Ramin Altaha

Epothilones: A Novel Class of Non-taxane Microtubule-stabilizing Agents

The epothilones are a novel class of non-taxane microtubule-stabilizing agents obtained from the fermentation of the cellulose degrading myxobacteria, Sorangium cellulosum. Preclinical studies have shown that the epothilones are more potent than the taxanes and active in some taxane-resistant models. Similar to paclitaxel and other taxanes, the epothilones block cells in mitosis, resulting in cell death. The chief components of the fermentation process are epothilones A and B, with epothilones C and D found in smaller amounts. Trace amounts of other epothilones have also been detected. Pre-clinical studies have shown that epothilone B is the most active form, exhibiting significantly higher antitumor activity than paclitaxel and docetaxel. Several phase I and phase II clinical trials are ongoing with epothilone B and BMS 247550, an epothilone B analog. Preliminary reports indicate these agents are active against human cancers in heavily pre-treated patients. The epothilones appear to be well tolerated, with a side effect profile that is similar to that reported with the taxanes. This article will review some basic aspects of epothilone chemistry and biology, and pre-clinical and preliminary clinical experience with epothilone B and its analog, BMS 247550.

Increased risk of brain metastases in patients with HER-2/neu-positive breast carcinoma

Preliminary data have indicated that overexpression of HER-2/neu is correlated with more aggressive disease, an increased metastatic potential, and a poorer prognosis in patients with breast carcinoma. Trastuzumab, a humanized anti-HER-2 antibody, reportedly is unable to penetrate the blood– brain-barrier and to our knowledge its efficacy in patients with brain metastases remains unclear. – 6 We conducted a retrospective study to evaluate whether patients with HER-2/neu-positive breast carcinoma have an increased risk of developing brain metastases. After approval from the institutional review board of West Virginia University, the pathology reports of 703 breast carcinoma patients who were diagnosed between April 1998 and January 2003 were reviewed. Based on immunohistochemistry or fluorescence in situ hybridization positivity, all patients who were positive for HER-2/neu were identified and their medical charts reviewed with regard to their course of disease and sites of metastases. Of the 703 patients studied, 164 (23%) were found to be positive for HER-2/neu; a sufficient oncologic history was available for 102 patients. Thirty-one patients (30%) developed distant metastases (95% confidence interval [95% CI], 0.223– 0.399) during follow-up lasting a median of 57 months. Brain metastases were reported to have developed in 15 of these 31 patients (48%)(95% CI, 0.320 – 0.652). A proportional hazards model was fit to the data to explore the association between patient age and time to the development of metastases. A significantly positive association (P 0.01) was found to exist between the two variables. Other models for censored data (Weibul, log-normal, and exponential models) were fitted and were found to produce nearly identical P values (Fig. 1). The results of this small retrospective study demonstrate that younger women with HER-2/neu-positive breast carcinoma may have a higher risk of developing brain metastases than previously reported for the general metastatic breast carcinoma patient population. This 442

5-Hydroxyindoleacetic acid and substance P profiles in patients receiving emetogenic chemotherapy.

Background. Even though direct cause and effect has not been proved, clinical evidence suggests serotonin and substance P (SP) are involved in the emetic response following chemotherapy. Because of several parallels, we hypothesized that SP release, like serotonin, may be propagated by chemotherapy and both substances can be measured in biological fluids, and correlated with a particular phase of emesis. Methods. Urinary 5-hydroxyindoleacetic acid (5-HIAA) was assessed by HPLC; serum and urine SP were measured by immunoassay. In addition to construction of neurotransmitter profiles, all SP data were grouped according to cisplatin dosages, = or>75 mg/m 2 versus <75 mg/m2, and phase of emesis, acute versus delayed. Analyses of these data were performed by repeated measures analysis of variance. Results. Samples were collected over a 72-hour period from 26 adult patients who received cisplatin-(n=13) or non-cisplatin-containing (n=13) chemotherapy. Mean baseline 5-HIAA: creatinine ratios were 5.23 and 5.16 in females and males, respectively; mean baseline SP levels were 392 and 181 pg/mL in females and males, respectively. Comparisons between SP data stratified by cisplatin dosage and emetic phase were significantly different, P <0.0001. Conclusions. Laboratory studies provide additional evidence that serotonin and SP are involved primarily, though not exclusively, in acute and delayed vomiting, respectively.

Oncocytic, focally anaplastic, thyroid cancer responding to erlotinib††

Objective. To highlight the molecular findings and clinical response of a patient with rapidly progressing, focally anaplastic, oncocytic thyroid carcinoma (OTC) treated with erlotinib. Case Summary. A 69-year-old woman with recurrent, focally anaplastic OTC was given a therapeutic trial of erlotinib, a small molecule inhibitor of epidermal growth factor receptor (EGFR). Formalin-fixed, paraffin-embedded portions of the tumor were analyzed for EGFR expression, and tumor genomic DNA was amplified by polymerase chain reaction (PCR) and subjected to EGFR mutation analysis. Discussion. An early and dramatic response was achieved with erlotinib. The tumor was focally positive for EGFR by immunostaining and two point mutations were identified, one on exon 18 and one on exon 20 in the tyrosine kinase (TK) domain. Conclusion. Erlotinib or other novel protein kinase pathway inhibitors should be evaluated further in patients with aggressive thyroid cancer variants, who may exhibit these and perhaps other tyrosine kinase mutations. J Oncol Pharm Practice (2009) 15: 111—117.

Paraneoplastic Neurologic Syndrome Associated with Occult Breast Cancer: A Case Report and Review of Literature

Abstract:  We report a case of occult breast cancer presenting as paraneoplastic sensory and motor neuropathy. The paraneoplastic antibody panel was negative and no other unknown identifiable antibody could be detected in the serum. Systemic treatment with four cycles of Adriamycin and cyclophosphamide was given with no significant improvement in the neurologic condition. We reviewed the literature of the last 10 years and identified 31 reported cases of paraneoplastic neurologic syndrome due to breast cancer. Paraneoplastic antibodies could be found in only 36% of patients, no identifiable antibodies in 32% of patients, and unknown antibodies in 16% of patients. The status of the paraneoplastic antibodies was not reported in 16% of patients. Only 29% of patients responded to chemotherapy with improvement in neurologic deficits. The role of systemic treatment in the progression of neurologic impairment is unclear.

Reinduction of Bevacizumab in Combination with Pegylated Liposomal Doxorubicin in a Patient with Recurrent Glioblastoma Multiforme Who Progressed on Bevacizumab/Irinotecan

Glioblastoma multiforme (GBM) carries a dismal prognosis despite the current standard of multimodality treatments. Recent studies showed promising results to a regimen consisting of a VEGF inhibitor, (bevacizumab) and a topoisomerase I inhibitor (irinotecan) [BI] in recurrent GBM. However, those patients with GBM who progress on BI will succumb to their disease generally in a very short period of time. We report a case of a 56-year-old male patient with GBM who declined surgical resection and received chemoradiation with temozolomide. This treatment was withheld secondary to significant thrombocytopenia. Subsequently, he achieved stable disease for 10 months with a regimen consisting of thalidomide and tamoxifen before progressing. This was followed by bevacizumab with irinotecan [BI], for which he had a significant partial response for 8 months with subsequent progression. Reinducing the patient with bevacizumab in combination with a pegylated liposomal doxorubicin [PLD] (a topoisomerase II inhibitor) demonstrated antitumor activity with significant shrinkage of contrast enhancing mass and peritumoral edema.

Cerebrospinal Fluid Leak During Treatment With Bevacizumab and Irinotecan After Carmustine-Impregnated Wafers Placement in Patients With Grade 2 Oligodendroglioma and Glioblastoma Multiforme: Report of Two Cases and Review of Literature

ABSTRACT Placement of carmustine-impregnated wafers has become a common practice after surgical resection of malignant gliomas. Bevacizumab is used as a second-line agent for the treatment of malignant gliomas and is sometimes used in patients who have had recent wafer implantation. We describe two cases of fatal cerebrospinal fluid (CSF) leak in patients treated with bevacizumab and irinotecan after 4 weeks of carmustine wafer implantation. Possible mechanisms for the CSF leak in these patients are discussed. We recommend waiting for a longer period of time before starting bevacizumab in patients who had implantation of carmustine wafers.

A fatal outcome in a patient with glioblastoma multiforme after receiving high-dose methotrexate.

The most common adult primary brain tumor is glioblastoma multiforme (GBM). Current treatment is surgical resection, adjuvant radiation and chemotherapy, which can extend the median survival 20—36 weeks (Mansky et al. Central nervous system tumors. In Abraham J, Allegra CJ, Gulley J, eds. Bethesda Handbook of clinical oncology, 2nd edn. Philadelphia, Pennsylvania: Lippincott Williams and Wilkins, 2000: 440—2; Knox S. Intracranial tumors. In Pillot G, Chantler M, Magiera H, Peles S, et al., eds. The Washington Manual Hematology and Oncology Subspecialty Consult. Philadelphia, Pennsylvania: Lippincott Williams and Wilkins, 2004: 204—6.). But treatment efficacy is limited, mandating the exploration of more effective treatments. We report on a patient with GBM treated as per a clinical protocol with high-dose methotrexate (12 g/m2), who expired within hours after the initiation of treatment secondary to transtentorial herniation. Although it is not completely clear what caused the patients herniation, we think that high-dose methotrexate therapy may have played a crucial role. We suggest that high-dose methotrexate should be used cautiously in patients with GBM. J Oncol Pharm Practice (2008) 14: 57—60.