Breast cancer and leptomeningeal disease (LMD): hormone receptor status influences time to development of LMD and survival from LMD diagnosis.

Leptomeningeal disease (LMD) occurs in 5 % of breast cancer patients. The aim of this study was to identify risk factors related to survival and time to development of LMD in breast cancer patients. A retrospective analysis of breast cancer patients with LMD, evaluated in MDACC between 1995 and 2011. 103 patients with diagnosis of breast cancer and LMD were identified (one male). The median age at LMD diagnosis was 49.2 years. 78.2 % had invasive ductal carcinoma. Hormone receptors (HRs) were positive in 55.3 % of patients, 47.4 % were human epidermal growth factor receptor 2-positive and 22.8 % were triple negative. 52 % of the patients were treated with WBRT, 19 % with spinal radiation, 36 % with systemic chemotherapy and 55 % with intrathecal chemotherapy. Estimated median overall survival from time of breast cancer diagnosis was 3.66 years. Median survival from time of LMD diagnosis was 4.2 months. Time from breast cancer diagnosis to LMD was 2.48 years. In multivariate analysis, HR status and stage at diagnosis were significantly associated with time to LMD diagnosis (p < 0.05). In triple negative patients, time to LMD was shorter. In patients who were HR positive, time to LMD was longer. Survival from LMD diagnosis was significantly associated with both treatment, as well as positive HR status (multivariate analysis p < 0.05). In conclusion LMD has dismal prognosis in breast cancer patients. HR status contributes to time to LMD diagnosis and survival from LMD diagnosis. The impact of treatment aimed at LMD cannot be ascertained in our retrospective study due to the inherent bias associated with the decision to treat.

A randomized trial on the efficacy of methylphenidate and modafinil for improving cognitive functioning and symptoms in patients with a primary brain tumor.

Limited research is available regarding the efficacy of psychostimulants in treating cognitive function in primary brain tumor patients. An open-label, randomized, pilot trial examined both the general and differential efficacy of 4 weeks of methylphenidate (MPH) and modafinil (MOD) in 24 brain tumor patients. Participants completed cognitive tests and self-report measures of fatigue, sleep disturbance, mood and quality of life at baseline and after 4 weeks.Following stimulant treatment, there was evidence of a beneficial effect on test performance in speed of processing and executive function requiring divided attention. Patients with the greatest deficit in executive function at baseline appeared to derive the greatest benefit following stimulant therapy. Inconsistent, differential effects were found on a measure of attention in favor of MPH and on a measure of processing speed in favor of MOD. There was also evidence of a general beneficial effect on patient-reported measures of fatigue, mood, and quality of life, with no statistically significant differences between treatment arms in these measures over time. The results from this small pilot study should be interpreted with caution, but appear to warrant additional research, in larger study samples, targeting fatigue, processing speed and executive function, and exploring different doses of stimulants. Future studies may also wish to explore the specific patient factors that may be associated with responsiveness to psychostimulant treatment.

Two phase II trials of temozolomide with interferon-alpha2b (pegylated and non-pegylated) in patients with recurrent glioblastoma multiforme.

BACKGROUND: Because of the poor outcomes for patients with recurrent glioblastoma multiforme (GBM), and some laboratory and clinical evidence of efficacy using interferon in GBM, we assessed the toxicity and efficacy of temozolomide (TMZ) combined with either short-acting (IFN) or long-acting (pegylated) interferon alpha2b (PEG) in two single-arm phase II studies, and compared the results to 6-month progression-free survival (PFS-6) data from historical controls. METHODS: Two single-arm phase II studies were carried out in adults with GBM. Patients were treated with the standard regimen of TMZ (150-200 mg m(-2) per day x 5 days every month) combined with either 4 million units per m(2) subcutaneously (SQ) three times weekly of IFN or 0.5 microg kg(-1) SQ weekly of PEG. Physical exams and imaging evaluations were carried out every 8 weeks. RESULTS: On the IFN study, 34 adults (74% men) were enrolled, and 29 adults (55% men) on the PEG study; median Karnofsky performance status was 80 and 90 for the IFN and PEG studies, respectively. Grade 3 or 4 toxicities were common, leucopoenia and thrombocytopoenia occurring in 35-38% and 18-21% of patients, respectively. Grade 3 or 4 fatigue occurred in 18% of patients on both studies. Lymphopoenia was infrequent. PFS-6 was 31% for 29 evaluable patients in the IFN study and 38% for 26 evaluable patients in the PEG study. CONCLUSION: In recurrent GBM patients, both studies of standard dose TMZ with either IFN or PEG showed improved efficacy when compared to historical controls, or reports using TMZ alone. Even though the TMZ+PEG study met criteria for further study, the results of both of these studies must be considered in light of the standard of care (TMZ plus radiotherapy) for newly diagnosed GBM, which has evolved since the inception of these studies. Despite the results of the current studies being eclipsed by the new GBM standard of care, these results can still inform the development of newer approaches for GBM, either in an earlier, upfront setting, or by extrapolation of the results and consideration of the use of PEG or IFN in conjunction with other antiglioma strategies.

Phase II study of carboplatin and erlotinib (Tarceva, OSI-774) in patients with recurrent glioblastoma.

Targeting the epidermal growth factor receptor (EGFR) may be effective in a subset of glioblastoma patients. This phase II study assessed the clinical activity of erlotinib plus carboplatin and to determine molecular predictors of response. The primary endpoint was progression free survival (PFS). Patients with recurrent glioblastoma with no more than two prior relapses received carboplatin intravenously on day 1 of every 28-day cycle (target AUC of 6 mg x ml/min). Daily erlotinib at 150 mg/day was dose escalated to 200 mg/day, as tolerated. Clinical and MRI assessments were made every 4 and 8 weeks, respectively. Tumor tissue was evaluated for EGFR, AKT and phosphatase and tensin homolog (PTEN) status. One partial response (PR) was observed out of 43 assessable patients. Twenty patients (47%) had stable disease (SD) for an average of 12 weeks. Median PFS was 9 weeks. The 6-month PFS rate was 14%. Median overall survival (OS) was 30 weeks. This regimen was well tolerated with grade 3/4 toxicities of fatigue, leukopenia, thrombocytopenia and rash requiring dose reductions. A recursive partitioning analysis (RPA) predicted that patients with KPS >or=90 treated with more than 1 prior regimen had the highest OS. No correlation was observed between EGFR, Akt or PTEN expression and either PFS or OS. Carboplatin plus erlotinib is well tolerated but has modest activity in unselected patients. Future trials should be stratified based on optimal molecular or clinical characteristics.

Combination chemotherapy with 13-cis-retinoic acid and celecoxib in the treatment of glioblastoma multiforme.

In a phase II clinical trial, we sought to determine if combining celecoxib with 13-cis-retinoic acid (13-cRA, Accutane) was efficacious in the treatment of recurrent (progressive) glioblastoma multiforme (GBM). In parallel, we also sought to determine to what extent the outcomes from this clinical trial correlated with the findings from studies utilizing two murine intracerebral GBM models, U87MG and U251HF, to determine the predictive value of these murine models. In the clinical trial, 25 patients were studied at recurrence. Stable disease, which occurred in 44% of the patients, was the best response. The median progression-free survival (PFS) was 8 weeks, with a PFS at 6 months of only 19%. For the patients with stable disease, the median PFS was 24 weeks. The toxicity profile was unremarkable. The modest effect on PFS seen in this study agreed with the recent findings of another study, which showed a 19% PFS at 6 months in patients treated with 13-cRA alone. Thus, the combination of 13-cRA with celecoxib is not more effective than 13-cRA in the treatment of progressive GBM. In the murine model study, we found that long-term dosing with 13-cRA or celecoxib alone or in combination did not increase survival in animals with U87MG tumors but modestly increased survival in animals with U251HF tumors. There was no evidence of synergism between the two drugs. From this, we concluded that the animal studies generally predicted that the two agents would have only a modest effect alone and no additive effect when given in combination to patients.

A dimension-breaking phenomenon in the theory of steady gravity-capillary water waves.

The existence of a line solitary-wave solution to the water-wave problem with strong surface-tension effects was predicted on the basis of a model equation in the celebrated 1895 paper by D. J. Korteweg and G. de Vries and rigorously confirmed a century later by C. J. Amick and K. Kirchgässner in 1989. A model equation derived by B. B. Kadomtsev and V. I. Petviashvili in 1970 suggests that the Korteweg-de Vries line solitary wave belongs to a family of periodically modulated solitary waves which have a solitary-wave profile in the direction of motion and are periodic in the transverse direction. This prediction is rigorously confirmed for the full water-wave problem in the present paper. It is shown that the Korteweg-de Vries solitary wave undergoes a dimension-breaking bifurcation that generates a family of periodically modulated solitary waves. The term dimension-breaking phenomenon describes the spontaneous emergence of a spatially inhomogeneous solution of a partial differential equation from a solution which is homogeneous in one or more spatial dimensions.

Adenovirally-mediated transfer of E2F-1 potentiates chemosensitivity of human glioma cells to temozolomide and BCNU.

The therapeutic efficacy of standard cancer treatments such as chemotherapy may be improved if they are combined with gene-therapy. Less than 30% of patients with glioblastoma multiforme respond to adjuvant chemotherapy. Actively dividing cells are generally more sensitive to chemotherapy than are non-dividing cells. To determine whether forced cell-cycle progression selectively sensitizes tumor cells to alkylating agents, we examined the effects of overexpressing the E2F-1 protein (a positive regulator of cell-cycle progression) on the sensitivity of two malignant human glioma cell lines, U-251 MG and D-54 MG, to BCNU and temozolomide. Treating these cells with 20-35 microM BCNU or 20-30 microM temozolomide resulted in 50% growth inhibition (IC50) within 4 or 6 days, respectively. By contrast, cells that were first induced to overexpress E2F-1 protein by infection with an adenoviral vector had IC50s that were 37-50% lower. Conversely, transferring the cyclin-dependent kinase inhibitors p16 and p21 to the cells, also by adenoviral infection, produced 3 to 4-fold increases in chemoresistance. Cell-cycle analyses showed that the combination of E2F-1 overexpression and treatment with BCNU or temozolomide increased the proportion of cells in S phase, but the combination of p16 or p21 overexpression and drug treatment reduced the proportion of cells in S phase. These observations suggest that overexpression of genes that positively control cell-cycle progression may be useful for increasing the sensitivity of glioma cells to alkylating agents.

Peripheral nerve injury after brief lithotomy for transurethral collagen injection.

Two patients with prior prostate surgery sustained peripheral nerve injuries after transurethral collagen injection for the treatment of urinary incontinence. In the first patient, brief lithotomy positioning caused a gluteal compartment syndrome and sciatic neuropathy. In the second patient, obturator neuropathy was due to leakage of collagen along the course of the obturator nerve. This is the first report of peripheral nerve injury in patients undergoing transurethral collagen injection.

A phase II trial of high-dose bromodeoxyuridine with accelerated fractionation radiotherapy followed by procarbazine, lomustine, and vincristine for glioblastoma multiforme.

PURPOSE: To conduct a Phase II study to evaluate the long-term efficacy and safety of high-dose 5'-bromodeoxyuridine (BrdU) and accelerated radiotherapy followed by procarbazine, lomustine (CCNU), and vincristine (PCV) chemotherapy in patients with glioblastoma multiforme. METHODS AND MATERIALS: Between 1994 and 1996, 88 patients were enrolled to receive 1.9 Gy of radiation three times a day for two 5-day cycles separated by 2 weeks; each 5-day cycle was preceded by a continuous 96-hour infusion of BrdU at a dose of 2.1 g/m2/day. After radiotherapy, patients received PCV chemotherapy. RESULTS: Median survival for all 88 patients was 50 weeks. Seventy (79.5 %) received one or more courses of PCV; their median survival was 57 weeks. Covariates predictive of improved survival were gross total versus subtotal resection or biopsy (p = 0.0048) and radiation dose > or = 56 Gy (p = 0.019). While receiving BrdU, 47 patients (53%) suffered grade 3 or 4 thrombocytopenia or leukopenia; 22 patients (25%) suffered grade 3 or 4 dermatologic toxicity. CONCLUSION: Survival was not extended in patients with glioblastoma or gliosarcoma who received BrdU at the dose and administration schedule used in this study. The BrdU dose used in this study resulted in substantial myelosuppressive and dermatologic toxicity.

Radicular pain can be a symptom of elevated intracranial pressure.

We report two patients with leptomeningeal metastatic disease, one from breast cancer and the other from a spinal cord glioma, who developed episodic elevated intracranial pressure (ICP), each episode accompanied by the gradual onset of severe spine and radicular pain. Symptoms of pain promptly and completely resolved with opening of the on-off valve of each patient's ventriculoperitoneal shunt. It is theorized that the patients' radicular pain was caused by nerve root ischemia secondary to elevated ICP.

Pernicious anemia manifesting as angina pectoris.

Here we describe a case of angina pectoris in a patient for whom an extensive cardiovascular workup was done, with negative results. Eventually, the cause of his symptoms was found to be pernicious anemia. Although angina is an uncommon manifestation of pernicious anemia, a review of the literature suggests that the correlation between anemia and angina has been well described. Our case highlights an important differential diagnosis to consider for patients with exercise-induced chest pain and serves to emphasize the attention that should be focused on simple screening laboratory studies. The emphasis in this case is the sequence in which the studies are done. A simple complete blood count with proper interpretation and intervention at the outset of evaluation could possibly have prevented a number of unnecessary, invasive, and costly studies.

Papillary carcinoma of the thyroid: additional evidence in support of a familial component.

Although a higher incidence of medullary carcinoma of the thyroid is well known to occur in families with syndromes of multiple endocrine neoplasia (MEN II and III), an epidemiologic familial component has only very rarely been ascribed to papillary carcinoma. In this report we describe a mother and daughter presenting with neck masses at an early age and subsequently found to have metastatic papillary thyroid carcinoma documented on pathology following thyroidectomy. The occurrence of the neoplasm at an advanced stage in closely related individuals early in life suggests that underlying genetic factors may predispose to this malignancy. Familial papillary carcinoma of the thyroid may have a hereditary basis independent of its association with the syndromes of multiple polyposis and of multiple hamartomas, and thus may represent a new entity with characteristics which distinguish it as a distinct subset of the more common disease.