Advanced germ cell tumors in male patients.

Germ cell tumors (GCTs) in male patients are particularly important in oncology because the impact of a cure in the young patient population is significant. Patients with poor-risk tumors by the international classification system have about a 50% likelihood of long-term survival. No randomized trial has proved a chemotherapy regimen to be superior to that of four courses of combination bleomycin, etoposide, and cisplatin. Ongoing research is evaluating the role of high-dose chemotherapy and hematopoietic stem cell transplantation as initial therapy in patients with intermediate-risk and poor-risk GCT. Newer agents such as gemcitabine and paclitaxel have shown promise and may be incorporated in future chemotherapeutic regimens. We review the major prognostication systems, areas of research directed at improving treatment outcome, and approaches that will improve understanding and management of these neoplasms in the future.

Empiric antimicrobial therapy of febrile neutropenic patients undergoing haematopoietic stem cell transplantation.

This study was conducted to assess the efficacy and toxicity of intravenous (i.v.) ceftazidime and ciprofloxacin in neutropenic febrile patients undergoing high dose myeloablative therapy and hematopoietic stem cell transplantation (HSCT). All patients undergoing HSCT for leukaemia, lymphoma, multiple myeloma and solid tumours received open-label ceftazidime 2 g i.v. every 8 h and ciprofloxacin 400 mg i.v. every 12 h if they developed fever while they were neutropenic. Success with or without modification of this regimen was defined as survival through the neutropenic period; failure was defined as death secondary to infection. Of 106 patients treated with this regimen, the success rate was 99%. Sixty-one of the patients (57.5%) defervesced within 48-72 h and remained afebrile without regimen modification. In 41.5% of the cases (44/106), the regimen was modified because of persistent fever. One patient died secondary to sepsis. The combination of ceftazidime and ciprofloxacin as initial empiric antibacterial therapy in febrile neutropenic patients undergoing myeloablative therapy and HSCT is highly effective and is associated with minimal toxicity.

Ceftazidime and ciprofloxacin as empiric therapy in febrile neutropenic patients undergoing hematopoietic stem cell transplantation.

This pilot study was done to assess the efficacy and toxicity of intravenous ceftazidime and ciprofloxacin in patients developing febrile neutropenia while undergoing high-dose myeloablative therapy and hematopoietic stem cell transplantation (HSCT). All patients undergoing high-dose chemoradiotherapy and HSCT for leukemias, lymphomas, multiple myeloma, and solid tumors received open-label ceftazidime 2 g intravenously every 8 hours and ciprofloxacin 400 mg intravenously every 12 hours if they developed fever while they were neutropenic. Success with or without modification of this regimen was defined as survival through the neutropenic period; failure was defined as death secondary to infection. Among 45 patients treated with this regimen, the success rate was 98%. Sixty-two percent (28 of 45) of the patients achieved defervescence within 48 to 72 hours and remained afebrile without regimen modification. In 16 patients (36%) the regimen was modified because of persistent fever. The combination of ceftazidime and ciprofloxacin as initial empiric antibacterial therapy in febrile neutropenic patients undergoing myeloablative therapy and HSCT appears to be highly effective and is associated with minimal toxicity.

The role of granulocyte colony-stimulating factor in hematopoietic stem cell transplantation.

Recombinant granulocyte colony-stimulating factor (G-CSF) has been shown to decrease the duration of severe neutropenia, the incidence of febrile neutropenic episodes, the overall duration of intravenous antibiotic therapy, and the length of hospitalization in patients receiving myelosuppressive chemotherapy. G-CSF has also been shown to accelerate myeloid recovery after autologous and allogeneic bone marrow transplantation, and to mobilize stem cells in peripheral blood for hematopoietic rescue. However, the optimal dose, schedule, and method of administration of G-CSF in these settings remain to be standardized. This review focuses on the role of G-CSF in bone marrow and peripheral blood stem cell transplantation, and in hematopoietic stem cell mobilization.

The clinical applications of granulocyte colony-stimulating factor in hematopoietic stem cell transplantation: a review.

The administration of recombinant human granulocyte colony-stimulating factor (G-CSF) following chemotherapy, has been shown, in controlled randomized trials, to decrease the incidence of febrile neutropenic episodes, the duration of severe neutropenia and intravenous antimicrobial therapy, and the length of hospitalization. This review focuses on the evolving role of G-CSF in bone marrow and peripheral blood stem cell transplantation, and in hematopoietic stem cell mobilization.

Allogeneic bone marrow transplantation.

Allogeneic bone marrow transplantation (BMT) after high-dose, marrow-ablative chemoradiotherapy has been established as the treatment of choice for various hematologic, neoplastic, and congenital disorders. The most common type of marrow graft is an allogeneic one from a sibling donor who has compatible human leukocyte antigen (HLA). Only 30% of patients requiring allogeneic BMT have an HLA-compatible sibling donor. Over the past few years, marrows from unrelated HLA-compatible donors have been used with increasing frequency and promising outcome in certain hematologic malignancies. Despite the morbidity and mortality associated with this treatment modality, allogeneic BMT may provide a 20% to 90% chance of long-term, disease-free survival to patients with a wide variety of neoplastic and abnormal marrow disorders.

Allogeneic bone marrow transplantation: acute and late complications.

Allogeneic bone marrow transplantation (BMT) following high-dose marrow-ablative chemoradiotherapy, has been established as the treatment of choice for various hematologic, neoplastic, and congenital disorders. This procedure is performed to restore lymphohematopoiesis in patients with bone marrow failure states, to replace a diseased marrow by a healthy donor marrow, and as "rescue" to reconstitute lymphohematopoiesis following marrow-ablative chemoradiotherapy to eradicate a malignancy. Only 30 percent of patients requiring marrow transplantation have an HLA-compatible sibling and very few patients have an identical twin donor (syngeneic graft). Over the past few years, marrows from unrelated HLA-compatible donors have been used with increasing frequency and promising outcome in certain hematologic malignancies. Infectious complications, graft-versus-host disease, veno-occlusive disease of the liver, leukemic relapse, and graft failure, remain major obstacles adversely affecting the outcome of patients undergoing allogeneic BMT. Despite these complications, allogeneic BMT remains a highly successful therapeutic procedure associated with a 20% to 90% long-term disease-free survival in a variety of patients.

Early drop in protein C and antithrombin III is a predictor for the development of venoocclusive disease in patients undergoing hematopoietic stem cell transplantation.

Venoocclusive disease (VOD) of the liver remains one of the major obstacles for patients undergoing high-dose chemotherapy and hematopoietic stem cell transplantation (HSCT). Many factors have been associated with the development of VOD, including a hypercoagulable state secondary to a drop in protein C and antithrombin III (AT III). We conducted a prospective nonrandomized trial to try to determine whether the development of clinical VOD was associated with a drop in protein C, protein S, and AT III. A total of 42 patients undergoing high-dose chemotherapy and HSCT were enrolled in this study. Eleven patients underwent allogeneic bone marrow transplantation (BMT) following high-dose cyclophosphamide and fractionated total body irradiation (TBI). Thirty-one patients received autologous stem cell rescue following different preparative regimens. Measurements of protein C, protein S, and AT III levels were obtained prior to conditioning therapy and weekly thereafter for 2-3 weeks. A significant difference was noted in the mean levels of protein C on day 7 between those who developed VOD and those who did not (57.5 versus 72.1, p = 0.009). Similarly, there was a significant difference in the mean levels of AT III on days 7 and 14 between the two groups (day 7, 95.5 versus 80.6, p = 0.002; day 14, 99.6 versus 85.2, p = 0.01). The drop in protein S levels on days 7 and 14 was not statistically significant between the two groups. In conclusion, the degree of drop in protein C and AT III levels on day 7 was predictive for the development and severity of VOD.

Voltage-activated K+ conductance and cell proliferation in small-cell lung cancer.

Whole-cell patch-clamp measurements indicate that human small-cell lung cancer (SCLC) cells express voltage-dependent potassium channels, whose function is blocked by K+ channel antagonist 4-aminopyridine (4-AP). Exposure of the tumour cells to 4 mM 4-AP reduced the peak outward K+ current (evoked by a depolarization to +80 mV) from 2.05 +/- 0.24 nA (mean +/- SEM, n = 28 cells) to 0.98 +/- 0.12 nA (n = 27). Incubation of SCL cells with 0.1, 4 and 16 mM 4-AP resulted in a concentration- and time-dependent reduction in the number of viable cells when compared with the control; over a period of 144 hours, the drug either significantly reduced the number of viable SCLC cells or caused an apparent cessation of neoplastic cell proliferation, whereas the untreated control cells demonstrated a more than 16-fold multiplication in the number of viable cells. The inhibitory effect on cell growth was also observed with an additional K+ channel antagonist, tetraethylammonium. These data suggest that voltage-activated K+ channels expressed by SCLC cells play a role in neoplastic cell proliferation.

Granulocyte colony-stimulating factor.

Recombinant human granulocyte colony-stimulating factor (G-CSF) is a nonglycosylated protein produced in Escherichia coli using recombinant DNA technology. G-CSF was first defined in vitro as a relatively selective stimulator of pure granulocyte colonies from normal marrow and as a factor that induces differentiation of leukemic cell lines. Additional studies have shown that it has significant effects on primitive marrow stem cells as well as on the differentiated cells of the granulocyte-macrophage pathway enhancing phagocytosis, superoxide release, antibody-dependent cellular cytotoxicity, and migration of both neutrophils and monocytes. The most extensively studied clinical application of G-CSF has been in chemotherapy-induced myelosuppression, where it was shown to reduce the duration of severe neutropenia, the incidence of febrile neutropenic episodes, the overall duration of intravenous antibiotic therapy, and the length of hospitalization. G-CSF has also been shown to correct primary and acquired forms of neutropenia, to accelerate neutrophil recovery after bone marrow transplantation, and to mobilize stem cells in peripheral blood or hemopoietic rescue. G-CSF is well tolerated, mild to moderate bone pain being the most frequently reported adverse side effect. The clinical applications of G-CSF are likely to expand as more information emerges from continuing clinical trials.

Peripheral hematopoietic stem cell transplantation: current concepts.

As methods for increasing stem cells are perfected and alternate regimens for transplantation developed, PSCT will undoubtedly see wider application in combination with BMT and may ultimately replace BMT. The initial encouraging results with PSCT so far portend a major therapeutic role of this modality in the approach to hematologic and oncologic diseases. Prospective randomized trials comparing PSCT and BMT in a variety of clinical settings are needed and are already underway.

Small-cell carcinoma of the head and neck. A novel treatment regimen.

Four patients with small-cell carcinoma (SCC) of the head and neck were treated in a pilot Phase I-II study to evaluate the response rate and toxicity of weekly non-cross-resistant combination chemotherapy administered as primary therapy in small-cell carcinomas. All four patients had locoregional disease without evidence of distant metastasis. The treatment regimen consisted of dose-intensive chemotherapy administered for 16 weeks. One or two of six cytotoxic agents (cisplatin, vincristine, methotrexate, Adriamycin, cyclophosphamide, and etoposide) were used weekly in different combinations followed by radiotherapy and/or surgical resection. To date, three of the four patients have completed therapy and achieved a complete response. The fourth patient is currently receiving chemotherapy and has achieved a partial response. Our treatment regimen appears effective in producing high initial response rates in SCC of the head and neck.

Hematopoietic growth factors.

Hematopoiesis is a complex process that underlines the production of multiple highly specialized cells. The intricate mechanisms involved in this process include both positive and negative feedback by humoral activities, pluripotent stem cell selfrenewal and differentiation, and local interactions between stromal components of the hematopoietic microenvironment and various stem and progenitor cells. A group of hematopoietic growth factors, as well as their genes and chromosomal locations, have been identified. Advances in biochemistry and molecular biology led to the purification, genetic sequencing and molecular cloning of these glycoproteins. They include interleukin-3 (IL-3), granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage colony-stimulating factor (M-CSF) and erythropoietin (EPO). The biologic specificity of these substances is defined by their ability to support proliferation and differentiation of hematopoietic cells in a semisolid clonal assay system. These factors share certain characteristics, including their ability to stimulate the function of mature cells, their overlapping activity affecting progenitor cells of several lineages, and their direct and indirect actions on nonhematopoietic cells. Trials using hematopoietic growth factors demonstrated their remarkable efficacy in a variety of clinical settings.

Spinal cord compression due to metastatic neoplasm.

A retrospective study of 73 assessable patients with spinal cord compression due to metastatic tumor was conducted. Fifty-five patients had paraparesis and 18 were paraplegic. Treatment consisted of surgical decompression in 22 patients, radiotherapy in 31 patients, and a combination of both modalities in 20 patients. The three groups were comparable in their pretreatment characteristics. Of patients treated with surgical decompression followed by radiotherapy, 45% showed improvement in motor deficit; of patients treated with either surgery or radiotherapy, 18% (P = .06) and 16% (P = .02) showed improvement, respectively. These results were most significant in patients with paraparesis, where 47% of those who received combined therapy improved compared to 17% (P = .06) and 9% (P = .009) in the surgical and radiotherapy groups, respectively. In our series of patients with spinal cord compression due to metastatic tumor, surgical decompression followed by radiotherapy was superior to either surgical decompression or radiotherapy in improving motor deficit.

Treatment of small-cell carcinoma of the cervix with weekly combination chemotherapy.

Three patients with small-cell carcinoma of the cervix entered a pilot study of combination chemotherapy with agents that are not cross-resistant. Two patients had local disease and the third had extensive metastatic disease of the liver. The regimen consisted of weekly chemotherapy for 16 weeks with cisplatin, vincristine, methotrexate, doxorubicin, cyclophosphamide and etoposide followed by radiotherapy and/or surgery. The two patients with local disease achieved a pathological complete response, with no evidence of disease at 24 months and 15 months from diagnosis. The third patient achieved a partial response and is alive at 13 months with progressive disease. Side-effects were tolerable.

Voltage-dependent ion channels in small-cell lung cancer cells.

Small-cell carcinoma of the lung is a highly lethal form of cancer associated with a wide variety of paraneoplastic syndromes. Using the patch-clamp technique, we have directly demonstrated the presence of voltage-gated K+, Na+, and Ca2+ channels in three cell lines of human small-cell carcinoma, NCI-H128, NCI-H69, and NCI-H146. Whole-cell currents were measured from the tumor cells held at -80 mV and depolarized to -60 to +120 mV. Outward K+ current (IK), which was found in every cell tested, reached 1.58 +/- 0.12 nA (mean +/- SE, n = 24 cells) for H128 cells and 2.14 +/- 0.18 nA (n = 41) for H69 cells in response to a test potential of +80 mV. Unlike H69 and H128 tumor cells, IK from H146 cells occasionally exhibited partial inactivation during the 60-ms pulse length and reached 0.94 +/- 0.15 nA (n = 18) in response to a +80 mV test potential. IK from each of the cell lines was significantly reduced by 4-aminopyridine and tetraethylammonium. The rapidly inactivating inward Na+ current (INa), recorded in H146 cells and about 30% of the H69 and H128 cells tested, demonstrated a peak amplitude of 58 +/- 6 pA (n = 11) at 0 mV and a reversal potential of 47 +/- 2 mV (n = 11). Externally applied tetrodotoxin quickly suppressed INa. For the H128 and H69 tumor cells, inward Ca2+ current (ICa), observed in about 25% of the cells exposed to 10 mM [Ca2+]o, peaked at 5.1 +/- 0.4 ms (n = 5) with an amplitude of 46 +/- 14 pA (n = 5) at +20 mV and partially inactivated over the 40-ms depolarization. In H128 cells exposed to isotonic Ba2+ (110 mM), inward currents with time courses similar to those of ICa were recorded. Nearly all H146 tumor cells demonstrated a significant inward Ca2+ current which peaked with an amplitude of 93 +/- 16 pA (n = 26) at +30 to +40 mV in the presence of 10 mM [Ca2+]o. Application of test potentials 2 s in duration revealed that H146 ICa inactivated in a voltage-dependent manner with a time constant on the order of seconds. Adjustment of the holding potential from -80 mV to -40 mV had no observable effect on the amplitude of the evoked current. These voltage-dependent ion channels may have integral roles in several small-cell carcinoma bioelectric phenomena, including secretion, resting membrane potential, and action potential generation.(ABSTRACT TRUNCATED AT 400 WORDS)

High-dose chemotherapy and autologous marrow transplantation for esthesioneuroblastoma and sinonasal undifferentiated carcinoma.

Eight patients with recurrent esthesioneuroblastoma or sinonasal undifferentiated carcinoma of the nasal or sinus cavities were treated with high-dose chemotherapy and autologous bone marrow transplantation. All patients had stage C disease initially and had received extensive prior conventional treatment with surgery, radiotherapy, and chemotherapy. Two patients achieved prolonged relapse-free survival for 18+ and 60 months. The latter patient relapsed at 60 months, but died of progressive disease after a second transplant. Two additional patients remain alive without disease progression at 17+ and 31+ months posttransplant. No deaths occurred secondary to toxicity. Progression of tumor accounted for failure in five patients. High-dose chemotherapy and autologous bone marrow transplantation should be considered as a salvage regimen for selected patients who fail conventional therapy for these diseases.

Treatment of small cell carcinoma with weekly combination chemotherapy. A pilot study.

We conducted a prospective non-randomized pilot study to evaluate the response rate and toxicity of weekly combination chemotherapy in pulmonary and extrapulmonary small cell carcinoma. A consecutive collection of 13 patients seen at the University of Virginia Medical Center was entered into the study after written informed consent. Ten of these patients had small cell carcinoma of the lung (4 with limited disease and 6 with extensive disease) and 3 patients had extrapulmonary small cell carcinoma (esophagus, cervix, and larynx). The treatment regimen consisted of weekly chemotherapy for 16 weeks using six cytotoxic agents (cisplatin, vincristine, methotrexate, adriamycin, cyclophosphamide, and VP-16) in different combinations followed by radiotherapy to the primary site. To date, ten patients have completed chemotherapy and radiotherapy with 9 (90%) achieving a complete response. The overall objective response rate was 100%. Of the remaining 3 patients who are currently receiving treatment, one achieved a complete response and two are showing significant responses. This ongoing trial shows that a weekly combination chemotherapy regimen is effective in producing high response rates in small cell carcinoma.