence suggests a rationale for coadministration of these agents to achieve complete estrogen blockade. EXPERIMENTAL DESIGN: We tested the safety and tolerability of combination exemestane and raloxifene in 11 postmenopausal women with a history of hormone receptor-negative breast cancer. Patients were randomized to either raloxifene (60 mg PO daily) or exemestane (25 mg PO daily) for 2 weeks. Patients then initiated combination therapy at the same dose levels for a minimum of 1 year. Pharmacokinetic and pharmacodynamic data for plasma estrogens, raloxifene, exemestane, and their metabolites were collected at the end of single-agent therapy and during combination therapy. RESULTS: Plasma concentration-time profiles for each drug were unchanged with monotherapy versus combination therapy. Raloxifene did not affect plasma estrogen levels. Plasma estrogen concentrations were suppressed below the lower limit of detection by exemestane as monotherapy and when administered in combination with raloxifene. The most common adverse events of any grade included arthralgias, hot flashes, vaginal dryness and myalgias. CONCLUSIONS: In this small study, coadministration of raloxifene and exemestane did not affect the pharmacokinetics or pharmacodynamics of either agent to a significant degree in postmenopausal women. The combination of estrogen receptor blockade and suppression of estrogen synthesis is well tolerated and warrants further investigation.

In vitro expansion of Ag-specific T cells by HLA-A*0201-transfected K562 cells for immune monitoring.

BACKGROUND: Development of a practical and sensitive assay for evaluating immune responses against cancer Ag has been a challenge for immune monitoring of patients. We have established a reproducible method using peptide-pulsed K562-A*0201 cells as APC to expand Ag-specific T cells in vitro. This method may be applied for monitoring T-cell responses in cancer immunotherapy clinical trials. METHODS: Autologous PBMC from HLA-A*0201+ healthy donors and patients with melanoma were stimulated with peptide-pulsed K562-A*0201 cells under varying conditions. We investigated (1) different culture conditions, including the requirements for serum and cytokines for expansion of CD8+ T lymphocytes; (2) a range of peptide concentrations for Ag loading; (3) phenotypic characterization of responding T cells; and (4) APC:responder ratios and their effects on T-cell expansion. We validated these conditions by ELISPOT and intracellular cytokine staining (ICS) assays using peptides from influenza, Epslein-Barr Virus (EBV) and tyrosinase. RESULTS: Conditions for optimal T-cell expansion using K562-A*0201 APC included input of 2 x 10(6) PBMC, a 10 microg/mL peptide concentration to pulse K562-A*0201 cells, a 1:30 APC:responder T-cell ratio and culture in 10% autologous plasma supplemented with IL-2 and IL-15. In these conditions, Ag-specific T cells expanded >100-fold over a 10-day culture period (peak at day 12). DISCUSSION: This bulk culture method is simple and reliable for expanding human Ag-specific T cells using peptide-pulsed K562-A*0201 cells. This HLA-matched APC line can be adapted to other HLA haplotypes, and has advantages for monitoring clinical trials of immunotherapy with limited availability of autologous APC and PBMC from patients.

The serum IL-12:IL-6 ratio reliably distinguishes infectious from non-infectious causes of fever during autologous stem cell transplantation.

BACKGROUND: Fever during neutropenia and after neutrophil engraftment (post-engraftment fever) occurs commonly during autologous transplantation (ASCT), but infections are infrequently identified. Tests that reliably exclude infection may reduce the cost and toxicity of unnecessary diagnostic testing and empiric treatment. We assessed whether serum levels of inflammatory cytokines could distinguish infectious from non-infectious causes of fever in patients undergoing ASCT. METHODS: Serum levels of IL-1beta, IL-2, IL-6, IL-8, IL-10, IL-12(p70), TNF-alpha and IFN-gamma were measured by sandwich ELISA at multiple pre-determined times and at the onset of the first fever during neutropenia and after neutrophil engraftment in patients with hematologic malignancies undergoing ASCT. Standard clinical criteria were used to assess for the presence of infection. RESULTS: Seventy-two febrile episodes occurred in 54 of 65 enrolled patients; 29 (40%) of the episodes occurred after neutrophil engraftment. Infections were identified as the cause of 28% and 24% of the neutropenic and post-engraftment febrile episodes, respectively. The level of IL-12 decreased and that of IL-6 increased significantly during fever because of infection, such that the IL-12:IL-6 ratio accurately excluded infection. The area under the ROC curve for the IL-12:IL-6 ratio was 0.88 (95% CI 0.79-0.97). The sensitivity, specificity, positive predictive and negative predictive values associated with a cut-off ratio of 4.1 were 95%, 75%, 60%, and 97%, respectively. DISCUSSION: The IL-12:IL-6 ratio effectively discriminates infectious from non-infectious causes of fever during ASCT. It may be useful in assessing the probability of infection in patients with post-engraftment fever.

Expression of osteoprotegerin (OPG), TNF related apoptosis inducing ligand (TRAIL), and receptor activator of nuclear factor kappaB ligand (RANKL) in human breast tumours.

BACKGROUND: Osteoprotegerin (OPG) is involved in the regulation of bone turnover through binding to the receptor activator of nuclear factor kappaB ligand (RANKL), and has also been reported to be a potential survival factor for several different cell types. The survival effects are mediated through inhibition of the activity of tumour necrosis factor related apoptosis inducing ligand (TRAIL). Both breast and prostate cancer cells produce sufficient amounts of OPG to be protected against the effects of TRAIL in vitro. AIMS: To investigate the spatial expression of OPG, RANKL, and TRAIL in non-neoplastic breast tissue and breast cancer, and its relation with oestrogen receptor (ER) expression. METHODS: Forty breast cancers (20 ER+, 20 ER-) and five non-neoplastic breast tissue samples were stained with antibodies against OPG, RANKL, and TRAIL. RESULTS: OPG was not expressed in non-neoplastic breast tissue except when colocalised with altered columnar epithelium. RANKL was expressed at the apical surface of luminal epithelial cells and TRAIL was expressed in myoepithelial cells. All three proteins were expressed in some breast cancers but showed no significant association with tumour type. OPG expression showed a significant positive correlation with ER expression (p = 0.011). CONCLUSIONS: This is the first published study of the spatial expression of OPG, RANKL, and TRAIL in breast tissue and breast cancer. The localisation of each protein was specific and they were not colocalised. This specificity may provide a useful marker of functional differentiation in breast cancer; for example, TRAIL expression as a marker of myoepithelial differentiation.

Association of melanoma and neurocutaneous melanocytosis with large congenital melanocytic naevi--results from the NYU-LCMN registry.

BACKGROUND: Large congenital melanocytic naevi (LCMN), which develop in utero and are present in approximately one in 20,000 newborns, are associated with markedly increased risks of cutaneous melanoma, leptomeningeal melanoma and neurocutaneous melanocytosis (NCM). OBJECTIVES: This study examined clinical characteristics associated with melanoma and NCM among patients with LCMN, and estimated the risk of developing melanoma and NCM in these patients. METHODS: Two hundred and five LCMN patients enrolled in the New York University registry were studied. One hundred and seventy of these patients were followed prospectively. The remaining 35 patients had either melanoma at the time of entry into the registry (n = 6), or had insufficient follow-up information (n = 29). The outcome measures were the occurrence of melanoma and NCM. The associations between these outcomes and the clinical covariates (anatomical location of the LCMN, size of the LCMN, number of satellite lesions, family history of melanoma, patient sex and treatment) were assessed. RESULTS: Four of 170 (2.3%) prospectively followed patients developed melanomas, representing a standardized morbidity ratio of 324. Among the entire cohort (n = 205), there were associations between increasing numbers of satellite naevi and the occurrence of melanoma (P = 0.04), and the presence of NCM (P = 0.06). Compared with patients who did not develop these diseases, median LCMN diameters were larger among patients who developed melanoma (49 vs. 39 cm) and NCM (55 vs. 46 cm). CONCLUSIONS: In LCMN patients, increasing numbers of satellite lesions and larger LCMN diameters are associated with melanoma and NCM.

Proton magnetic resonance spectroscopy in immunocompetent patients with primary central nervous system lymphoma.

BACKGROUND: Magnetic resonance spectroscopy imaging (MRSI) non-invasively evaluates the metabolic profile of normal and abnormal brain tissue. Primary central nervous system lymphoma (PCNSL) is a highly aggressive tumor responsive to high-dose methotrexate based regimens. Patients often have complete responses but relapses are common. We characterized the MR spectra of PCNSL patients, correlated MRSI with MRI and evaluated whether early recurrence could be detected by MRSI. METHODS: Patients with PCNSL had multi-voxel MRSI before, during, and after treatment. The region of interest was defined using axial FLAIR images. Metabolites assessed were N-acetyl-aspartate (NAA), choline (Cho), creatine (Cr), lipid, and lactate. Ratios of Cho/Cr, NAA/Cho, and NAA/Cr were calculated and correlated with MRI. Overall survival (OS), progression free survival (PFS), and relative risks of each of the ratios were determined. RESULTS: MRSI was performed on 11 men and seven women; median age of 59. Sixty-seven MRSI studies were performed, 17 baseline and 48 follow-up studies. Median ratios in 16 pretreated patients were Cho/Cr-1.90, NAA/Cho-0.39, and NAA/Cr-1.27. Two patients had lipid at baseline, five had lactate and two had both. MRSI correlated with tumor response or progression on MRI; in three patients MRSI suggested disease progression prior to changes on MRI. Univariate analysis of metabolite ratios, lipid, and lactate revealed that none significantly affected PFS or OS. Kaplan-Meier analysis of the presence or absence of lipid, lactate or both revealed a trend for increased PFS. CONCLUSION: MRSI and MRI correlate with tumor response or progression and may allow early detection of disease recurrence. The presence or absence of lipid and/or lactate may have prognostic significance. Further research using MRSI needs to be done to validate our findings and determine the role of MRSI in PCNSL.

Evaluation of Elispot assays: influence of method and operator on variability of results.

In this study, a comprehensive comparative analysis of different evaluation methods of Elispot plates was performed. Three investigators using three different evaluation approaches read 50 randomly selected wells at three different time points. The methods were: (1) manual evaluation using a stereomicroscope, (2) automated evaluation using an image analysis reader system with reading parameters established by each investigator, and (3) automated evaluation using a reader system with preset reading parameters using assay-specific controls. We demonstrate that manual evaluation had the highest variability both within the same method and when comparing all methods, followed by automated evaluation with investigator-dependent parameters. The variability was low only when all investigators used the same parameters established using assay-specific controls. This variability was independent of operator or spot number per well. Based on this study, recommendations for standardization and validation procedures of Elispot assay performance and evaluation procedures are presented.

Stroke in patients with cancer: incidence and etiology.

OBJECTIVE: To assess the incidence and type of strokes in patients with cancer at Memorial Sloan-Kettering Cancer Center. METHODS: Retrospective review of all ischemic strokes diagnosed by a neurologist and confirmed by neuroimaging between February 1997 and April 2001 was conducted. Age, gender, cancer diagnosis and stage, and vascular risk factors were recorded. NIH Stroke Scale and modified Rankin Scale scores were calculated retrospectively. Stroke etiology was assigned independently by two neurologists using the Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria. RESULTS: Ninety-six patients with a confirmed stroke were identified. The median age was 67, and 61.5% were men. The distribution of vascular risk factors was comparable with that seen in large stroke trials. Lung cancer (30%) was the most common primary tumor followed by brain and prostate cancer (9% each). Strokes were embolic in 52 (54%) and nonembolic in 44 (46%). Eleven of 12 tested patients had an elevated D-dimer level, but in only 3 patients could a definitive diagnosis of nonbacterial thrombotic endocarditis be made. The median survival was 4.5 months (95% CI 2.8 to 9.5) from the diagnosis of stroke; 25% of patients died within 30 days. Treatment had no effect on survival. CONCLUSIONS: Embolic strokes are the commonest cause of stroke in patients with cancer, due partially to hypercoagulability, whereas atherosclerosis accounted for only 22% of stroke in this population. Outcome was primarily determined by the underlying malignancy and the patient's neurologic condition.

Cytoreduction with iodine-131-anti-CD33 antibodies before bone marrow transplantation for advanced myeloid leukemias.

The monoclonal antibodies M195 and HuM195 target CD33, a glycoprotein found on myeloid leukemia cells. When labeled with iodine-131 ((131)I), these antibodies can eliminate large disease burdens and produce prolonged myelosuppression. We studied whether (131)I-labeled M195 and HuM195 could be combined safely with busulfan and cyclophosphamide (BuCy) as conditioning for allogeneic BMT. A total of 31 patients with relapsed/refractory acute myeloloid leukemia (AML) (n=16), accelerated/myeloblastic chronic myeloid leukemia (CML) (n=14), or advanced myelodysplastic syndrome (n=1) received (131)I-M195 or (131)I-HuM195 (122-437 mCi) plus busulfan (16 mg/kg) and cyclophosphamide (90-120 mg/kg) followed by infusion of related-donor bone marrow (27 first BMT; four second BMT). Hyperbilirubinemia was the most common extramedullary toxicity, occurring in 69% of patients during the first 28 days after BMT. Gamma camera imaging showed targeting of the radioisotope to the bone marrow, liver, and spleen, with absorbed radiation doses to the marrow of 272-1470 cGy. The median survival was 4.9 months (range 0.3-90+ months). Three patients with relapsed AML remain in complete remission 59+, 87+, and 90+ months following bone marrow transplantation (BMT). These studies show the feasibility of adding CD33-targeted radioimmunotherapy to a standard BMT preparative regimen; however, randomized trials will be needed to prove a benefit to intensified conditioning with radioimmunotherapy.

Analysis of multiple 2x2 tables with site-specific periodontal data.

Periodontal data typically consist of observations made at multiple sites within each patient. Observations within a patient tend to be positively correlated; hence, standard statistical techniques that assume independence are invalid. Regression techniques for correlated data have been proposed; communicating results from these models, however, is difficult, due to their inherent complexity. Simpler statistical approaches have also been proposed, but many of these methods can be applied only when covariates are specific to the subject, and do not vary from site to site within a subject. In this paper, we present two methods for the analysis of multiple 2x2 tables containing site-specific periodontal data. The methods presented are modifications of the well-known Mantel-Haenszel methods. We illustrate these methods using a subset of data from a clinical trial examining the effects of scaling and root planing on levels of interleukin-1 beta.

Clinical results using biochemotherapy as a standard of care in advanced melanoma.

Phase II studies of biochemotherapy in metastatic melanoma patients have reported response rates of 47-63%. Even though these were highly selected patients, we were intrigued by these promising response rates and began using this regimen as standard care in advanced melanoma patients. We report the results of the first 65 patients with AJCC stage IV melanoma (n = 57) or unresectable stage III (n = 8) melanoma treated with concurrent biochemotherapy at Memorial Hospital. Treatment was repeated every 3 weeks and patients were assessed for antitumour effects after every other cycle. The overall response rate among the 63 patients evaluable for response was 29% (three complete responses, 15 partial responses). The median duration of responses was 3.7 months. The response rate among previously treated and previously untreated patients was 6% and 38%, respectively. The estimated median survival for all patients was 8.5 months; the median survival for previously untreated patients was 9.2 months. Tumour response did not correlate with survival. Our experience, which is a retrospective evaluation, does not provide support for the routine use of biochemotherapy as standard treatment. The low response rate among previously treated patients indicates that biochemotherapy is not useful as second-line therapy.

Doxorubicin followed by sequential paclitaxel and cyclophosphamide versus concurrent paclitaxel and cyclophosphamide: 5-year results of a phase II randomized trial of adjuvant dose-dense chemotherapy for women with node-positive breast carcinoma.

PURPOSE: We conducted a randomized Phase II trial to directly compare toxicity, feasibility, and delivered dose intensities of two adjuvant dose-intensive regimens containing doxorubicin, paclitaxel, and cyclophosphamide for patients with node-positive breast carcinoma. EXPERIMENTAL DESIGN: Forty-two patients with resected breast carcinoma involving one or more ipsilateral axillary lymph nodes, were randomized to receive two different schedules of adjuvant chemotherapy using 14-day dosing intervals: either (a) three cycles of doxorubicin 80 mg/m(2) as i.v. bolus followed sequentially by three cycles of paclitaxel 200 mg/m(2) as a 24-h infusion and then by three cycles of cyclophosphamide 3.0 g/m(2) as a 1-h infusion (arm A); or (b) the same schedule of doxorubicin followed by three cycles of concurrent cyclophosphamide and paclitaxel at the same doses (arm B). All cycles were supported by granulocyte colony-stimulating factor administration. RESULTS: Forty-one patients were assessable for toxicity and feasibility; 37 (90%) completed all planned chemotherapy. There was no treatment-related mortality; however, increased toxicity was observed on arm B compared with arm A, manifested by an increase in hospitalization for toxicity, mainly neutropenic fever, and an increased incidence of transfusion of packed RBCs transfusions for anemia. The mean delivered dose intensities for paclitaxel and cyclophosphamide were significantly greater for arm A compared with arm B (P =.01 and P =.05, respectively). There is no long-term, treatment-related toxicity, and no cases of acute myelogenous leukemia or myelodysplastic syndrome have been observed. CONCLUSIONS: Dose-dense sequential single-agent chemotherapy is more feasible than doxorubicin with subsequent concurrent paclitaxel and cyclophosphamide.