Delivery of poorly soluble compounds by amorphous solid dispersions.

Solid state manipulation by amorphous solid dispersion has been the subject of intensive research for decades due to their excellent potential for dissolution and bioavailability enhancement. The present review aims to highlight the latest advancement in this area, with focus on the fundamentals, characterization, formulation development and manufacturing of amorphous solid dispersions as well as the new generation amorphization technologies. Additionally, specific applications of amorphous solid dispersion in the formulation of herbal drugs or bioactive natural products are reviewed to reflect the growing interest in this relatively neglected area.

Orofacial pain symptoms and associated disability and psychosocial impact in community-dwelling and institutionalized elderly in Hong Kong.

OBJECTIVE: The study investigated the experience of orofacial pain (OFP) symptoms and associated disability and psychosocial impact in community dwelling and institutionalized elderly people in Hong Kong. METHODS: A community-based cross-sectional survey involving elders aged 60 years and above. Participants were recruited at social centres for the elderly and homes for the aged throughout Hong Kong. Elders who reported OFP symptoms in the previous four weeks took part. Standard questions were asked about OFP conditions in the previous month and the Manchester Orofacial Pain Disability Scale (MOPDS), the Oral Health Impact Profile (OHIP-14) and the General Health Questionnaire (GHQ-12) were administered. The MOPDS was translated and validated for use in Chinese elders. RESULTS: 200 community dwelling and 200 institutionalized elders participated. Toothache was the most common symptom (62.0%) and burning sensation in the tongue was least common (0.5%). The distribution of pain symptoms, pain duration and severity and pain ratings were similar in both groups. The MOPDS (Chinese elders version) had good reliability and construct validity. The MOPDS and OHIP-14 summary scores was significantly higher in the institutionalized elderly (p < 0.001 and p < 0.013, respectively). Psychological distress (GHQ-12 score > or = 4) was more common among the institutionalized elderly (11%) than the community dwelling elderly (4.0%, p = 0.002). CONCLUSIONS: Orofacial pain symptoms were associated with significant disability and had a detrimental impact on psychological distress level and quality of life, particularly in the institutionalized elderly. There is a need to improve access to professional care and health-related outreach services generally for elderly people in Hong Kong.

Treatment outcomes in anaplastic thyroid carcinoma: survival improvement in young patients with localized disease treated by combination of surgery and radiotherapy.

BACKGROUND: Anaplastic thyroid carcinoma (ATC) is a notoriously aggressive malignancy associated with a highly lethal clinical course despite therapeutic intervention. Our present study attempts to identify factors that could potentially improve therapeutic strategies by analyzing the clinicopathological features, treatment and outcome of ATC patients managed over the past four decades at our institution. METHODS: Fifty patients with biopsy-proven ATC during the period 1966 to 2006 were studied. All patients were managed with surgery, radiotherapy, chemotherapy and/or chemoradiation. Survival was calculated by the Kaplan-Meier method. Potential factors affecting survival were compared by the log rank test. RESULTS: Most patients (88%) presented with a neck mass; 17 patients (34%) also had cervical lymphadenopathy. Distant metastases were clinically present in 9 (18%). Median survival was 97 days, whereas the 1- and 3-year survival was 14% and 8%, respectively. On univariate analysis, patients aged

Concurrent and adjuvant chemotherapy for nasopharyngeal carcinoma: a factorial study.

PURPOSE: To study the efficacy of concurrent chemoradiotherapy (CRT) and adjuvant chemotherapy (AC) for nasopharyngeal carcinoma (NPC). PATIENTS AND METHODS: Patients with Ho's stage T3 or N2/N3 NPC or neck node > or = 4 cm were eligible. Patients were randomly assigned to have radiotherapy (RT) or CRT with uracil and tegafur and to have AC or no AC after RT/CRT. AC comprised alternating cisplatin, fluorouracil, vincristine, bleomycin, and methotrexate for six cycles. There were four treatment groups: A, RT; B, CRT; C, RT and AC; D, CRT and AC. For CRT versus RT, groups B and D were compared with groups A and C. For AC versus no AC, groups C and D were compared with groups A and B. RESULTS: Three-year failure-free survival (FFS) and overall survival (OS) for CRT versus RT were 69.3% versus 57.8% and 86.5% versus 76.8%, respectively (P =.14 and.06; n = 110 v 109). Distant metastases rate (DMR) was significantly reduced with CRT (14.8% v 29.4%; P =.026). Locoregional failure rates (LRFR) were similar (20% v 27.6%; P =.39). Three-year FFS and OS for AC versus no AC were 62.5% versus 65% and 80.4% versus 83.1%, respectively (P =.83 and.69; n = 111 v 108). DMR and LRFR were not reduced with AC (P =.34 and.15, respectively). Cox model showed CRT to be a favorable prognostic factor for OS (hazard ratio, 0.42; P =.009). CONCLUSION: An improvement in OS with CRT was observed but did not achieve statistical significance. The improvement seemed to be associated with a significant reduction in DMR. AC did not improve outcome.

Patterns of failure after induction chemotherapy and radiotherapy for locoregionally advanced nasopharyngeal carcinoma: the Queen Mary Hospital experience.

PURPOSE: Our center contributed 183 patients to the Asian-Oceanian Clinical Oncology Association (AOCOA) multicenter randomized trial comparing induction chemotherapy (CT) followed by radiotherapy (RT) vs. RT alone in patients with locoregionally advanced undifferentiated nasopharyngeal carcinoma (NPC). In a preliminary report no difference in terms of overall survival or relapse-free survival was found between the 2 treatment arms. To study the long-term outcome and patterns of failure after CT for NPC, we analyzed our own center data for which a uniform radiation treatment protocol was adopted and a longer follow-up time was available. METHODS AND MATERIALS: Between September 1989 and August 1993, a total of 183 patients were recruited into the AOCOA randomized study from our center. Patients with newly diagnosed NPC of Ho's T3 disease, N2-N3 disease, or with neck node size of at least 3 cm were eligible. Stratification was made according to the nodal size (< or = 3 cm, >3- 6 cm, > 6 cm). Patients were randomized to receive 2-3 cycles of CT with cisplatin 60 mg/m(2) and epirubicin 110 mg/m(2) D1 followed by RT or RT alone. Four patients were excluded from the current analysis (2 died before treatment, 2 received treatment elsewhere). The remaining 179 patients were randomized to the two treatment arms, with 92 to the CT arm and 87 to the RT arm. Two patients in the CT arm had RT only, and all patients completed radiation treatment. Overall survival (OAS), relapse-free survival (RFS), local relapse-free survival (LRFS), nodal relapse-free survival (NRFS), and distant metastases-free survival (DMFS) were analyzed using Kaplan--Meier method and significance of survival curve differences calculated using log--rank test. Analysis was performed based on the intent-to-treat. RESULTS: The median follow-up was 70 months. At the time of analysis, 50% of patients in the CT arm and 61% in the RT arm had relapse, while 32% in the CT arm and 36% in the RT arm had died of the disease. The median RFS was 83 months in the CT arm and 37 months in the RT arm. The median OAS has not yet been reached for both arms. No significant differences were found for the various endpoints, although there was a trend suggesting better nodal control in the CT arm. The 5-year rates for the various endpoints in the CT arm vs. the RT arm were: 53% vs. 42% for RFS (p = 0.13), 70% vs. 67% for OAS (p = 0.68), 80% vs. 77% for LRFS (p = 0.73), 89% vs. 80% for NRFS (p = 0.079), and 70% vs. 68% for DMFS (p = 0.59). There was also no significant difference in the patterns of failure between both arms: in the CT arm, 28% of failures were local only, 13% regional only, 4% locoregional, 44% distant, and 11% mixed locoregional and distant. In the RT arm, 23% of failures were local only, 13% regional only, 11% locoregional, 43% distant, and 9% mixed locoregional and distant. CONCLUSION: Induction chemotherapy with the regimen used in the current study did not improve the treatment outcome or alter the failure patterns in patients with locoregionally advanced NPC, although there was a trend suggesting better nodal control in the combined modality arm. Alternative strategies of combining chemotherapy and radiotherapy should be tested and employed instead.

Insular and anaplastic carcinoma of the thyroid: a 45-year comparative study at a single institution and a review of the significance of p53 and p21.

OBJECTIVE: To analyze the clinicopathologic features of a large cohort of patients with insular or anaplastic carcinomas treated at a single institution. SUMMARY BACKGROUND DATA: Insular and anaplastic carcinomas of the thyroid, although uncommon, have more aggressive clinical behavior than well-differentiated carcinomas of the thyroid. In the literature, the incidence and features of these carcinomas have not been fully characterized. METHODS: The authors reclassified 740 primary thyroid carcinomas diagnosed and treated between January 1, 1954, and December 30, 1998, to select those with features that met the histologic criteria of insular or anaplastic carcinoma. The clinicopathologic features of these carcinomas were studied and compared. The expression of p53 and p21 in these tumors was analyzed by immunohistochemistry. RESULTS: Twenty-two patients (5 men, 17 women) with insular carcinoma and 38 patients (7 men, 31 women) with anaplastic carcinoma were found. Patients with insular carcinomas were younger (mean age 45 vs. 70 years) and had smaller tumors than those with anaplastic carcinomas (mean diameter 5 vs. 8 cm). Insular carcinomas were commonly mislabeled as other histologic subtypes, whereas anaplastic carcinomas might be overdiagnosed on pathologic examination. A history of longstanding goiter (>10 years) was noted in 27% of patients with insular carcinoma and 24% of patients with anaplastic carcinomas. Concomitant well-differentiated carcinomas of the thyroid were noted in 59% of patients with insular carcinoma and 39% of patients with anaplastic carcinoma. In anaplastic carcinomas, 13% of patients had concomitant insular carcinoma. Calcification or bone was noted in the stroma of 23% of patients with insular carcinomas and 47% of those with anaplastic carcinomas. The 10-year survival rates for patients with insular carcinoma and anaplastic carcinoma were 42% and 3%, respectively. Distant metastases were seen in 32% of patients with insular carcinoma and in 47% of patients with anaplastic carcinomas. In both types of carcinomas, metastatic tumors were often seen in bone and lung. Distant metastases were noted in a variety of organs in anaplastic carcinomas. In insular carcinoma, neither p53 nor p21 expression was present. In anaplastic carcinoma, p53 and p21 expression was identified in 69% and 3%, respectively. Concomitant expression of p53 and p21 was noted in one tumor. CONCLUSIONS: Insular carcinoma and anaplastic carcinoma had distinctive clinicopathologic features, and recognition of these histologic variants is important for better management of these tumors in the future. p53 overexpression might have a role in dedifferentiation from insular carcinoma to anaplastic carcinoma.

Anaplastic carcinoma of the thyroid.

BACKGROUND: Anaplastic thyroid carcinoma, albeit rare, is one of the most aggressive human tumors, with a dismal prognosis. METHODS: Twenty-eight patients with anaplastic thyroid carcinoma were identified during the past 30 years to evaluate its clinicopathologic features and to document our experience in management. Potential risk factors for survival time were analyzed. RESULTS: The usual presentation was that of a rapidly enlarging neck mass. Distant metastases were present in 50% of patients on presentation. Palliative resection was performed in 16 patients. The median survival was 38 days, and the 2-year survival rate was 4%. Among factors analyzed, patients selected for surgical resection, absence of distant metastases at presentation, young age, and tumor size <6 cm were associated with an increased survival time. Concomitant well-differentiated thyroid carcinoma and p53 overexpression were present in 12 of the 22 and 13 of the 19 specimens, respectively. CONCLUSIONS: Patients with anaplastic carcinoma of thyroid have a dismal prognosis heralding imminent death. Surgical ablation followed by adjuvant therapy can provide palliation for selected patients only.

The time course of histologic remission after treatment of patients with nasopharyngeal carcinoma.

BACKGROUND: The objective of this study was to define the time course of histologic remission and to evaluate the prognostic significance of delayed histologic remission of patients with nasopharyngeal carcinoma (NPC). METHODS: Between 1986-1994, 803 patients underwent serial postradiotherapy nasopharyngeal biopsies. Patients with positive histology underwent repeated biopsies every 2 weeks until the biopsies were found to be negative or, if remission did not occur by the 12th week after radiotherapy, treatment was initiated for persistent disease. Patients with positive histology found after the fifth week but who achieved spontaneous remission before the twelfth week were considered to have delayed histologic remission. Negative histology by the sixth week was considered early histologic remission. The outcome of patients with delayed histologic remission, early histologic remission, and persistent disease were compared. RESULTS: Six hundred and seventeen patients (76.8%) had negative histology within 12 weeks of the completion of radiotherapy and 55 (6.9%) had persistent disease at Week 12. In 131 patients (16.3%) spontaneous remission was observed in repeat biopsies after initial positive histology. With increasing time after radiotherapy, the incidence of positive histology decreased but more patients were found to have persistent disease. Patients with early and delayed histologic remission had 5-year NPC control rates of 82.4% and 76.8%, respectively (P = 0.35) versus a 40% NPC control rate among patients with persistent disease (P < 0.001). The 5-year survival rates were 75.3%, 79.4%, and 54.2%, respectively, for the 3 groups (P < 0.001). CONCLUSIONS: A high proportion of early positive histology remitted spontaneously. Delayed histologic remission in NPC patients is not a poor prognostic factor and additional treatment is not necessary. A confirmatory biopsy at 10 weeks is recommended before the initiation of salvage treatment.

Phase diagram of the Biham-Middleton-Levine traffic model in three dimensions.

We study numerically the behavior of the Biham-Middleton-Levine traffic model in three dimensions. Our extensive numerical simulations show that the phase diagram for this model in three dimensions is markedly different from that in one and two dimensions. In addition to the full speed moving as well as the completely jamming phases, whose respective average asymptotic car speeds (v) equal one and zero, we observe an extensive region of car densities rho with a low but nonzero average asymptotic car speed. The transition from this extensive low average asymptotic car speed region to the completely jamming region is at least second order. We argue that this low speed region is a result of the formation of a spatially limited-extended percolating cluster. Thus, this low speed phase is present in the (n>3)-dimensional Biham-Middleton-Levine model as well.

Follicular carcinoma of the thyroid gland in Hong Kong Chinese.

A total of 64 Chinese patients (eight men, 56 women) undergoing primary treatment for follicular thyroid cancer between 1961 and 1986 were studied retrospectively to report the local experience in treatment of this condition and to identify the risk factors for mortality. The minimum follow-up was 7 (median 14) years. The mean tumour size was 3.0 (range 0.1-11.0) cm. The majority of patients (91 per cent) underwent total or near-total thyroidectomy. Distant metastases were detected in ten patients at the time of initial diagnosis and in three during follow-up. Locoregional recurrence had developed in six patients at follow-up. There were 13 deaths, with a median survival of 45 months. The 5- and 10-year survival rates were 87 and 80 per cent respectively. Six risk factors for mortality were selected for multivariate analysis using logistic regression; the presence of distant metastasis was the only significant risk factor for survival.

Multivariate analysis of risk factors influencing survival in 110 ethnic Chinese with papillary thyroid cancer.

Data from 110 Chinese patients presenting with papillary thyroid cancer to a single institution up to December 1985 have been analyzed to evaluate the possible risk factors affecting survival. There were 83 women and 27 men with an age range of 15 to 78 years (mean 45 years, median 42 years). The longest follow-up period is 39 years and the median 10 years. Cervical lymph node recurrence more than 6 months after surgery developed in 12 patients, of whom 1 died with a concomitant distant metastasis. "Thyroid bed" tumor recurrence, after apparently complete surgery, presented in 10 patients and resulted in 5 deaths. Distant metastases were identified in 17 patients with 7 deaths. Another 4 patients died from advanced local disease incompletely resectable on presentation. The following seven risk factors for survival were selected for multivariate analysis: age, sex, tumor size, histologic evidence of extrathyroidal spread, lymph node recurrence, neck recurrence, and distant metastases. Age, size, neck recurrence, and distant metastases were all significant on univariate analysis. Using Cox proportional hazards regression in the multivariate analysis of these seven factors, only age (p < 0.0001) was shown to be significant. Age over 40 years on first diagnosis was a highly significant indicator of high risk (p = 0.0003, log-rank).

Radiotherapy for nasopharyngeal carcinoma: shielding the pituitary may improve therapeutic ratio.

PURPOSE: Nasopharyngeal carcinoma (NPC) is well known for its invasiveness and erosion of the base of the skull is not uncommon. Before the advent of computed tomography, the evaluation of the base of the skull was by plain radiography. Because of the low sensitivity of these investigations, traditional teaching has included the sphenoid sinus in the volume of irradiation. Increase in longevity of patients allows the manifestation and documentation of the long-term sequelae of irradiating the hypothalamic-pituitary axis and the temporal lobes. This study is an attempt to evaluate whether the hypothalamic-pituitary axis can be shielded from the target volume in a proportion of NPC patients. METHODS AND MATERIALS: One hundred fifty-two NPC patients with no evidence of erosion of the base of the skull and sphenoid, nor extension to the nasal fossa and ethmoid sinuses were randomized to receive standard radiotherapy covering the whole sphenoid sinus or radiotherapy using a modified technique that shields the pituitary and the anterior part of the hypothalamus. This modified technique also shields a large part of the lower temporal lobes that are otherwise covered by standard treatment portals. The characteristics and treatment of the two subgroups of patients were otherwise comparable. RESULTS: At a median follow-up of 31.5 months, the tumor control between the two subgroups of patients were comparable (p = 0.3928). However, 8 of the 71 patients in the unshielded group had developed symptomatic neuroendocrine complications, while none of the other group did (p = 0.0061). Two patients developed secondary hypothyroidism, one patient developed oligomenorrhoea associated with raised prolactin, and five patients developed temporal lobe necrosis. CONCLUSIONS: The protective effect on neuroendocrine complication of this shield was demonstrated at median follow-up of 31.5 months, and the local control was not jeopardized. Modification of treatment technique as presently described, which is applicable to one-third of NPC patients to improve the therapeutic ratio, is recommended for general use.

Clear cell rhabdomyosarcoma of the nasal cavity and paranasal sinuses.

This report describes two cases of alveolar rhabdomyosarcoma of the nasal cavity with unusual histological appearances mimicking clear cell carcinoma. The closely packed tumour cells were polygonal and arranged in sheets and packets. They had an appreciable amount of clear cytoplasm due to accumulation of glycogen. The diagnosis of rhabdomyosarcoma was confirmed by positive staining for desmin and myoglobin. Rhabdomyosarcoma should be included in the differential diagnosis of nasal clear cell tumours, particularly in young adults. A correct diagnosis is important, because chemotherapy is indicated even for apparently localized disease.