Interaction between intruders in vibrated granular beds.

Two neutrally buoyant intruder particles in a granular bed fluidized by vertical, sinusoidal vibration are known to interact with each other over a range of about five intruder diameters. Using molecular dynamics simulations, we investigate in detail the spatial and temporal nature of this interaction. We show that the force of attraction between intruders can be calculated from the local density and kinetic energy using a simple equation of state. Moreover, the interaction can be changed from attractive to repulsive by reducing the coefficient of restitution between the intruders and host particles, one of the key results of this work.

Intruder clustering in three-dimensional granular beds.

We present results of computer simulations for neutrally buoyant intruders in a vertically vibrated three-dimensional granular bed of smaller host particles. Under sinusoidal excitation, pairs of intruders interact over a distance of several intruder diameters; a group of intruders forms a cluster. The strength of the interaction grows as the number of intruders is increased. We show that the tendency to cluster may be manipulated through the use of nonsinusoidal excitation, which allows partial mixing. Finally, we investigate the effects of walls on the clustering of intruders.

Gemcitabine and cisplatin in a multimodality treatment for locally advanced non-small cell lung cancer.

The role of new cytotoxic agents like gemcitabine has not yet been proven in the neoadjuvant settings. We designed a phase II study to test the feasibility of using gemcitabine and cisplatin before local treatment for stage III non-small cell lung cancer patients. Patients received three cycles of induction chemotherapy of gemcitabine (1000 mg m(-2), days 1, 8, 15) and cisplatin (90 mg m(-2), day 15) every 4 weeks before evaluation for operability. Operable patients underwent radical resection. Inoperable patients and patients who had incomplete resection received concurrent chemoradiotherapy with daily low dose cisplatin. All patients who did not progress after local treatment received three more cycles of adjuvant chemotherapy of gemcitabine and cisplatin. Fifty-two patients received induction treatment. Two patients had complete response and 31 patients had partial response (response rate 63.5%) after induction chemotherapy. Thirty-six patients (69%) were operable. Eighteen patients (35%) had their tumours completely resected. Two patients had pathological complete response. Median overall survival was 19.1 months, projected 1-year survival was 66% and 2-year survival was 34%. Three cycles of gemcitabine and cisplatin is effective and can be used as induction treatment before surgery for locally advanced non-small cell lung cancer patients.

Induction chemotherapy with mitomycin, epirubicin, cisplatin, fluorouracil, and leucovorin followed by radiotherapy in the treatment of locoregionally advanced nasopharyngeal carcinoma.

PURPOSE: Survival in advanced nasopharyngeal carcinoma (NPC) is compromised by distant metastasis. Because mitomycin is active against hypoxic and G0 cells, which may help to eradicate micrometastasis, we investigated the effect of mitomycin-containing cisplatin-based induction chemotherapy. PATIENTS AND METHODS: Recruited for this study were American Joint Committee on Cancer (AJCC) 1992 staging system stage IV NPC patients with the following adverse features: obvious intracranial invasion, supraclavicular or bilateral neck lymph node metastasis, large neck node (> 6 cm), or elevated serum lactate dehydrogenase (LDH) level. Patients were given three cycles of chemotherapy before radiotherapy. The chemotherapy comprised a 3-week cycle of mitomycin, epirubicin, and cisplatin on day 1 and fluorouracil and leucovorin on day 8 (MEPFL). RESULTS: From January 1994 to December 1997, 111 patients were recruited. The median follow-up period was 43 months. The actuarial 5-year overall survival rate was 70% (95% confidence interval [CI], 60% to 80%; n = 111). For patients having completed radiotherapy (n = 100), the 5-year locoregional control rate was 70% (95% CI, 55% to 84%) and the distant metastasis-free rate was 81% (95% CI, 73% to 89%). The 5-year distant metastasis-free rate of N3a and N3b disease of AJCC 1997 staging system were 79% (95% CI, 62% to 95%) and 74% (95% CI, 60% to 89%), respectively. By Cox multivariate analysis, high pretreatment serum LDH level (P = .04) and neck nodal enlargement before radiotherapy (P = .001) were adverse prognostic factors of survival. CONCLUSION: The good 5-year survival of N3 disease supports the effectiveness of induction MEPFL in the primary treatment of advanced NPC. Further investigation to incorporate concurrent chemoradiotherapy is warranted.

Concurrent chemoradiotherapy for locally advanced esophageal cancer--a pilot study by using daily low-dose cisplatin and continuous infusion of 5-fluorouracil.

BACKGROUND: Concurrent chemoradiotherapy (CCRT) has recently become a promising treatment for esophageal cancer. However, most investigators have adopted the conventional or modified Wayne-State PF (cisplatin plus 5-fluorouracil) regimen, which is inevitably associated with moderate to severe treatment-related toxicities. In this pilot study, we incorporated a daily low-dose regimen of cisplatin and 5-fluorouracil into CCRT in order to improve the compliance of the patients. PATIENTS AND METHODS: Between July 1993 and Dec. 1997, 25 patients with locally advanced esophageal cancer (T3, or N1 disease), received CCRT which consisted of daily low-dose cisplatin (6 mg/m2/day) and continuous infusion of 5-FU (225 mg/m2/day) with radiotherapy (fraction size = 200-250 cGy/day). Except for the initial 9 patients, for whom post-CCRT esophagectomy was compulsory, all subsequent patients underwent esophagectomy only when inadequate response to CCRT was noted. The scheduled radiation dose was 50 Gy for the first 9 patients, and 60 Gy for the rest of the patients. RESULTS: Eighteen patients (72%) completed the CCRT without interruption. Clinically, there were 8 CR and 9 PR, with a total response rate of 68% (47-87%, 95% C.I.). All patients were evaluable for toxicity. Grade 3/4 leukopenia and thrombo-cytopenia developed in 14 (56%) and 7 (28%) patients, respectively. Grade 3/4 non-hematologic toxicity was seen in 4 (16%) patients. The median survival of the whole group was 8 months (range: 2-59+). The projected 3-year overall survival was 24%. CONCLUSION: We suggest that for locally advanced esophageal cancer CCRT with the aforementioned daily low-dose regimen, is a treatment with good patient compliance.

High-dose therapy with peripheral blood stem cell (PBSC) support using an innovative mobilization regimen in patients with high-risk primary or chemoresponsive metastatic breast cancers.

High-dose therapy followed by peripheral blood stem cell (PBSC) support was performed in 29 patients with primary high-risk (Group I) or chemoresponsive metastatic (Group II) breast cancer patients. Group I patients had received PBSC mobilization within 4 weeks of modified radical mastectomy. Group II patients had to achieve minimal residual disease (MRD) by induction chemotherapy before being considered eligible for PBSC mobilization and high-dose therapy. An innovative FE120C regimen (5-FU 600 mg/m2, i.v., day 1; epirubicin 120 mg/m2, i.v., day 1; cyclophosphamide 600 mg/m2, i.v., day 1) plus G-CSF (300 microg/day, subcutaneous injection for 9 days, from day 4 post-FE120C) was used to mobilize PBSCs. After high-dose CTCb (cyclophosphamide 6,000 mg/m2, thiothepa 500 mg/m2, carboplatin 800 mg/m2, in 4 days), patients received PBSC infusion and daily C-CSF 300 microg subcutaneous injection. There were 19 and 16 patients enrolled into Group I and Group II, respectively. Ten of the Group II patients had achieved minimal residual disease (MRD) after induction chemotherapy. The median numbers of mobilized total CD34 + cells for Group I and Group II patients were 27.3 (9.2 to 114.1) x 10(6)/kg and 17.1 (5.9 to 69.1) x 10(6)/kg respectively. The median time to neutrophil recovery (ANC > or = 500/microL) was 8 and 9 days in Group I and II, respectively. The median time to platelet recovery (> or = 50,000/microL) was 10 and 15 days in Group I and II, respectively. No major treatment-related toxicities were noted. In Group I, 13 out of 19 patients (68.4%; 43-87%, 95% C.I.) remained recurrence-free with a median follow-up of 31 months (6 + to 55 + months). In Group II, 3 out of 10 patients (30%; 7-65%, 95% C.I.) remained progression-free at 33 +, 35 +, 39 + months from induction therapy. We suggest that the FE120C plus G-CSF is an effective and innovative regimen for PBSC mobilization in breast cancer patients, and high-dose CTCb therapy with PBSC support is a safe and well-tolerated treatment modality.

Increased mutagen sensitivity in patients with head and neck cancer is less pronounced in patients with nasopharyngeal carcinoma.

BACKGROUND: Mutagen sensitivity tested with bleomycin sulfate can determine a susceptible phenotype, which is relevant only in organs and tissues that have direct contact with the external environment. Patients with head and neck cancers have more mutagen sensitivity than control subjects without cancer, and the hypersensitive phenotype has a risk for the development of a second primary cancer. Head and neck cancers, however, represent a heterogeneous group of neoplasm. The biological behavior of nasopharyngeal carcinoma (NPC) and other head and neck cancers differs. OBJECTIVE: To evaluate the difference in mutagen sensitivity among patients without cancer, patients with NPC, patients with oral or oropharyngeal cancer (ORC), and patients with laryngeal or hypopharyngeal cancer (LHC). DESIGN: Peripheral blood was cultured at 37 degrees C, using 5% carbon dioxide, for 72 hours. After 67 hours of incubation, bleomycin in a concentration of 30 IU/L was added to induce chromatid breaks. The number of chromatid breaks per cell was scored in 50 metaphases of cultured lymphocytes and compared in the 4 groups. SUBJECTS: Patients with histologically proven squamous cell carcinoma of the mucosa of the upper digestive tract, which included 3 groups: patients with NPC, patients with ORC, and those with LHC. Control subjects were hospital inpatients with no tumor history. There were 35 patients in each group. RESULTS: The mean (+/-SD) number of breaks per cell in the control group and in the groups with NPC, ORC, and LHC were 0.80 (+/-0.32), 1.03 (+/-0.45), 1.30 (+/-0.44), and 1.35 (+/-0.46), respectively. All the cancer groups had significantly higher mean breaks per cell and a higher prevalence of hypersensitivity than the control group. Patients with NPC had a significantly lower mean number of breaks per cell than the group with ORC or that with LHC. CONCLUSIONS: Patients with NPC had less mutagen sensitivity than those with ORC or LHC. Our results support the clinical and epidemiological findings of a difference between NPC and other head and neck cancers. Environmental factors might play a less pronounced role in the carcinogenesis of NPC.

Radiation-induced malignant fibrous histiocytoma in patients with nasopharyngeal carcinoma.

OBJECTIVE: To evaluate the prevalence, 15-year cumulative incidence, time interval, and prognosis of radiation-induced malignant fibrous histiocytoma of the head and neck in long-term survivors of nasopharyngeal carcinoma. DESIGN: Cohort. SETTING: Tertiary care hospital. PATIENTS: Eight long-term survivors of nasopharyngeal carcinoma with malignant fibrous histiocytoma in the maxillary sinus or nasal cavity. MAIN OUTCOME MEASUREMENT: Survival of postirradiation malignant fibrous histiocytoma in patients with nasopharyngeal carcinoma. RESULTS: The prevalence of radiation-induced malignant fibrous histiocytoma in long-term survivors of nasopharyngeal carcinoma was 0.38%. The 15-year cumulative incidence was 2.2%. Most tumors occurred in the maxillary sinus and were characterized by spindle-shaped tumor cells with plump nuclei arranged in a whorl or storiform pattern in a fibrous stroma. The mean interval between malignant fibrous histiocytoma and nasopharyngeal carcinoma was 121 months. Local recurrence developed in all cases within 9 months after surgery. Six patients died of disease without distant metastasis within 30 months. Two patients were alive with disease for 20 and 32 months, respectively. CONCLUSIONS: Radiation-induced malignant fibrous histiocytoma in the head and neck region in long-term survivors of nasopharyngeal carcinoma is rare. It takes a long time to occur after irradiation and is locally invasive with poor prognosis.

Experience of radiotherapy in lethal midline granuloma with special emphasis on centrofacial T-cell lymphoma: a retrospective analysis covering a 34-year period.

Lethal midline granuloma (LMG) is characterized by progressive ulceration and destruction of the midfacial tissue. It occurs more frequently in Oriental than in Western populations. Because of the progress in clinical pathology and immunohistochemistry, most cases have been proven to be malignant lymphomas, especially of T-cell lineage. We describe 92 cases of lethal midline granuloma or centrofacial malignant lymphoma in the period 1959-1993. All received complete courses of radiotherapy. Twenty of them also received combination chemotherapy. Thirty-six cases had specimens available for immunohistochemical study; 25 (69%) of these had a T-cell phenotype, and 6 (17%) were of B-cell lineage. The dose to the nasal region was in the range of 3000-7500 cGy in 11-58 days, and to the neck 3000-6400 cGy in 11-48 days. The overall survival rate for the LMGs was 59.5% at 5 years and 56.2% at 10 years (Kaplan-Meier). Combined chemotherapy seemed not to improve the overall survival in this study (p = 0.63), but the patient number was too small to make a firm conclusion. Based on the results of this study, we recommend a dose of 4500-5000 cGy to the midfacial region, since a higher dosage did not improve the treatment results (p = 0.88). Irradiation has a definite role in good locoregional control of this disease. The recent clarification of the disease nature and the recognition of the background clinicopathological features should provide valuable information for future patient management and prospective studies.

Chromosome aberrations induced in human lymphocytes after partial-body irradiation.

Chromosomal aberrations in peripheral blood lymphocytes obtained from two patients before and after they received one fraction of partial-body irradiation for palliative treatment were analyzed. Blood samples were taken 30 min and 24 h after radiation treatment. The yield of dicentrics obtained from case A 30 min after a partial-body (about 21%) treatment with 8 Gy was 0.066/cell, while the yield obtained 24 h after radiation treatment was 0.071/cell. The fraction of irradiated lymphocytes that reached metaphase at 52 h was 0.08 as evaluated by mixing cultures of in vitro irradiated and unirradiated blood. The yield of dicentrics for blood from case B 30 min after 6 Gy partial-body (about 24%) irradiation was 0.655/cell, while the yield 24 h after irradiation was 0.605/cell. The fraction of irradiated cells was 0.29. Estimation of doses and irradiated fractions for the two cases using the method proposed by Dolphin and the Qdr method is discussed. Although there was no significant difference between the mean yields of dicentrics per cell obtained 30 min and 24 h after radiation treatment, the data obtained at 24 h seemed more useful for the purpose of dose estimation. When a higher dose (8 Gy) was delivered to a smaller percentage of the body, underestimation of the dose was encountered.

Allogeneic bone marrow transplantation for children with acute lymphoblastic leukemia in second remission or relapse.

Most children with acute lymphoblastic leukemia (ALL) are successfully treated by chemotherapy. For those patients, who relapse on therapy, bone marrow transplantation (BMT) is considered most appropriate after a subsequent remission is achieved. Three boys with ALL aged from 9 to 13 years met these criteria and received BMT from their HLA-compatible sisters after marrow ablation with total body irradiation 12 Gy plus high dose cytosine arabinoside 3 gm/m2/12h x 12 doses and graft-versus-host disease (GVHD) prophylaxis with cyclosporine plus short course methotrexate from March 10, 1989 to May 23, 1992. Filgrastim (rhG-CSF) was used to hasten the recovery of granulocyte in one patient. All three patients got full engraftment and two had grade 1 acute GVHD. None of them developed chronic GVHD. Two patients have disease-free survival over 51 and 12 months respectively post BMT without further chemotherapy. One patient died of recurrent refractory leukemia 5 months after BMT. The toxicity of this conditioning regimen included photophobia, conjunctivitis and erythematous skin rashes. One patient who received filgrastim from day 1 to 21 developed severe bone pain. However, this patient had faster recovery of granulocyte count than the other two patients. The preliminary results of this work favors BMT for children with recurrent ALL whose ultimate survival is usually poor when treated with chemotherapy. Further efforts are necessary to investigate new methods for reducing leukemic relapse in ALL patients undergoing BMT.

Cell kinetics and radiosensitivity of cervical squamous cell carcinoma.

Flow cytometry analyses of tumors from 12 patients with cervical squamous cell carcinoma under radiotherapy were performed in this preliminary study. Six patients with a high (> 10%) G2/M fraction before treatment showed greater than 50% tumor reduction after initial 2000 cGy radiotherapy. Only two out of six patients with a low (< 10%) G2/M fraction before treatment responded favorably and three of them already had recurrence during the follow-up period of 33-40 months. Hyperploidy (DNA index > 1.1) was observed in 5 patients; all of them responded well to radiotherapy in contrast to three out of seven diploid tumors.

Bone marrow transplantation for severe aplastic anemia.

Fifteen patients (nine male, six female) with severe aplastic anemia (SAA) undergoing HLA-identical allogeneic bone marrow transplantation (BMT) received preparative regimens consisting of cyclophosphamide and total lymphoid irradiation. Patients were aged from eight to 26 years (median 15 years). Prophylaxis of graft versus host disease (GVHD) including cyclosporine and short course methotrexate was administered. One early death occurred at day 8 post BMT. Among the other 14 patients, one died of sepsis at day 53 with no evidence of engraftment, 13 were engrafted despite the number of donors exposed in transfusions of previous blood components. Eleven patients have survived from six to 100 months (median, 54 months), post BMT. The remaining two patients died of acute GVHD-related infections on days 44 and 63. Acute GVHD occurred among eight of 13 engrafted patients, five of whom were grades II-IV clinically. Chronic GVHD developed among five patients, three of whom were clinically progressive and extensive. Two of three patients with extensive chronic GVHD had received transfusion of donor's buffy coat after BMT. Our data indicate an engraftment rate of 87% (13/15). The projected probability of disease-free survival was 73% (11/15) at 9.3 years after BMT according to the Kaplan-Meier model. Further efforts must be made to eliminate GVHD and to control fatal infections.

Bizarre parosteal osteochondromatous proliferation of the phalanx: report of a case.

The bizarre parosteal osteochondromatous proliferation of the hand and foot is a benign lesion which occasionally may mimic osteochondromas, chondrosarcomas or osteosarcomas clinically, radiologically and histopathologically. This rare benign entity should be recognized in order to avoid unwarranted destructive therapy. The authors report a case of this disease and discuss the differential diagnosis and the relevant features of this disease entity. A 27-year-old female patient suffered from a painful swelling at the proximal middle phalanx of the right middle finger for five months. The lesion was excised but the residual lesion developed a distinct parosteal growth by radiologic studies one-and-a-half years later. The patient underwent reexcision of the lesion twice. No recurrence was noted 11 months following the last excision. Histopathologically, the first specimen contained bizarre chondrocytes. The recurrent nodular tumors, submitted in the second and third operations, were composed of cancellous bone with fatty marrow and a few marrow elements, and focally capped by cartilage. The adjacent soft tissue contained proliferating fibrous tissue. The osteochondral junctions in the latter two specimens were irregular. We believe that the documentation of this tumor at different stages of development has helped in the further understanding of this rare entity.

Effect of cranial irradiation on hypothalamus-pituitary function: follow-up study one year after radiotherapy.

Hypothalamic pituitary functions were studied in 24 patients before, 6 months after and 1 year after cranial irradiation with or without radiosensitizing chemotherapy for nasopharyngeal carcinoma (NPC). The estimated average total dose was 5,000 cGy to the hypothalamus and pituitary gland. The radiosensitizing chemotherapy used was endoxan, 4,900 +/- 873 mg (mean +/- SD) and/or methotrexate, 113 +/- 30 mg. All patients had normal pituitary function before radiotherapy. There was a progressive increase in baseline serum thyrotropin (TSH) after radiotherapy. The basal serum follicle stimulating hormone (FSH) was significantly increased 6 months after radiotherapy and remained so at 1 year after radiotherapy. The TSH response to thyrotropin-releasing hormone (TRH) also progressively increased after radiotherapy, suggesting primary hypothyroidism due to neck irradiation. The peak serum TSH response to TRH became delayed after radiotherapy, suggesting a defect in TRH release. In male patients who did not receive chemotherapy, the LH response to luteinizing hormone-releasing hormone (LHRH) decreased after radiotherapy. After an initial rise in the FSH response to LHRH 6 months after radiotherapy, there was a reduction in the FSH response at 1 year. This suggests a defect in LHRH pulsatile release. However, in male patients who received radiosensitizing chemotherapy, both the FSH and LH responses to LHRH had declined at 1 year after radiotherapy, as compared with their responses at 6 months. However, these were still higher than those obtained before radiotherapy. This suggests further GnRH neuron damage, which was previously masked by chemotherapy-induced primary hypogonadism. The adrenocorticotropic hormone (ACTH) response to ovine corticotropin-releasing hormone (CRH) had not changed further at 1 year after radiotherapy.(ABSTRACT TRUNCATED AT 250 WORDS)