Early glottic carcinoma treated by radiotherapy: defining a population for surgical salvage.

OBJECTIVES/HYPOTHESIS: Not all patients with early Glottis squamous cell carcinoma will be cured by radiotherapy. This is an audit of a single center's experience with those patients who fail by this approach. STUDY DESIGN: This retrospective study was approved by the IRB (Institutional Review Board); eligibility criterion was patients treated between 1967 and December 2006, T(IS), T(1), T(2) N(0) SCC glottic carcinoma, with analysis occurring in 2009, and with a minimum follow-up of 2 years. METHODS: The eligibility criteria for this ethics-approved study was that all patients started a course of radiotherapy for early glottic laryngeal SCC. Data included in the Larynx Cancer database includes information from the Radiation Oncology Department notes, referral letters, and follow-up information. This is categorized into patient, disease, and treatment factors. RESULTS: Of 522 patients who commenced radiotherapy, local failure occurred in 105 patients; a salvage procedure was performed in 89, with surgery only in 83. For these 89 patients, the ultimate local control was 67%, with a larynx preservation procedure in 34%. Nodal failure occurred in 20 of the 522 patients (4%). There was a much higher failure rate in patients unfit for surgery (10/26-38%). Laryngectomy was the main salvage procedure in 55 patients. CONCLUSIONS: Early recognition of local failure following radiotherapy for early glottic carcinoma may avoid laryngectomy as a salvage procedure.

Floor of mouth carcinoma: surgery still the dominant mode of treatment.

INTRODUCTION: To evaluate the care and outcomes for patients presenting with floor of mouth (FOM) cancers. METHODS: In this Ethics-approved audit, all eligible patients were evaluated with eligibility defined as having a squamous cell carcinoma originating in the FOM. Patient, disease and treatment factors were defined. Primary end points were ultimate local/regional control and cancer-specific survival. These were analysed according to the Kaplan-Meier method. The log-rank test was used to determine statistical significance between survival curves. Multivariate analysis was conducted using Cox regression. RESULTS: A total of 157 patients were eligible for analysis, 76% males and 24% females, with 38 (24%) having a prior diagnosis of cancer. Surgery was performed in 126 patients (54 with pre/postoperative radiotherapy), radiotherapy only in 30 patients and chemotherapy only in 1 patient. Surgery had the best local control (85%), with 23/30 (77%) patients having radiotherapy failing locally. Ultimate regional control was achieved in 89% of patients, while new primaries occurred in 45 (29%) CONCLUSIONS: Surgery remains an essential component of the treatment of patients with FOM cancers, with a high likelihood of other cancers developing.

Retained role of surgery for olfactory neuroblastoma.

BACKGROUND: Olfactory neuroblastoma is a rare paranasal sinus malignancy. The traditional approach was craniofacial resection (CFR) and then postoperative radiotherapy until 1998. This review will chart development of a new protocol. METHODS: This ethics-approved audit evaluated the number of new patients diagnosed with olfactory neuroblastoma, with information relating to patient, disease, and treatment factors noted. RESULTS: There were 24 eligible patients, 16 men, 8 women, 7 Kadish stage B, 17 stage C. The planned treatment was: chemotherapy (cisplatin/etoposide) and determine treatment dependent on response in 6 patients, surgery and radiotherapy in 16 patients, and single-modality treatment only (surgery, radiotherapy 1) in 2 patients. Surgery to radiotherapy occurred in 17 patients. With salvage treatment ultimate local control was 79%. CONCLUSIONS: There was a higher local control in those patients who had surgery; abandoning this may carry a higher risk of local failure. The use of response to chemotherapy to determine local treatment remains experimental.

Recurrent nasopharyngeal carcinoma: current management approaches.

OBJECTIVES: Providing the primary recurrence is localized, salvage treatment is possible for nasopharyngeal carcinoma (NPC). This is a review of the experience of retreatment of this malignancy highlighting the roles of surgery and repeat radiotherapy. METHODS: The Tumor Registry of the Prince of Wales Cancer Centre was audited for patients with an initial diagnosis of squamous/nonsquamous cell NPC who had primary treatment with radiotherapy, and now presented for retreatment. Features relating to patient, disease and treatment factors were evaluated. The primary end point was subsequent local control, and secondary endpoints were overall and cancer-specific survival. RESULTS: Over a 30-year period 39 patients were eligible, with 25 receiving both primary and retreatment at Prince of Wales Hospital. There were 25 males and 14 females with a median age of 50 years. Thirty-six patients had radiotherapy, 4 had stereotactic radiosurgery, 5 had brachytherapy, and the remainder had external treatment. Surgery was performed in 10 patients, of whom 3 had this as the only retreatment modality. Radiotherapy doses for retreatment ranged from 15 Gy (stereotactic radiosurgery) to 71.28 Gy (mean fractionated dose). Local control was achieved in 16 patients giving an overall rate of 41.0%, and the 5-year overall survival rate was 33.3%. Treatment modality was a significant prognostic factor for local control (P < 0.001) and cancer-specific survival (P < 0.05). CONCLUSION: The presence of local recurrence after definitive treatment of NPC may still be salvageable. The best outcomes with reirradiation occur in the context of limited volume recurrence and a disease-free interval greater than 18 months.

Safety and preliminary efficacy of plerixafor (Mozobil) in combination with chemotherapy and G-CSF: an open-label, multicenter, exploratory trial in patients with multiple myeloma and non-Hodgkin's lymphoma undergoing stem cell mobilization.

Plerixafor, a novel CXCR4 inhibitor, is effective in mobilizing PBSCs particularly when used in conjunction with G-CSF. In four cohorts, this pilot study explored the safety of plerixafor mobilization when incorporated into a conventional stem cell mobilization regimen of chemotherapy and G-CSF. Forty (26 multiple myeloma and 14 non-Hodgkin's lymphoma) patients were treated with plerixafor. Plerixafor was well tolerated and its addition to a chemo-mobilization regimen resulted in an increase in the peripheral blood CD34+ cells. The mean rate of increase in the peripheral blood CD34+ cells was 2.8 cells/microl/h pre- and 13.3 cells/microl/h post-plerixafor administration. Engraftment parameters were acceptable after myeloblative chemotherapy, with the median day for neutrophil and plt engraftment being day 11 (range 8-20 days) and day 13 (range 7-77 days), respectively. The data obtained from the analysis of the cohorts suggest that plerixafor can safely be added to chemotherapy-based mobilization regimens and may accelerate the rate of increase in CD34+ cells on the second day of apheresis. Further studies are warranted to evaluate the effect of plerixafor in combination with chemomobilization on stem cell mobilization and collection on the first and subsequent days of apheresis, and its impact on resource utilization.

Role of radiotherapy in early glottic carcinoma.

BACKGROUND: Early glottic carcinoma has a high local control prospect with radiotherapy. This review evaluates a single center's experience. METHODS: All patients from 1967 to 2006 diagnosed with Tis/T1/T2/N0 early glottic carcinoma treated definitively with radiotherapy at Prince of Wales Hospital were reviewed. Local control and cancer-specific survival (CSS) rates were primary endpoints, and the impact of various factors on these outcomes was statistically analyzed. RESULTS: This review of 522 patients includes 24 with Tis, 356 with T1, and 142 with T2. Ultimate local control rates were as follows: Tis 87.5%, T1 94.7%, and T2 84.5%. Multivariate analysis found fitness for surgery, no involvement of anterior commissure, normal cord movement, and radiotherapy dose >60 Gy significant for local control. Fitness for surgery, no involvement of the anterior commissure, normal cord movement, and no ventricular involvement were significant prognostic factors for CSS. CONCLUSION: Definitive radiotherapy for early glottic carcinoma provides high local control rates, with the option of surgical salvage to achieve ultimate local control.

The management dilemmas of invasive subglottic carcinoma.

AIMS: To evaluate a single centre's experience with subglottic laryngeal carcinoma. MATERIALS AND METHODS: The laryngeal cancer database at the Prince of Wales Hospital was sourced to define a sub-population of patients presenting with primary subglottic carcinoma. Excluded from the analysis were patients having a glottic origin for their carcinoma and secondarily involving the subglottis. RESULTS: Of 969 patients with newly diagnosed laryngeal cancer, 10 (1%) had subglottic origin. T stage was six T2 and four T3, all were N0. A total laryngectomy was carried out in five patients, four of whom had postoperative radiotherapy, a hemilaryngectomy in one patient and definitive radiotherapy in four patients. There was only one local failure, who could not be salvaged, and one patient died locally controlled with metastatic disease. Thus, local control was achieved in nine of 10 patients. CONCLUSION: Although an infrequent sub-population, subglottic carcinoma has a high likelihood of being locally controlled.

AMD3100 plus G-CSF can successfully mobilize CD34+ cells from non-Hodgkin's lymphoma, Hodgkin's disease and multiple myeloma patients previously failing mobilization with chemotherapy and/or cytokine treatment: compassionate use data.

AMD3100 given with G-CSF has been shown to mobilize CD34+ cells in non-Hodgkin's lymphoma (NHL), multiple myeloma (MM), and Hodgkin's disease (HD) patients who could not collect sufficient cells for autologous transplant following other mobilization regimens. These poor mobilizers are usually excluded from company-sponsored trials, but have been included in an AMD3100 Single Patient Use protocol, referred to as a Compassionate Use Protocol (CUP). A cohort of 115 data-audited poor mobilizers in CUP was assessed, with the objective being to collect > or =2 x 10(6) CD34+ cells per kg following AMD3100 plus G-CSF mobilization. The rates of successful CD34+ cell collection were similar for patients who previously failed chemotherapy mobilization or cytokine-only mobilization: NHL -- 60.3%, MM -- 71.4% and HD -- 76.5%. Following transplant, median times to neutrophil and PLT engraftment were 11 days and 18 days, respectively. Engraftment was durable. There were no drug-related serious adverse events. Of the adverse events considered related to AMD3100, two (1.6%) were severe (one patient -- headache, one patient -- nightmares). Other AMD3100-related adverse events were mild (84.8%) or moderate (13.6%). The most common AMD3100-related adverse events were gastrointestinal reactions, injection site reactions and paresthesias. AMD3100 plus G-CSF offers a new treatment to collect CD34+ cells for autologous transplant from poor mobilizers, with a high success rate.

A pharmacokinetic-pharmacodynamic model for the mobilization of CD34+ hematopoietic progenitor cells by AMD3100.

BACKGROUND: AMD3100 is a small-molecule CXCR4 antagonist that has been shown to induce the mobilization of CD34 + hematopoietic progenitor cells from bone marrow to peripheral blood. AMD3100 has also been shown to augment the mobilization of CD34 + cells in cancer patients when administered in combination with granulocyte colony-stimulating factor (G-CSF) (filgrastim). The purpose of this study was to characterize the exposure-response relationship of AMD3100 in mobilizing CD34 + cells when administered as a single agent in healthy volunteers. METHODS: AMD3100 concentrations and CD34 + cell counts obtained from 29 healthy subjects in a single-dose, intensively sampled pharmacokinetic/pharmacodynamic (PK-PD) study were analyzed by use of nonlinear mixed effects regression with the software NONMEM. FOCE (first order conditional estimation) with interaction was the estimation method, and simultaneous PK-PD fitting was adopted. RESULTS: The pharmacokinetics of AMD3100 was described by a 2-compartment model with first-order absorption. The population estimates (+/-SE) for clearance and central volume of distribution were 5.17 +/- 0.49 L/h and 16.9 +/- 3.79 L, respectively. CD34 + cell mobilization was best described by an indirect effect model that stimulates the entry process of CD34 + from bone marrow to peripheral blood in the form of a sigmoid maximum effect model. The population estimates (+/-SE) of maximum effect, concentration causing 50% of maximum response, and equilibration time were 12.6 +/- 4.89, 53.6 +/- 11.9 mug/L, and 5.37 +/- 1.31 hours, respectively. CONCLUSIONS: This study characterizes the exposure-response relationship of AMD3100 in mobilizing CD34 + cells after subcutaneous administration. This PK-PD model will be useful in assessing relevant covariates and for optimizing the use of AMD3100 in various patient populations.

Experience with mucosal melanoma of the nose and paranasal sinuses.

PURPOSE: Sinonasal mucosal melanoma is a rare and aggressive disease and its incidence does not mimic that of its cutaneous counterpart in the Australian population. The present study examines one unit's experience with the disease and proposes a treatment strategy. The significance of macroscopic widespread mucosal melanosis and histological melanoma in situ is considered in the present study to be crucial in overall survival and the main cause of local failure and is specifically addressed. METHODS: The present study represents the retrospective experience of the multidisciplinary Head and Neck Clinic at the Prince of Wales Hospital over a 30-years period (from 1970 to end 1999) in the management of the disease, including both primary and salvage treatment approaches. The study includes 27 patients treated with surgery with or without postoperative radiation therapy. Management of recurrence was also considered. RESULTS: The mean time to local recurrence was 14.7 months and the mean time to distant metastases was 23.2 months. Mean survival time was 52 months and mean time from local recurrence to death was 75 months. Overall, disease free and disease specific survival and survival post-recurrence were analysed by the Kaplan-Meir method. A cancer specific 5 years survival of 46% was achieved, which compares favourably with recent international series. CONCLUSION: Sinonasal mucosal melanoma remains an aggressive disease with the possibility of local recurrence years after initial treatment, however, initial radical surgery encompassing the primary lesion and distant in situ or satellite disease and postoperative radiotherapy can offer long-term control, as can reoperation for local recurrence where appropriate.

Salvage nasopharyngectomy for radiation recurrences.

BACKGROUND: Salvage nasopharyngectomy has proven to be worthwhile in the management of persistent or recurrent nasopharyngeal cancer after radiotherapy failure; however, surgical complications are common and the indications for surgery and the choice of operation remain controversial. METHODS: Over a 17-year period from 1985 to 2001 salvage nasopharyngectomy was undertaken on 11 patients. In six patients an anterolateral disassembly approach was employed and five patients were treated with the more limited maxillary swing approach. In seven patients the nasopharynx was reconstructed with a revascularized forearm free graft. RESULTS: Six patients remain alive and free of disease with a minimum follow up of 4 years. There were no incidences of serious postoperative complications. The five patients who failed all did so locally. CONCLUSIONS: Nasopharyngectomy is safe and effective in the treatment of recurrent nasopharyngeal cancer even after multiple courses of radiotherapy.

X4 HIV-1 induces neuroblastoma cell death by interference with CXCL12/CXCR4 interaction.

Human neuroblastoma SK-N-SH cells strongly express CXC-chemokine receptor 4 (CXCR4), the principal coreceptor for X4 HIV-1 strains, and its natural ligand stromal cell-derived factor 1 (SDF-1, recently renamed CXCL12). We investigated the impact of CXCR4 blockade by the specific CXCR4 antagonist AMD3100 or by X4 HIV-1 virus particles on the growth and survival of neuroblastoma SK-N-SH cells. SK-N-SH cell proliferation was inhibited byAMD3100 and anti-CXCL12 neutralizing antibodies, but enhanced by exogenously added CXCL12. Upon prolongedexposure to AMD3100, SK-N-SH cell death occurred throughdeficit of survival-promoting and growth-stimulatory signals generated by endogenous CXCL12. In analogy with the observations made with the CXCR4 inhibitor AMD3100, the X4 HIV-1 strains IIIB and SF-2, but not the R5 strain BaL, caused a marked cytopathic effect and strongly effected SK-N-SH cell death after at least 10 days of incubation. However, no virus production could be detected in the HIV-1-inoculated SK-N-SH cell cultures. Exogenously added CXCL12 afforded partial protection against X4 HIV-1-induced cytopathicity in SK-N-SH cells. Our data indicate that the endogenous CXCL12/CXCR4 signaling axis is critical for neuroblastoma cell survival and proliferation. Long-term blockade of CXCR4 through physical contact with the X4 HIV-1 envelope can cause neuronal cell death. This mechanism may possibly play a role in X4 HIV-associated neurodegeneration.

Malignancies of the external auditory canal and temporal bone: a review.

BACKGROUND: Malignancies of the external auditory canal and temporal bone are uncommon. A retrospective review was conducted of a large series treated at the Prince of Wales hospital between 1974 and 1995. METHODS: Retrospective review of 59 cases of ear canal and temporal bone malignancies. These were analysed according to histopathology, disease extent, surgery, margin status and survival. A TNM-type staging system was applied to 51 cases and Kaplan-Meier survival analysis applied to this group. RESULTS: The 5-year cancer-specific survival (CSS) for the series was 54%. For stages 1, 2, 3 and 4 disease, the CSS were 90, 45, 40 and 19%, respectively. Survival was significantly higher where clear surgical margins were achieved (80 vs 35%). CONCLUSIONS: Carcinoma of the external ear canal is rare and, in Australia, is often related to recurrence of periauricular cutaneous malignancy. Surgical extirpation with clear margins provides the best survival.

AMD3100, a potent and specific antagonist of the stromal cell-derived factor-1 chemokine receptor CXCR4, inhibits autoimmune joint inflammation in IFN-gamma receptor-deficient mice.

Autoimmune collagen-induced arthritis (CIA) in IFN-gammaR-deficient DBA/1 mice was shown to be reduced in severity by treatment with the bicyclam derivative AMD3100, a specific antagonist of the interaction between the chemokine stromal cell-derived factor-1 (SDF-1) and its receptor CXCR4. The beneficial effect of the CXCR4 antagonist was demonstrable when treatment was initiated between the time of immunization and appearance of the first symptoms. Treatment also reduced the delayed-type hypersensitivity response to the autoantigen, collagen type II. These observations are indicative of an action on a late event in the pathogenesis, such as chemokine-mediated attraction of leukocytes toward joint tissues. The notion of SDF-1 involvement was further supported by the observation that exogenous SDF-1 injected in periarthritic tissue elicited an inflammatory response that could be inhibited by AMD3100. The majority of leukocytes harvested from inflamed joints of mice with CIA were found to be Mac-1(+) and CXCR4(+), and AMD3100 was demonstrated to interfere specifically with chemotaxis and Ca(2+) mobilization induced in vitro by SDF-1 on Mac-1(+)/CXCR4(+) splenocytes. We conclude that SDF-1 plays a central role in the pathogenesis of murine CIA, by attracting Mac-1(+)/CXCR4(+) cells to the inflamed joints.

Mutation of Asp(171) and Asp(262) of the chemokine receptor CXCR4 impairs its coreceptor function for human immunodeficiency virus-1 entry and abrogates the antagonistic activity of AMD3100.

The bicyclam AMD3100 is a highly potent and selective CXCR4 antagonist with strong antiviral activity against human immunodeficiency virus (HIV)-1 and HIV-2, which use CXCR4 as coreceptor for host cell entry. Here, we investigated the interaction of AMD3100 with CXCR4 at the molecular level by mutational analysis. We established a set of stably transfected U87.CD4 cell lines expressing different mutant forms of CXCR4 (i.e., CXCR4[WT], CXCR4[D171N], CXCR4[D262N], CXCR4[D171N,D262N], and CXCR4[H281A]), to compare the activity of the compound against mutated versus wild-type CXCR4. We found that the antagonistic action of AMD3100 against CXCR4--as assessed by the inhibitory effects of the compound on stromal cell-derived factor (SDF-1) binding to its receptor and on SDF-1-induced intracellular calcium signaling, and by displacement of the CXCR4-specific antibody, clone 12G5--was greatly reduced by substitution of Asp(171) and/or Asp(262) by neutral asparagine residue(s). Both aspartates, but most particularly Asp(262), also proved essential for the anti-HIV-1 activity of AMD3100 against the viruses NL4.3, IIIB, and HE. In contrast, substitution of His(281) by a neutral alanine potentiated the antagonistic and antiviral effects of the compound in the different assay systems. Importantly, compared with the wild-type receptor, CXCR4[D262N] was much less effective, whereas CXCR4[D171N,D262N] completely failed as a coreceptor for infection by HIV-1 NL4.3. Thus, the negatively charged aspartate residues at positions 171 and 262, located in transmembrane domains 4 and 6 of the 7-transmembrane receptor, respectively, may represent crucial sites for electrostatic interaction of the positive charges of the bicyclams, as well as for the highly basic V3 loop of the gp120 envelope protein of certain HIV-1 strains.

Molecular interactions of cyclam and bicyclam non-peptide antagonists with the CXCR4 chemokine receptor.

The non-peptide CXCR4 receptor antagonist AMD3100, which is a potent blocker of human immunodeficiency virus cell entry, is a symmetrical bicyclam composed of two identical 1,4,8,11-tetraazacyclotetradecane (cyclam) moieties connected by a relatively rigid phenylenebismethylene linker. Based on the known strong propensity of the cyclam moiety to bind carboxylic acid groups, receptor mutagenesis identified Asp(171) and Asp(262), located in transmembrane domain (TM) IV and TM-VI, respectively, at each end of the main ligand-binding crevice of the CXCR4 receptor, as being essential for the ability of AMD3100 to block the binding of the chemokine ligand stromal cell-derived factor (SDF)-1alpha as well as the binding of the receptor antibody 12G5. The free cyclam moiety had no effect on 12G5 binding, but blocked SDF-1alpha binding with an affinity of 3 microm through interaction with Asp(171). The effect on SDF-1alpha binding of a series of bicyclam analogs with variable chemical linkers was found to rely either only on Asp(171), i.e. the bicyclams acted as the isolated cyclam, or on both Asp(171) and Asp(262), i.e. they acted as AMD3100, depending on the length and the chemical nature of the linker between the two cyclam moieties. A positive correlation was found between the dependence of these compounds on Asp(262) for binding and their potency as anti-human immunodeficiency virus agents. It is concluded that AMD3100 acts on the CXCR4 receptor through binding to Asp(171) in TM-IV and Asp(262) in TM-VI with each of its cyclam moieties, and it is suggested that part of its function is associated with a conformational constraint imposed upon the receptor by the connecting phenylenebismethylene linker.

Craniofacial resection for paranasal sinus cancers.

BACKGROUND: Combined anterior craniofacial resection (CFR) has been in use for more than 25 years. The advent of the free revascularized tissue transfer flap in l980 permitted safe resection of tumors that had spread beyond the confines of the paranasal sinuses with immediate reconstruction of the sino-orbital cranial defect. The purpose of this study was to examine the outcomes and morbidity of a management policy of primary CFR and postoperative radiotherapy for paranasal sinus cancers infiltrating the skull base over a 21-year period. METHODS: Seventy-three patients with paranasal sinus cancers were treated at the Prince of Wales Hospital between l975 and l996. All were newly diagnosed with the exception of one patient who had received radiotherapy elsewhere 5 years earlier. Only 22% were early lesions and 31% were advanced (more than six sites involved). There were 59 men and 14 women. The mean age was 57 years. All but two patients had a performance status of either 0 or 1. Orbital exenteration was performed in 31 patients. Since l980, all major defects were reconstructed with free tissue transfer flaps. RESULTS: The 5-year cancer-specific survival (CSS) for the 73 patients was 69%, which was unchanged at 10 years. Twenty two patients died from or with their index cancer. An additional 11 patients died from unrelated causes. The actuarial overall survival (OS) at 5 and 10 years was 61% and 48%, respectively. The 5-year recurrence-free rate was 59%. The CSS for the three dominant pathologic conditions were adenocarcinoma 70%, squamous cancer 51%, and olfactory neuroblastoma 84%. The difference was not significant; however, there was a significant difference in OS, with olfactory neuroblastoma having the best prognosis. Orbital involvement, radiologic evidence of skull base erosion, and involvement of the infratemporal fossa were not poor prognostic indicators. Patients with a performance status of 0 had improved OS. There was no operative mortality. CONCLUSIONS: An aggressive policy of combined CFR and postoperative radiotherapy with free-flap reconstruction for large defects gave survival results that were comparable to less-advanced lesions and superior to many other treatment alternatives. There was a high exenteration rate (42%). Squamous cancers were associated with the greatest morbidity and poorest OS.

Pharmacokinetics and safety of AMD-3100, a novel antagonist of the CXCR-4 chemokine receptor, in human volunteers.

AMD-3100, a bicyclam, is a novel agent that uniquely inhibits the entry of human immunodeficiency virus type 1 (HIV-1) into CD4(+) T cells via selective blockade of the chemokine CXCR-4 receptor. Twelve healthy volunteers were given AMD-3100 as a single 15-min intravenous infusion at 10, 20, 40, or 80 microg/kg. Five subjects also received a single subcutaneous injection of AMD-3100 (40 or 80 microg/kg). Three subjects received two escalating oral doses each (80 and 160 microg/kg). All subjects tolerated their dose(s) well without any grade 2 toxicity or dose adjustment. Six subjects experienced mild, transient symptoms, primarily gastrointestinal in nature and not dose related. All subjects experienced a dose-related elevation of the white blood cell count, from 1.5 to 3.1 times the baseline, which returned to the baseline 24 h after dosing. AMD-3100 demonstrated dose proportionality for the maximum drug concentration in serum (C(max)) and the area under the concentration-time curve from 0 h to infinity (AUC(0-infinity)) over the entire dose range. At the highest intravenous dose (80 microg/kg), the median C(max) was 515 (range, 470 to 521) ng/ml and the AUC(0-infinity) was 1,044 (range, 980 to 1,403) ng-h/ml. The median systemic absorption after subcutaneous dosing was 87% (range, 67 to 106%). No drug was detectable in the blood following oral dosing. Using a two-compartment model, the median pharmacokinetic parameter estimates (ranges) were as follows: volume of distribution, 0.34 (0. 27 to 0.36) liter/kg; clearance, 1.30 (0.97 to 1.34) liters/h; elimination half-life, 3.6 (3.5 to 4.9) h. After a single, well-tolerated intravenous dose of AMD-3100, concentrations were sustained for 12 h above the in vitro antiretroviral 90% inhibitory concentrations and for 8 h above antiviral concentrations identified in the SCID-hu Thy/Liv mouse model of HIV infection.

Early glottic carcinoma: results of treatment by radiotherapy.

The purpose of the present paper was to review the results of treating early (stages T1-2N0) glottic, squamous cell carcinoma by radiotherapy in the Department of Radiation Oncology, Prince of Wales Hospital, Sydney. A retrospective review was carried out of all patients seen in the department from 1967 to 1994, inclusive. To be eligible, patients had to have newly diagnosed cancer and to have been treated with curative intent by radiotherapy alone. Three hundred and sixty-nine patients satisfied the eligibility requirements. The mean follow-up time was 12.2 years (maximum: 28 years). At 5 years the actuarial local control rate was 80% (84% for stage T1 and 72% for T2). The ultimate local control rate was 96%. The overall survival rates at 5 and 10 years were 73% and 52%, respectively. The risk of nodal recurrence was much higher after persisting disease or local recurrence. Our results confirm the high cure rates achieved with this modality of treatment and are comparable with those reported in the literature.