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.

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.

Concordance between substance P levels and antiemetic guidelines.

Practice guidelines now include an antagonist of the substance P/NK1 (neurokinin 1) receptor pathway as part of the standard antiemetic regimen for patients receiving highly, as well as certain moderately, emetogenic chemotherapy regimens. Accumulated laboratory data were used to determine the degree of concordance between substance P levels and the current antiemetic guidelines. Five blood samples were collected over 72 hours from 22 adult patients treated with cisplatin-containing chemotherapy regimens. Overall, the mean baseline substance P level was 318 pg/mL. Although increases in substance P were observed during both phases of the emetic response, analysis by least squares means grouped by cisplatin dosage and vomiting phase was significantly different (P< 0.0001). Preliminary analysis of substance P levels appears to provide additional justification for including the NK1 receptor antagonist in the current antiemetic practice guidelines. In addition, these data provide biochemical justification for the cisplatin dosage criterion used in clinical trials.

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.

Excision repair cross complementing-group 1: gene expression and platinum resistance.

Platinum compounds induce their cytotoxic effect by binding to a DNA molecule in the form of a platinum-DNA-adduct. Many previous studies have shown that the level of platinum-DNA-adduct correlats with response to platinum-based chemotherapy. Although the mechanism of platinum resistance in vivo is not clearly understood, laboratory studies on cancer cell lines suggest that nucleotide excision repair (NER) is the main mechanism responsible for this resistance by increased platinum-DNA-adduct removal. NER pathway is a network of many proteins gathered in a DNA-repair system. The excision repair cross complementing-group 1 (ERCC1) gene has the leading role in NER-pathway because of its damage recognition and excision ability. In this report we reviewed the pathway leading to ERCC1 gene transcription and translation in cancer cells when exposed to cisplatin. We summarized data from different cancer cell lines and human cancers showing that the high level of ERCC1-mRNA and/or ERCC1 protein is associated with resistance to platinum compounds with direct impact on cancer patient survival and finally we analyzed drugs interfering with ERCC1 gene expression and causing the reversal of the platinum resistance when given to cancer cells prior to platinum-based chemotherapy.

Breast and ovarian cancer genetics and prevention.

Inherited breast and ovarian cancers account for 10% of all breast and ovarian cancers. Relative to sporadic breast and ovarian cancers, these cancers tend to occur at an earlier age and grow more aggressively. Women with BRCA1 and BRCA2 mutations (BRCA1/2 mutation) have a 65% to 85% cumulative lifetime risk of developing invasive breast cancer and a 15% to 65% cumulative lifetime risk of developing invasive ovarian cancer. Identification of patients with the mutation is therefore crucial, because preventive measures such as prophylactic bilateral mastectomy, prophylactic bilateral salpingpo-oophorectomy and chemoprevention with Tamoxifen can prevent breast and ovarian cancer. Likewise, genetic counseling prior to testing is important, considering the major impact of the test results on an individual's life.

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.

Comparative analysis of temozolomide (TMZ) versus 1,3-bis (2-chloroethyl)-1 nitrosourea (BCNU) in newly diagnosed glioblastoma multiforme (GBM) patients.

PURPOSE: Although TMZ replaced BCNU as the standard initial chemotherapy in the treatment of GBM, no studies have been reported comparing BCNU with TMZ. We therefore did a retrospective analysis comparing these agents as initial therapy in GBM. PATIENTS AND METHODS: Eighty-one patients with GBM in our institution received both radiation and chemotherapy as initial treatment after surgery or biopsy; 49 receiving BCNU and 32 TMZ. These were analyzed for overall survival (OS) and progression-free survival (PFS) versus the type of chemotherapy used. The influence of salvage therapy on the outcome was investigated also. RESULTS: Median OS was superior in the TMZ versus the BCNU group (15.9 vs. 11.5 months) and the curves were judged to be significantly different by the log-rank test; P < 0.02. However, PFS was not significantly different between the two groups. Bevacizumab plus irinotecan (BI) was used as salvage therapy in one-third of the TMZ patients but in none of the BCNU patients. When patients receiving BI were omitted from the TMZ group the OS curve overlapped that of BCNU patients. CONCLUSION: These data suggest that the superior OS of the TMZ-treated GBM patients was not due to better tumor control by TMZ but was possibly related to the newer salvage therapy that was available to them.

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/m(2)), who expired within hours after the initiation of treatment secondary to transtentorial herniation. Although it is not completely clear what caused the patient's 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.

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.

Use of rituximab in refractory autoimmune thrombocytopenia following an autologous stem cell transplant.

Immune thrombocytopenia is well recognized post both allogeneic and autologous transplantation. The diagnosis can be difficult as there are generally several complicating features, including delayed marrow recovery and the use of multiple therapies. Treatment can be difficult and conventional approaches are often unsuccessful. We describe a case of presumed immune thrombocytopenia post autologous stem cell transplantation, who appeared to respond to the monoclonal B-cell antibody, rituxmab, which is being increasingly recognized as a therapeutic option in a variety of autoimmune disorders.

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/m(2), 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.

Paraneoplastic neurologic syndrome associated with occult breast cancer: a case report and review of literature.

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.