Degree Of Chemosensitivity Research Articles

Should Patients With Aggressive Peripheral T-Cell Lymphoma All Be Treated the Same?

The peripheral T-cell lymphomas represent about 15% to 20% of non-Hodgkin lymphomas and are marked by clinical and pathologic heterogeneity. The most common T-cell entities include peripheral T-cell lymphoma, not otherwise specified, angioimmunoblastic T-cell lymphoma, and anaplastic large cell lymphoma anaplastic lymphoma kinase-negative, which account for approximately 60% of T-cell lymphoma cases. Because of the rarity of T-cell lymphomas and lack of randomized prospective studies, treatment for these diseases is not well defined. Current treatment strategies draw from data from phase II studies, retrospective analyses, and personal experience. For fit patients who can tolerate treatment with curative intent, we treat peripheral T-cell lymphoma, not otherwise specified, angioimmunoblastic T-cell lymphoma, and anaplastic large cell lymphoma anaplastic lymphoma kinase-negative similarly with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)-based induction therapy followed by consolidation with autologous stem cell transplant. Given the marked differences in histology, biology, and clinical presentation for these diseases, it is likely that they should be approached differently. Furthermore, prognostic factors and degree of chemosensitivity as measured by FDG-PET (fluorodeoxyglucose positron emission tomography) should likely be used to guide patients along different treatment pathways. We have a long way to go toward perfecting the treatment for T-cell lymphoma. We believe that a uniform treatment approach for patients with aggressive T-cell lymphoma is not appropriate; however, we do not yet have enough data to support an individualized approach to treatment. Clinical and biologic prognostic factors, degree of chemosensitivity as measured by FDG-PET, and histology should all likely have a role in directing patients along different treatment pathways, but prospective studies are needed to confirm this.

In vitro detection of cross-resistant and non-cross-resistant agents with fluorouracil for patients with colorectal cancer

Fluorouracil-based chemotherapy, such as that with 5-fluorouracil (5-FU)/leucovorin, is standard as first-line chemotherapy for advanced colorectal cancer (CRC) in Japan. However, the best agent for second-line chemotherapy after fluorouracil failure is yet to be determined. This study was undertaken to find an appropriate agent for second-line chemotherapy. Seventy-five tumor specimens from CRC patients with no prior chemotherapy were obtained operatively and their chemosensitivity to five anticancer agents; i.e., 5-FU, mitomycin C (MMC), cisplatin, docetaxel, and an active metabolite of irinotecan (SN-38), was analyzed in an in vitro chemosensitivity test. In this method, the degree of chemosensitivity was expressed as the percent T/C ratio, where T was the total volume of the tumor colonies in the treated group and C was that of the control group. Pearson's correlation coefficients were used to assess the relationship between two agents. Fifty-eight specimens (colon, 28; rectum, 30) were successfully analyzed. Positive correlations with 5-FU chemosensitivity were verified for the chemosensitivity of MMC, cisplatin, and docetaxel. No correlation with 5-FU chemosensitivity was verified for SN-38 chemosensitivity. Although the functional mechanism of each of the agents differs from that of 5-FU, with the exception of irinotecan, they all had a spectrum closely similar to the 5-FU spectrum. Only irinotecan exhibited a spectrum independent of that of 5-FU, thus indicating that it could be an appropriate agent for second-line chemotherapy after fluorouracil failure.

Re: Retrotrapezoid nucleus: a litmus test for the identification of central chemoreceptors

Re: Retrotrapezoid nucleus: a litmus test for the identification of central chemoreceptors

Cellular mechanisms of chemosensitivity in serotonergic raphe neurons

Serotonergic neurons of the medullary raphe nuclei are strongly stimulated by acidosis [1,2], and are putative central respiratory chemoreceptors. We have examined the relationship between serotonergic neurons and blood vessels in the adult rat brain by using immunohistochemistry for tryptophan hydroxylase (TpOH) and injections of arteries with fluorescent albumin in gelatin. Serotonergic neurons within the raphe were closely associated with the basilar artery and its large penetrating branches. There were also homologous serotonergic neurons near large arteries of the rostral and caudal ventrolateral medullary surface (VLMS). We propose that serotonergic neurons on the VLMS contributed to the ventila-tory response to application of acidic solution in classical in vivo experiments that localized the chemoreceptors to that region. However, these neurons may not be specifically sensing CSF pH, but rather the PCO2 of blood in proximal arteries that happen to be located adjacent to the CSF space. In addition, a large number of homologous chemosensitive neurons are also located within the midline raphe nuclei. Perforated patch clamp recordings were made from raphe neurons in tissue culture, and the responses to respiratory acidosis, metabolic acidosis and isohydric hypercapnia were quantified. From a baselin firing rate of 0.2 Hz to 1.5 Hz, an increase in PCO2 from 5% to 9% and a decrease in pHo from 7.4 to 7.17 (at a constant [NaHCO3] of 26 mM) induced a mean increase in firing rate of 1.38 Hz (to 285% of control; n = 11). Metabolic acidosis (5% PCO2, 15 mM [NaHCO3], pHo 7.16) induced a mean increase in firing rate of 1.15 Hz (to 309% of control). Isohydric hypercapnia (9% PCO2, 40 mM [NaHCO3], at constant pHo) induced a mean increase in firing rate of 1.01 Hz (to 384% of control). These neurons also increased their firing rate in response to a decrease in pHo in the absence of CO2 and bicarbonate (in HEPES buffer).The only acid/base change that is shared by these four manipulations is a decrease in pHi, suggesting that this is the primary stimulus for these neurons – as is true for other chemosensitive neurons, including carotid body glomus cells. Using voltage clamp recordings, we have identified a novel ionic current in serotonergic neurons that is highly pH sensitive. This current was activated by calcium influx during depolarization. The major charge carrier was K+ under physiological conditions, but it also had a high permeability to Na+, with a permeability ratio for K+:Na+ of 4:1. It was not blocked by apamin (400 nM), charybdotoxin (240 nM), or TEA (15 mM). The current was extremely sensitive to changes in pH centered near 7.3. The current at pH7.61 was 95% of the maximum current, while the current at pH 6.99 was 2% of the maximum. To our knowledge, a current with these properties has not been reported previously. This current would be predicted to induce changes in membrane potential that have been observed during whole-cell current clamp recordings. Serotonergic medullary raphe neurons are strongly stimulated by a decrease in pHi due to the presence of a novel highly pH-sensitive calcium-activated cation channel. The degree of chemosensitivity of these neurons is large enough to make a major contribution to the changes in ventilation observed in whole animals in response to respiratory acidosis. The location of serotonergic neurons next to blood vessels and their widespread projections suggest that these neurons are chemoreceptors that modulate a variety of brain functions, including but not limited to respiratory control, and thus contribute to pH homeostasis.

Clinical trials with ifosfamide: the Indiana University experience.

At Indiana University, we began clinical trials with ifosfamide in 1981. Although our initial efforts were in a variety of tumor types, including pancreatic cancer, we have most recently focused our attention on two tumors that have historically exhibited a higher degree of chemosensitivity--testicular cancer and small cell lung cancer (SCLC). In phase II trials, ifosfamide has proven to have single-agent activity in both diseases. Coupling this data with preclinical observations of synergy with cisplatin and etoposide, we began trials of ifosfamide plus cisplatin with either vinblastine (VeIP) or etoposide (VIP) in patients with recurrent germ cell tumors; we also investigated the use of VIP in SCLC. In third-line or greater therapy for recurrent germ cell tumors, a 36% disease-free status was attained, with 16% of patients continuously free of disease for 5 or more years. Currently, ifosfamide is being evaluated as part of initial therapy in patients with advanced disease. In SCLC, VIP has also been investigated as part of initial therapy in patients with extensive disease. The complete response rate of 38% achieved in 37 evaluable patients has spurred the Hoosier Oncology Group to compare the VIP regimen to cisplatin/etoposide in patients with extensive-disease SCLC. Ifosfamide has the broad range of clinical activity, but its ultimate role as part of initial therapy remains to be discerned.