Biomedical subjects

J S Sham

Publications and source records attributed to J S Sham.

At least 55 records · Page 3Linked to original sources

PubMed1999

Roles of ion channels in carotid body chemotransmission of acute hypoxia.

In this review, we have highlighted the roles of ion channels in carotid body chemotransmission of acute hypoxia. With the application of new technologies, significant breakthroughs have been made in the last decade. The discovery of oxygen-sensitive K(+) channels in rabbit glomus cells has generated the membrane model of hypoxic chemotransmission: the inhibition of oxygen-sensitive K(+) channels by hypoxia initiates the depolarization of glomus cells and increases the firing frequency of glomus cells. The depolarization of glomus cells activates voltage-gated Ca(2+) channels, elevating intracellular Ca(2+) which triggers the release of neurotransmitters. The correlation of these events in rabbit glomus cells has been shown. However, a large corpus of data indicates that various mechanisms may be involved in different species. In rats, Ca(2+)-activated K(+) channels are inhibited by hypoxia. The role of this inhibition on rat glomus cell function is controversial, and the contribution of leak-type K(+) channels to rat glomus cell depolarization has recently been proposed. On the other hand, in cats, nicotinic ACh receptors (ligand-gated cation channels) may play a key role in initiating the depolarization of glomus cells and increasing the cytosolic Ca(2+) of glomus cells in response to hypoxia. Hypoxic inhibition of oxygen-sensitive K(+) channels would participate to further depolarize cat glomus cells. Additionally, the activity of Cl(-) channels and the modulation of ion channels by neurotransmitters may influence the excitability of glomus cells. For generating action potentials in chemoreceptor afferent nerves, nicotinic ACh receptors appear to be involved in cats and rats.

Acute Disease↗

PubMed1999

Cisplatin-induced p53-independent growth arrest and cell death in cancer cells.

In a recent study, it was shown that DNA damaging agent cisplatin-induced growth arrest and cell death in cancer cells by a pathway sharing some of the characteristics of replicative senescence. The aim of this study was to determine the role of p53, p21WAF1 and p16INK4A proteins in this alternative route to cancer cell death in additional human cancer cell lines. After exposure to cisplatin, all the cell lines underwent growth arrest and expressed the senescence marker senescence-associated beta-galactosidase, but showed none of the features of apoptosis. However, there was no change in p53 protein expression, and neither p21WAF1 nor p16INK4A was expressed before or up to 4 days after cisplatin exposure. These findings provide further evidence that cells carrying mutations resulting in loss of function in the p53 gene can be killed by cisplatin via a p53-independent route with some similarities to replicative senescence, but not apoptosis.

Antineoplastic Agents↗

PubMed1998

Termination of Ca2+ release by a local inactivation of ryanodine receptors in cardiac myocytes.

In heart, a robust regulatory mechanism is required to counteract the regenerative Ca2+-induced Ca2+ release from the sarcoplasmic reticulum. Several mechanisms, including inactivation, adaptation, and stochastic closing of ryanodine receptors (RyRs) have been proposed, but no conclusive evidence has yet been provided. We probed the termination process of Ca2+ release by using a technique of imaging local Ca2+ release, or "Ca2+ spikes", at subcellular sites; and we tracked the kinetics of Ca2+ release triggered by L-type Ca2+ channels. At 0 mV, Ca2+ release occurred and terminated within 40 ms after the onset of clamp pulses (0 mV). Increasing the open-duration and promoting the reopenings of Ca2+ channels with the Ca2+ channel agonist, FPL64176, did not prolong or trigger secondary Ca2+ spikes, even though two-thirds of the sarcoplasmic reticulum Ca2+ remained available for release. Latency of Ca2+ spikes coincided with the first openings but not with the reopenings of L-type Ca2+ channels. After an initial maximal release, even a multi-fold increase in unitary Ca2+ current induced by a hyperpolarization to -120 mV failed to trigger additional release, indicating absolute refractoriness of RyRs. When the release was submaximal (e.g., at +30 mV), tail currents did activate additional Ca2+ spikes; confocal images revealed that they originated from RyRs unfired during depolarization. These results indicate that Ca2+ release is terminated primarily by a highly localized, use-dependent inactivation of RyRs but not by the stochastic closing or adaptation of RyRs in intact ventricular myocytes.

Animals↗

PubMed1998

Preliminary report of the Asian-Oceanian Clinical Oncology Association randomized trial comparing cisplatin and epirubicin followed by radiotherapy versus radiotherapy alone in the treatment of patients with locoregionally advanced nasopharyngeal carcinoma. Asian-Oceanian Clinical Oncology Association Nasopharynx Cancer Study Group.

BACKGROUND: The aim of this trial was to compare the outcome achieved with neoadjuvant chemotherapy followed by radiotherapy to that achieved with radiotherapy alone for patients with locoregionally advanced undifferentiated or poorly differentiated nasopharyngeal carcinoma (NPC) meeting one of the following criteria: Ho's T3 disease, Ho's N2-N3 disease, or lymph node size > or =3 cm. METHODS: Between September 1989 and August 1993, 334 patients were enrolled in the study, with equal numbers of patients randomized to the neoadjuvant chemotherapy arm (CT arm) and the radiotherapy arm (RT arm). Neoadjuvant chemotherapy consisting of 2-3 cycles of cisplatin (60 mg/m2 on Day 1) and epirubicin (110 mg/m2 on Day 1) followed by radiotherapy was given to the CT arm. For radiotherapy, a dose of 66-74 gray (Gy) (median, 71 Gy) was delivered to the primary tumor and 60-76 Gy (median, 66 Gy) to the neck. Two hundred eighty-six eligible patients completed the treatment and were evaluable for treatment response (134 in the CT arm, 152 in the RT arm). All patients were included in the survival analysis based on the intention to treat. The median follow-up was 30 months for the whole cohort and 41 months for the surviving patients. RESULTS: Analysis of the 334 patients based on the intention to treat showed no significant difference in relapse free survival (RFS) or overall survival (OS) between the 2 treatment arms (3-year RFS rate: 48% in the CT arm vs. 42% in the RT arm, P = 0.45; 3-year OS rate: 78% vs. 71%, P = 0.57). In an efficacy analysis based on only the 286 evaluable patients, a trend of improved RFS favoring the CT arm was observed (3-year RFS rate: 58% vs. 46%, P = 0.053), with again no significant difference in OS (3-year OS rate: 80% vs. 72%, P = 0.21). In the subgroup of 49 patients with bulky neck lymph nodes >6 cm, improved RFS (3-year RFS rate: 63% vs. 28%, P = 0.026) and OS (3-year OS rate: 73% vs. 37%, P = 0.057) were observed, favoring the CT arm. CONCLUSIONS: This multicenter randomized study did not demonstrate any benefit with the addition of cisplatin-epirubicin neoadjuvant chemotherapy for patients with locoregionally advanced nasopharyngeal carcinoma; therefore routine administration of neoadjuvant chemotherapy to this target group cannot be recommended. Although the overall incidence of recurrence was reduced with the addition of chemotherapy in the efficacy analysis, the overall survival was not affected. A more effective chemotherapy regimen, the selection of an appropriate target group, and the use of an alternative strategy for combining chemoradiotherapy should be explored in future trials.

Adult↗

PubMed1998

Evidence of cisplatin-induced senescent-like growth arrest in nasopharyngeal carcinoma cells.

Cellular senescence is a programmed cell response leading to growth arrest in human diploid fibroblasts. We have shown that a nasopharyngeal carcinoma cell line, CNE1, following treatment by the DNA-damaging agent cisplatin, can undergo cellular senescent-like growth arrest, similar to fibroblasts, judged by cellular morphological changes and the expression of senescence-associated beta-galactosidase (SA-beta-gal). This senescent-like change was dose related; at 0.5 microgram/ml, the percentage of cisplatin-induced SA-beta-gal-positive cells was high (40-96%), and the staining was intense. Higher doses (1.0 and 2.0 micrograms/ml) of cisplatin induced lower SA-beta-gal expression (30-70%), and the process was irreversible. This cisplatin-induced cellular senescent-like response was not due to the inhibition of telomerase activity. Our results indicate that cellular senescent-like pathways exist in nasopharyngeal carcinoma cells and can be induced by cisplatin. Our evidence suggests that cellular senescent-like responses may be a cellular protection mechanism that acts differently in response to different degrees of cellular damage.

Antineoplastic Agents↗

PubMed1998

Direct measurement of SR release flux by tracking 'Ca2+ spikes' in rat cardiac myocytes.

1. Ca2+ release flux across the sarcoplasmic reticulum (SR) during cardiac excitation-contraction coupling was investigated using a novel fluorescence method. Under whole-cell voltage-clamp conditions, rat ventricular myocytes were dialysed with a high concentration of EGTA (4.0 mM, 150 nM free Ca2+), to minimize the residence time of released Ca2+ in the cytoplasm, and a low-affinity, fast Ca2+ indicator, Oregon Green 488 BAPTA-5N (OG-5N; 1.0 mM, Kd approximately 31 microM), to optimize the detection of localized high [Ca2+] in release site microdomains. Confocal microscopy was employed to resolve intracellular [Ca2+] at high spatial and temporal resolution. 2. Analytical and numerical analyses indicated that, under conditions of high EGTA concentration, the free [Ca2+] change is the sum of two terms: one major term proportional to the SR release flux/Ca2+ influx, and the other reflecting the running integral of the released Ca2+. 3. Indeed, the OG-5N transients in EGTA-containing cells consisted of a prominent spike followed by a small pedestal. The OG-5N spike closely resembled the first derivative (d[Ca2+]/dt) of the conventional Ca2+ transient (with no EGTA), and mimicked the model-derived SR Ca2+ release function reported previously. In SR Ca2+-depleted cells, the OG-5N transient also closely followed the waveform of L-type Ca2+ current (ICa). Using ICa as a known source of Ca2+ influx, SR flux can be calibrated in vivo by a linear extrapolation of the ICa-elicited OG-5N signal. 4. The OG-5N image signal was localized to discrete release sites at the Z-line level of sarcomeres, indicating that the local OG-5N spike arises from 'Ca2+ spikes' at transverse (T) tubule-SR junctions (due to the imbalance between calcium ions entering the cytosol and the buffer molecules). 5. Both peak SR release flux and total amount of released Ca2+ exhibited a bell-shaped voltage dependence. The temporal pattern of SR release also varied with membrane voltage: Ca2+ release was most synchronized and produced maximal peak release flux (4.2 mM s-1) at 0 mV; in contrast, maximal total release occurred at -20 mV (71 versus 61 microM at 0 mV), but the localized release signals were partially asynchronous. Since the maximal conventional [Ca2+] transient and contraction were elicited at 0 mV, it appears that not only the amount of Ca2+ released, but also the synchronization among release sites affects the whole-cell Ca2+ transient and the Ca2+-myofilament interaction.

Algorithms↗

PubMed1998

Expression of P-glycoprotein, a multidrug-resistance gene product, is induced by radiotherapy in patients with oral squamous cell carcinoma.

BACKGROUND: It has been observed that patients who have previously undergone radiotherapy have a lower rate of response to chemotherapy. METHODS: The authors investigated the effects of radiation on the expression of P-glycoprotein (Pgp), a multidrug-resistance gene product, in 56 patients with primary oral cancer. No patients received prior or concurrent chemotherapy. The 56 patients consisted of 3 groups: 1) 20 patients with preradiation or pretreatment specimens only, 2) 18 patients with both pre- and postradiation specimens, and 3) 18 patients with postradiation specimens only. Pgp expression was determined by immunohistochemistry with two monoclonal antibodies, C219 and C494. RESULTS: Among patients in Groups 1 and 2, only 1 (2.6%) and 2 (5.3%) patients had Pgp expression in their tumors before treatment with C219 and C494, respectively. For Group 2 patients, 66.7% and 72.2% had tumors that expressed Pgp with the two antibodies, respectively, only after and not prior to radiation. When patients in Groups 2 and 3 were combined, 63.9% and 72.2% had Pgp expression with the two antibodies, respectively, after radiation. Pgp expression was significantly induced after radiation compared with expression before treatment (P < 0.001). Overexpression of p53 protein, detected by immunohistochemistry with DO-7 antibody, was seen in the tumors of 40 patients (71.4%), and the status was quite consistent throughout radiotherapy. Pgp expression had no significant association with p53 protein expression. CONCLUSIONS: Pgp expression was significantly induced by radiation in human oral cancers. This induction of Pgp expression likely confers multidrug resistance to the cancer cells and may affect the efficacy of subsequent or concurrent chemotherapy. It may explain the lower rate of response to chemotherapy among patients who have previously had radiotherapy.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1998

Locally recurrent nasopharyngeal carcinoma: treatment results for patients with computed tomography assessment.

PURPOSE: To study the treatment outcome in patients with locally recurrent nasopharyngeal carcinoma as restaged by computed tomography (CT). PATIENTS AND METHODS: One hundred forty patients with CT restaged locally recurrent nasopharyngeal carcinoma were reviewed. Patients were restaged at recurrence according to the AJCC stage classification with the following distribution: T1-T2:30%, T3:19%, T4:51%. Ninety-seven patients received reirradiation; among these 62 had external irradiation, 34 had brachytherapy, and 1 had both. Twelve patients received surgery. Thirty-one patients were treated with palliative intent and received either chemotherapy or supportive treatment only. Overall survival (OAS) and performance-adjusted survival (PAS, defined as surviving with a Karnofsky performance score [KPS] > 50) were calculated by Kaplan-Meier method. Multivariate analysis was performed using the Cox model. RESULTS: The median survival for all patients was 23.8 months. After reirradiation, the 3-yr and 5-yr OAS rates were 46% and 36%, respectively. The corresponding PAS rates were 40% and 28%. The 3-yr OAS rates for recurrent T1-2, T3, and T4 disease after reirradiation were 71%, 42%, and 30%; the corresponding 5-yr OAS rates were 57%, 42%, 17%. The 3-yr and 5-yr OAS rates in patients receiving palliative treatments only were 19% and 0%, respectively. The 3-yr OAS rate after surgery was 42%. In the multivariate analysis, older age, recurrent T3-4 disease, and palliative treatment were unfavorable factors in predicting overall survival, whereas recurrent T3-4 disease, baseline KPS < 70, and palliative treatment were unfavorable factors in predicting PAS. A high complication rate was observed after reirradiation, with 34% of patients developing neurological sequel. CONCLUSION: Aggressive treatment for locally recurrent nasopharyngeal carcinoma is warranted especially for those with disease confined to the nasopharynx. Survival after retreatment for more extensive disease remains poor but was still superior to supportive treatment only. Early diagnosis of local recurrence allows prompt administration of treatment and is associated with better outcome. Future studies should aim at improving the therapeutic ratio in the retreatment of recurrent disease especially in patients with more extensive local recurrence.

Adult↗

PubMed1998

Electrophysiological and immunocytological demonstration of cell-type specific responses to hypoxia in the adult cat carotid body.

We have recently shown two types of cat carotid body cells based on the oxygen sensitivity of voltage-gated potassium channels. In the present study, we attempted to determine the correlation between cell types (glomus cells, sheath cells, and subtypes of glomus cells) and oxygen sensitivity of potassium channels. Further, changes in membrane potentials in response to hypoxia were also examined. Carotid body cells harvested from adult cats were cultured, and a whole cell patch clamp method was applied to determine the oxygen sensitivity of outward current. The tested cells were identified by Lucifer Yellow in the patch pipette. Glomus cells and sheath cells were immunocytochemically identified using tyrosine hydroxylase (TH) and glial fibrillary acidic protein (GFAP) as markers. The cells whose outward current was inhibited by hypoxia showed TH-immunoreactivity but not GFAP-immunoreactivity. The cells whose outward current was not sensitive to hypoxia were GFAP-positive or TH-negative. One TH-positive cell had oxygen-insensitive outward current. The resting membrane potentials of the cells having oxygen-sensitive outward current were significantly higher (-55+/-3 mV) than those of the cells having oxygen-insensitive outward current (-35+/-2 mV). The former type of cells was depolarized during hypoxia, but not the latter type of cells. These results suggest that most glomus cells of the adult cat carotid body possess oxygen-sensitive potassium channels and are depolarized in response to hypoxia. On the other hand, sheath cells and possibly a small fraction of glomus cells possess oxygen-insensitive potassium channels and their membrane potential is not affected by hypoxia.

Animals↗

PubMed1998

Epstein-Barr virus expression within keratinizing nasopharyngeal carcinoma.

Three stages of maturation can be seen in keratinizing nasopharyngeal carcinomas. These stages are similar morphologically to basal cells, intermediate and superficial squamous cells seen in normal squamous epithelium. Taking advantage of such a diverse tumour cell population, 10 keratinizing nasopharyngeal carcinoma (NPC) were examined by in situ hybridization for the presence of latent Epstein-Barr Virus (EBV) using EBV encoded RNAs (EBERs) and by immunohistology for the presence of EBV early antigen-diffuse (EA-D) and the 350/220 kd membrane glycoprotein of the EBV. The basal cell-like tumour cells are mainly infected latently with the virus; viral replication was found in isolated intermediate squamous cells, whilst superficial squamous cells are largely depleted of all the viral markers. We used a control series of nonkeratinizing nasopharyngeal carcinomas composed of undifferentiated and poorly differentiated tumour cells and EBV latency was present in these tumours. Viral replication was detected by RT-PCR, in the undifferentiated tumours but viral replication was not seen by immunohistology. The possible relationship between EBV life cycle in these tumours and tumour cell differentiation is discussed in the light of these findings.

Antibodies, Monoclonal↗

PubMed1998

Telomerase activation in nasopharyngeal carcinomas.

Nasopharyngeal carcinomas (NPC) are common in Hong Kong and southern China but rare in Western countries. Telomerase activation is common in human cancers but has not been reported previously in NPC. Telomerase activation in NPC was determined using the sensitive TRAP (telomerase rapid amplification protocol) assay in 45 nasopharyngeal biopsies (36 NPC, nine normal nasopharyngeal mucosae) in four xenografted NPC tumours established in nude mice and in five in vitro NPC cell lines. Telomerase activation is common in NPC and can be detected at high frequencies (85% in primary tumours and 100% in recurrent tumours). The frequency of telomerase activation was lowest in NPC biopsies without lymph node involvement (60%) compared with those with positive lymph node involvement (100%), and the difference is statistically significant (P < 0.05; Fisher exact test). All the xenografted NPC tumours and in vitro NPC cell lines were strongly positive for telomerase activity. Our results suggest that telomerase activation is common in NPC and it may be useful as a diagnostic marker in the detection of tumour cells in nasopharyngeal biopsies. The high frequency of telomerase activation in stage I NPC (80% positive) suggests that it is an early event in tumour progression.

Adolescent↗

PubMed1998

Inhibition of voltage-gated K+ current in rat intrapulmonary arterial myocytes by endothelin-1.

Although endothelin (ET)-1 is an important regulator of pulmonary vascular tone, little is known about the mechanisms by which ET-1 causes contraction in this tissue. Using the whole cell patch-clamp technique in rat intrapulmonary arterial smooth muscle cells, we found that ET-1 and the voltage-dependent K+ (Kv)-channel antagonist 4-aminopyridine, but not the Ca(2+)-activated K(+)-channel antagonist charybdotoxin (ChTX), caused membrane depolarization. In the presence of 100 nM ChTX, ET-1 (10(-10) to 10(-7) M) caused a concentration-dependent inhibition of K+ current (56.2 +/- 3.8% at 10(-7) M) and increased the rate of current inactivation. These effects of ET-1 on K+ current were markedly reduced by inhibitors of protein kinase C (staurosporine and GF 109203X) and phospholipase C (U-73122) or under Ca(2+)-free conditions and were mimicked by activators of protein kinase C (phorbol 12-myristate 13-actetate and 1,2-dioctanoyl-sn-glycerol). These data suggest that ET-1 modulated pulmonary vascular reactivity by depolarizing pulmonary arterial smooth muscle, due in part to the inhibition of Kv current that occurred via activation of the phospholipase C-protein kinase C signal transduction pathway.

4-Aminopyridine↗

PubMed1998

Serological diagnosis of nasopharyngeal carcinoma by enzyme linked immunosorbent assay: optimization, standardization and diagnostic criteria.

OBJECTIVES: To produce an enzyme linked immunosorbent assay (ELISA) to detect antibodies against Epstein Barr virus (EBV) specified nuclear antigen 1 (EBNA 1) and the 18 kD EBV matrix protein, and to determine and optimize its sensitivity and specificity for the diagnosis of nasopharyngeal carcinoma (NPC). METHODS: We used a combination of highly purified glutathione transferase fusion proteins of the 40 kD carboxy domain of EBNA1 and the 18 kD EBV matrix protein for coating ELISA plates. In three separate studies, we tested for IgA antibodies in serum specimens from 28 EBV seronegative donors, 284 EBV seropositive donors and 160 newly diagnosed NPC patients. By comparing the sensitivity and specificity of diagnosis obtained for different cutoff values, we derived several quantitative parameters to evaluate assay performance, establish objective diagnostic criteria which optimize the intrinsic diagnostic capability of the assay and assess the significance of individual test results, respectively. Optimum cutoff optical density (OD) is defined as the cutoff OD where sensitivity of the assay equals its specificity, and resolution of the assay is indicated by the value of sensitivity (or specificity) determined at the optimum cutoff OD. Diagnosis of NPC was achieved by setting a cutoff zone at +/- 20% of this value. RESULTS: All the EBV seronegative donors tested were not reactive, and most of the EBV seropositive donors were weakly reactive, while the majority of NPC patients were moderately or strongly reactive. While the assay was thus shown to be specific for EBV, there was an overlap in the level of these serum antibodies between few individuals of the two latter groups. It was shown that the assay performed equally well in two separate studies conducted under different testing conditions and using different collections of sera in that assay resolution determined on these occasions were 86% and 87% respectively. Diagnosis of NPC can be achieved at the same expected sensitivity of 89% and 83% determined at the lower and upper limits of the cutoff zones, with the corresponding values of specificity being 78% and 91%. It was further shown in the third study that resolution of the assay can be increased to 90% using an assay produced with a higher concentration of the same antigens, and that diagnosis of NPC can be achieved at a higher sensitivity ranging between 86% and 95% at a corresponding specificity of 93% and 86%. CONCLUSIONS: After optimization and standardization, the ELISA can achieve a sensitivity ranging from 86% to 95%, with corresponding specificities of 93% and 86% respectively for the diagnosis of NPC.

Antibodies, Viral↗

PubMed1997

The effect of interruptions and prolonged treatment time in radiotherapy for nasopharyngeal carcinoma.

PURPOSE: The effect of interruptions and prolonged overall treatment time in radiotherapy for nasopharyngeal carcinoma and the significance of timing of interruption was investigated. METHODS AND MATERIALS: Treatment records of 229 patients treated with continuous course (CC) and 567 patients treated with split course (SC) radiotherapy for nonmetastatic NPC were reviewed. Overall treatment time without inclusion of time for boost was calculated. Treatment that extended 1 week beyond scheduled time was considered prolonged. Outcome in patients who completed treatment "per schedule" were compared with those who had "prolonged" treatment. Because of known patient selection bias between CC and SC, patients on the two schedules were analyzed separately. Multivariate analysis was performed for patients on SC. Total number of days of interruption, age, sex, T and N stage, and the use of boost were tested for the whole SC group. Analysis on the effect of timing of interruption was performed in a subgroup of 223 patients on SC who had a single unplanned interruption. Timing of interruption, either before or after the fourth week for the unplanned interruption, was tested in addition to the other variables in multivariate analysis for this subgroup of SC. RESULTS: Twenty-seven (11.8%) patients on CC and 96 (16.9%) patients on SC had prolonged treatment. Patients on SC who had prolonged treatment had significantly poorer loco-regional control rate and disease free survival when compared with those who completed radiotherapy per schedule (p = 0.0063 and 0.001, respectively, with adjustment for stage). For CC, the effect of prolonged treatment on outcome was not significant. The small number of events for patients on CC probably account for the insignificant finding. The number of days of interruption was confirmed as prognostic factor, independent of T and N stages, for loco-regional control and disease-free survival in multivariate analysis for SC. The hazard rate for loco-regional failure increased by 3.3% for each day of interruption. The timing of interruption, at the beginning or towards end of treatment, did not significantly alter outcome. CONCLUSION: Interruptions and prolonged treatment adversely affect outcome in radiotherapy for NPC and the effect of repopulation was confirmed. Every effort should be made to keep treatment on schedule and interruptions for whatever reasons should be minimized.

Adolescent↗

PubMed1997

Volumetric analysis of tumor extent in nasopharyngeal carcinoma and correlation with treatment outcome.

PURPOSE: To investigate the variability of tumor volume in nasopharyngeal carcinoma using quantitative measurements of tumor bulk derived from computed tomography, and to study the prognostic value of tumor volume in comparison with other variables. METHODS AND MATERIALS: Two hundred ninety patients with newly diagnosed nasopharyngeal carcinoma were included in the study. The primary tumor volume (PTV) and nodal tumor volume (NTV) were obtained by outlining the tumor contour followed by summation of areas in sequential pretreatment computed tomography axial scans. Total tumor volume (TTV) was obtained by adding the PTV and NTV. All patients had radiotherapy as the primary treatment, 67 patients also received cisplatin-based neoadjuvant chemotheraphy. RESULTS: A large variation in tumor volume was observed, especially in advanced stage disease. The median PTV (cc) in Ho's T1, T2, and T3 disease were: 6.9 (range: 0.9-42.7), 18.8 (1.6-127.9), and 52.4 (3.3-166.8). The median TTV (cc) in Ho's stage I to IV disease were: 7.6 (range: 1.3-42.7), 19.8 (3.2-55.7), 40.7 (4.1-222.7), and 51.1 (3.1-274.7). Patients with a large PTV (>60 cc) were associated with significantly poorer local control (5-year local control rate: 56%) and disease-specific survival (5-year survival rate: 53%). In patients with a small PTV (< or =20 cc), there were no significant differences in local control among different T stages. Large NTV (>30 cc) was associated with significantly higher distant failure rate (5-year distant relapse-free survival rate: 54%) and lower disease-specific survival (5-year survival rate: 40%). In multivariate analysis, only PTV was found to be an independent factor in predicting local control. CONCLUSION: A large variation of tumor volume was present in different T stage disease of nasopharyngeal carcinoma, and PTV represents an independent prognostic factor of local control that appears to be more predictive than Ho's T stage classification.

Adult↗

PubMed1997

Ca2+ release-induced inactivation of Ca2+ current in rat ventricular myocytes: evidence for local Ca2+ signalling.

1. Inactivation of Ca2+ current (ICa) induced by Ca2+ release from sarcoplasmic reticulum (SR) was studied in single rat ventricular myocytes using whole-cell patch-clamp and indo-1 fluorescence measurement techniques. 2. Depolarizing pulses to 0 mV elicited large Ca2+ transients and ICa with biexponential inactivation kinetics. Varying SR Ca2+ loading by a 20 s pulse of caffeine showed that the fast component of ICa inactivation was dependent on the magnitude of Ca2+ release. 3. Inactivation of ICa induced by Ca2+ release was quantified, independently of voltage and Ca2+ entry, using a function termed fractional inhibition of ICa (FICa). The voltage relation of FICa had a negative slope, resembling that of single-channel Ca2+ current (iCa) rather than the bell-shaped current-voltage (I-V) relation of macroscopic ICa and Ca2+ transients. 4. Intracellular dialysis of myocytes with 10 mM EGTA (150 nM free [Ca2+]) had no effect on ICa inactivation induced by Ca2+ release, despite abolition of Ca2+ transients and cell contraction. Dialysis with 3 or 10 mM BAPTA (180 nM free [Ca2+]) attenuated FICa in a concentration-dependent manner, with greater inhibition at positive than at negative potentials, consistent with more effective buffering of Ca2+ microdomains of smaller iCa. 5. Spatial profiles of [Ca2+] near an opened Ca2+ channel were simulated. [Ca2+] reached submillimolar levels at the mouth of the channel, and dropped steeply as radial distance increased. At any given distance from the channel, [Ca2+] was higher at negative than at positive potentials. The radii of Ca2+ microdomains were significantly reduced by 3 or 10 mM BAPTA, but not by 10 mM EGTA. 6. In conclusion, the distinctive voltage dependence and susceptibility of Ca2+ release-induced ICa inactivation to fast and slow Ca2+ buffers suggests that the process is mediated through local changes of [Ca2+] in the vicinity of closely associated Ca2+ channels and ryanodine receptors.

Animals↗

PubMed1997

Tumor control probability of nasopharyngeal carcinoma: a comparison of different mathematical models.

PURPOSE: Radiation dose and tumor volume are factors known to affect the local control of a given type of tumor. Local tumor control is a major factor to consider when a treatment plan is evaluated. This article reports the correlation between tumor control probability, dose, and volume in a retrospective study of 142 patients with nasopharyngeal carcinoma (NPC). METHODS AND MATERIALS: The tumor volume was outlined and calculated from a computed tomographic scan. Patients were categorized according to tumor volume and radiation dose received in treatment. Local control rate was calculated for each category by the Kaplan-Meier method. Mathematical models were fitted to correlate the local control rate, dose, and volume. Both empirical and mechanistic approaches were attempted; the former included logistic models with two and three parameters, and the latter, the formulation from Brenner and Bentzen with a radiobiological basis. RESULTS: Brenner's model estimated alpha at 0.041 Gy(-1) with 95% confidence limits (-0.032, 0.113) Gy(-1). The volume dependent constant h was estimated at 0.160 cm(-3) with 95% confidence limits (-0.729, 1.048) cm(-3). The Pearson correlation coefficient was 0.64. The magnitude and sign of the fitted parameters were reasonable and consistent with reported clinical experience. The other models were fitted with slightly better goodness of fit (r = 0.65 - 0.68), but with less interpretable parameters. CONCLUSION: Brenner's model is considered appropriate for a description of the dose and volume effect on the local control of the NPC. It could be used in combination with normal tissue complication probability for treatment plan evaluation to optimize treatment results.

Adult↗

PubMed1997

Retropharyngeal lymphadenopathy in patients with nasopharyngeal carcinoma: a computed tomography-based study.

BACKGROUND: The purpose of this study was to investigate the incidence and prognostic value of retropharyngeal lymphadenopathy in nasopharyngeal carcinoma patients using contrast enhanced computed tomography (CT). METHODS: From January 1989 to December 1991, 364 patients with newly diagnosed nasopharyngeal carcinoma without distant metastasis had a baseline CT performed. All patients had radiotherapy as their primary treatment. Eighty-seven patients also received neoadjuvant chemotherapy for locally advanced disease. All patients with clinical N0 disease had prophylactic lymph node irradiation. The contrast enhanced CT given prior to all treatment was evaluated for the presence of retropharyngeal lymphadenopathy. Criteria for involved lymph nodes included a lymph node size of 10 mm or more, the presence of central necrosis within the lymph node, or the presence of a contrast enhancing rim. RESULTS: The incidence of retropharyngeal lymphadenopathy was 29.1%. A higher incidence of retropharyngeal lymph node involvement was observed in Ho's T2/T3 disease compared with T1 disease, and a higher incidence was also found in patients with cervical lymph node disease compared with those with clinical N0 disease. No significant differences in relapse free survival rates, local control rates, lymph node control rates, or distant failure rates were observed between patients with or without retropharyngeal lymphadenopathy after adjusting for T and N classifications. In 134 patients with clinical N0 disease, retropharyngeal lymphadenopathy was found in 21 patients, whereas 113 had no evidence of retropharyngeal lymphadenopathy. However, no significant difference in treatment outcome was observed between the two groups. CONCLUSIONS: Using CT imaging, the presence of retropharyngeal lymphadenopathy in patients with nasopharyngeal carcinoma does not appear to affect the prognosis. In patients with clinical N0 disease, the identification of retropharyngeal lymphadenopathy based only on CT imaging is not sufficient evidence for an N1 classification.

Carcinoma↗