Incidence of Brain Metastasis as First Event in Patients with Esophageal Carcinoma: a Report from Three Prospective Alliance Clinical Trials.

PURPOSE: Historically, reported incidence of brain metastasis secondary to esophageal carcinoma is low. We sought to determine the incidence of brain metastasis in a contemporary cohort of patients with carcinoma of the esophagus. METHODS: Data from patients with localized esophageal carcinoma prospectively enrolled on three curative intent Alliance treatment trials (N0044, N0342, N044E) were reviewed including time to diagnosis of first progression event (brain versus other site) and overall survival. RESULTS: Eighty-five patients comprised the cohort of which 85% were male and 86% had adenocarcinoma primary tumor histology. Thirty-nine of the 85 patients had documented progression to any site, and of those, brain metastasis occurred as the first event in 15% (6 of 39). Adenocarcinoma was the primary histology in all 6 patients and tumor grade was high (3 or 4) in 5 of the 6 patients (one not documented). Median time to brain metastasis (9.6 months) versus non-brain metastasis (12.4 months) and median survival after first progression (5.4 months versus 8.1 months, respectively) were not statistically different. CONCLUSION: In this prospective cohort of patients with esophageal carcinoma, those with high-grade adenocarcinoma appear to have a higher incidence of brain metastasis than historically reported. The pattern of brain metastases corroborates recent findings in terms of incidence, predominance of adenocarcinoma primary tumor histology, timing after diagnosis, and overall survival. Further study to confirm these findings, as well as the value of baseline, restaging and follow-up cranial imaging for brain metastasis is recommended. GOV IDENTIFIERS: NCT00022139 (NCCTG N0044), NCT00100945 (NCCTG N0342), and NCT00100945 (NCCTG N044E).

Thrombotic Microangiopathy Care Pathway: A Consensus Statement for the Mayo Clinic Complement Alternative Pathway-Thrombotic Microangiopathy (CAP-TMA) Disease-Oriented Group.

Thrombotic microangiopathies (TMAs) comprise a heterogeneous set of conditions linked by a common histopathologic finding of endothelial damage resulting in microvascular thromboses and potentially serious complications. The typical clinical presentation is microangiopathic hemolytic anemia accompanied by thrombocytopenia with varying degrees of organ ischemia. The differential diagnoses are generally broad, while the workup is frequently complex and can be confusing. This statement represents the joint recommendations from a multidisciplinary team of Mayo Clinic physicians specializing in the management of TMA. It comprises a series of evidence- and consensus-based clinical pathways developed to allow a uniform approach to the spectrum of care including when to suspect TMA, what differential diagnoses to consider, which diagnostic tests to order, and how to provide initial empiric therapy, as well as some guidance on subsequent management.

Initial report of a family registry of multiple myeloma.

About 20,000 Americans are diagnosed with multiple myeloma (MM) each year, and more than 10,000 die of MM in the United States annually. The etiology of MM remains unknown, although genetic and environmental factors have been implicated. Patients (n = 68) from the Myeloma Institute for Research and Therapy at the University of Arkansas for Medical Sciences and their family members with MM or a related malignancy were interviewed for environmental factors associated with MM and for family history data to complete pedigrees. In collaboration with Dr Henry Lynch at Creighton University, pedigrees of at least 3 generations were analyzed. Eighteen families (27%) have a putative autosomal dominant mode of genetic transmission of MM. Furthermore, the pedigrees indicate that pancreatic cancer, malignant melanoma, breast cancer, and lymphoma may be part of a myeloma syndrome. Environmental factors associated with MM present in this patient population were being born and raised in a rural area, raising cattle or cotton, and exposure to pesticides, insecticides, or herbicides. This work will be part of the efforts to create an international consortium to study familial MM. Research in the area of molecular epidemiology is needed to discover the genetic and environmental determinants of this disease.

Familial multiple myeloma.

In this issue of Blood, there are 2 reports on the increased risk of plasma cell disorders in the first-degree relatives of patients with multiple myeloma or MGUS.

Genetic counseling for DAPK1 mutation in a chronic lymphocytic leukemia family.

Genetic counseling has become the clinical bedrock of hereditary cancer management. Countless advances in molecular genetics contributing to the identification of cancer-causing germline mutations have increased its importance. We report a unique genetic counseling experience involving a family with hereditary chronic lymphocytic leukemia and the cancer-causing mutation in the death-associated protein kinase 1 gene (DAPK1). This hereditary disorder currently lacks any preventive or curative interventions for mutation carriers. This family has been under our investigation for a decade, during which time genealogy, cancer of all anatomic sites, medical and pathology records, and, whenever possible, slides and tissue blocks were reviewed. Family attendance at three group-oriented family information service sessions provided intensive education about this disease. Blood and skin fibroblasts were obtained for molecular genetic studies of DNA leading to the discovery of the DAPK1 mutation in the family. Their intellectual and emotional reaction to its presence or absence in them was assessed. This family serves as a model for genetic counseling in disorders for which lifesaving intervention is not yet possible.

Pooled analysis of fluorouracil-based adjuvant therapy for stage II and III colon cancer: who benefits and by how much?

PURPOSE: Although it is well-established that fluorouracil- (FU-) based adjuvant therapy improves survival for patients with resected high-risk colon cancer, the magnitude of adjuvant therapy benefit across specific subgroups and for individual patients has been uncertain. PATIENTS AND METHODS: Using a pooled data set of 3,302 patients with stage II and III colon cancer from seven randomized trials comparing FU + leucovorin or FU + levamisole to surgery alone, we performed an analysis based on a Cox proportional hazards regression model. Treatment, age, sex, tumor location, T stage, nodal status, and grade were tested for both prognostic and predictive significance. Model derived estimates of 5-year disease-free survival and overall survival (OS) for surgery alone and surgery plus FU-based therapy were calculated for a range of patient subsets. RESULTS: Nodal status, T stage, and grade were the only prognostic factors independently significant for both disease-free survival and OS. Age was significant only for OS. In a multivariate analysis, adjuvant therapy showed a beneficial treatment effect across all subsets. Treatment benefits were consistent across sex, location, age, T-stage, and grade. A significant stage by treatment interaction was present, with treatment benefiting stage III patients to a greater degree than stage II patients. CONCLUSION: Patients with high-risk resected colon cancer obtain benefit from FU-based therapy across subsets of age, sex, location, T stage, nodal status, and grade. Model estimates of survival stratified by T stage, nodal status, grade, and age are available at http://www.mayoclinic.com/calcs. This information may improve patients' and physicians' understanding of the potential benefits of adjuvant therapy.

Determination of potential adjuvant systemic therapy benefits for patients with resected cutaneous melanomas.

OBJECTIVE: To facilitate both better physician understanding of prognostic information (baseline and with adjuvant interferon) for individual patients who present with resectable melanomas and more informed patient decisions about whether they should receive adjuvant high-dose interferon therapy after resection of primary melanomas. PATIENTS AND METHODS: Baseline survival estimates were derived from a surgical database composed of 17,600 patients with complete clinical, pathologic, and follow-up data. Potential survival benefits ascribed to adjuvant interferon were obtained from results of a meta-analysis of Eastern Cooperative Oncology Group studies, which provided evidence for a uniform relative benefit of high-dose interferon across different baseline risk groups. A mathematical formula was then applied to these data to allow for individual prognostic information. RESULTS: The 5-year survival benefits in patients who received high-dose interferon after surgery, using the assumptions of the provided prognoses and interferon survival improvements, ranged up to 13%. CONCLUSIONS: These data should allow for a better understanding of baseline prognosis in individual patients and a better understanding of the potential benefits of adjuvant interferon. They should also help patients make more informed decisions regarding their treatment options.

Unusual presentation of multiple myeloma with unilateral visual loss and numb chin syndrome in a young adult.

A 39-year-old man presented with unilateral visual loss as the first sign of multiple myeloma (MM). His visual loss was due to a plasmacytoma in the sphenoid sinus compressing the optic nerve with resultant optic nerve atrophy. Shortly after this presentation he developed numb chin syndrome due to a mandibular plasmocytoma compressing the mental nerve. His MM progressed rapidly despite treatment with high-dose steroids and alkylating agents and he required allogeneic bone marrow transplantation in order to achieve a remission. We reviewed the published medical literature on the presentation of MM with visual impairment and present a summary in tabular form in this paper. This is the first reported case of MM presenting with isolated complete visual loss due to intracranial extrinsic compression of the optic nerve since the advent of modern cross-sectional imaging. Multiple myeloma needs to be included in the differential diagnosis of cranial neuropathies and skull base neoplasms even in adults under 40 years of age.

Safety of thrice-daily hyperfractionated radiation and BCNU for high-grade gliomas.

PURPOSE: To investigate the safety of thrice-daily hyperfractionated radiotherapy (RT) given in conjunction with BCNU (carmustine) in high-grade gliomas. METHODS AND MATERIALS: Patients >18 years old with newly diagnosed high-grade gliomas were eligible. The dose of radiation was 5040 cGy, with a 1440-cGy boost in 180 cGy fractions delivered thrice daily in two 6-day periods with a 2-week interval. BCNU (200 mg/m(2)) was administered on the first day of radiation, then every 7 weeks for 1 year and every 10 weeks for another year. RESULTS: Eighteen patients were enrolled. The mean age was 49.6 years. Sixteen patients had astrocytomas (Grade 3 or 4 in 5 and 11 patients, respectively) and 2 had oligoastrocytomas (Grade 3 and 4 in 1 patient each). One underwent total resection, 9 subtotal resection, and 8 biopsy only. Thirteen patients had stable disease, 4 regression, and 1 progression. The median time to progression was 37.8 weeks. The median overall survival was 44.4 weeks. Nine patients had neurologic toxicities, including 2 deaths at 69 and 139 weeks. CONCLUSION: This regimen is unacceptably toxic. Factors that could have contributed to the toxicity may include the total radiation dose, thrice-daily hyperfractionation, and the concurrent use of i.v. BCNU.

Analysis of the human herpesvirus 8 (HHV-8) genome and HHV-8 vIL-6 expression in archival cases of castleman disease at low risk for HIV infection.

Lymph nodes from 44 patients with Castleman disease (CD) without risk factors for HIV infection were analyzed with polymerase chain reaction (PCR), in situ hybridization (ISH), and immunohistochemical analysis for human herpesvirus 8 (HHV-8) and viral interleukin-6 (vIL-6). PCR detected HHV-8 genome in 2 of 4 cases; ISH detected it in 9 of 16 cases. HHV-8 vIL-6 peptides were detected in 2 of 44 cases. vIL-6- and ISH-positive cells were found in large transformed and small lymphocytes of the follicular mantle, respectively. Of 9 cases of plasma cell (PC) CD that demonstrated HHV-8 genome by PCR or ISH, 1 expressed vIL-6. Clonal populations of PCs in CD by immunohistochemical analysis or immunoelectrophoresis of serum and urine were associated with neuropathy. HHV-8 vIL-6 detection was associated with poor survival and lack of HHV-8 IL-6, with low risk for subsequent lymphoma. Although HHV-8 genome was detected in a considerable number of patients with PC CD, vIL-6 expression was infrequent. Expression of HHV-8 vIL-6 in CD may indicate poor prognosis in patients at risk for lymphoma who may prospectively require more aggressive treatment. The lack of vIL-6 expression in CD with HHV-8 genome suggests that human IL-6 rather than vIL-6 may be the principal pathogenic cytokine.