Thymocyte resistance to glucocorticoids leads to antigen-specific unresponsiveness due to "holes" in the T cell repertoire.

We have proposed that glucocorticoids antagonize TCR-mediated activation and influence which TCR avidities result in positive or negative selection. We now analyze the immune response of mice whose thymocytes express antisense transcripts to the glucocorticoid receptor (TKO mice). TKO mice responded normally to the complex antigen PPD but were proliferative nonresponders to pigeon cytochrome c 81-104 (PCC), having a large decrease in the frequency of PCC-responsive CD4+ T cells. Unlike wild-type T cells, few TKO T cells in PCC-specific cell lines expressed V alpha11+Vbeta3+. Furthermore, for naive CD4+ T cells from unimmunized TKO mice, the frequencies of many of the molecular features common to the CDR3 regions of PCC-responsive V alpha11+Vbeta3+ cells were substantially decreased. Thus, thymocyte glucocorticoid hyporesponsiveness resulted in loss of cells capable of responding to PCC, corresponding to an antigen-specific "hole" in the T cell repertoire.

Pion conformal radiation of prostate cancer: results of a randomized study.

PURPOSE: To compare the efficacy of pion radiation therapy with conventional external beam photon therapy, for the treatment of locally advanced stage T3/4, N0, M0 adenocarcinoma of the prostate. METHODS AND MATERIALS: Two hundred seventeen eligible patients were randomly allocated to either photon or pion therapy. No adjuvant hormone therapy was used. RESULTS: Median follow-up was 42 months (range 2-90). Acute bladder toxicity was worse in the pion arm, p = 0.2, but other acute toxicity did not differ. Late grade 2 toxicity was significantly less in the pion arm (29% at 5 years versus 48%, p = 0.002), but late grade 3 or 4 toxicity did not differ. Clinical local control was not significantly different between treatment arms (64% after 5 years with photons, 56% with pions, p = 0.6). Cause-specific and overall survival also did not differ (p = 0.7). There was a significant delay in time to first failure in the photon arm, largely as a result of decreased biochemical relapse, p = 0.01. A multivariate analysis is presented. CONCLUSION: Pion therapy was well tolerated, with increased acute toxicity and significantly decreased late tissue injury. This contrasts with the late toxicity observed with higher LET particle therapy such as neutron therapy. No improvement in local control with pion therapy was observed.

Pion radiation for high grade astrocytoma: results of a randomized study.

PURPOSE: This study attempted to compare within a randomized study the outcome of pion radiation therapy vs. conventional photon irradiation for the treatment of high-grade astrocytomas. METHODS AND MATERIALS: Eighty-four patients were randomized to pion therapy (33-34.5 Gy pi), or conventional photon irradiation (60 Gy). Entry criteria included astrocytoma (modified Kernohan high Grade 3 or Grade 4), age 18-70, Karnofsky performance status (KPS) > or = 50, ability to start irradiation within 30 days of surgery, unifocal tumor, and treatment volume < 850 cc. The high-dose volume in both arms was computed tomography enhancement plus a 2-cm margin. The study was designed with the power to detect a twofold difference between arms. RESULTS: Eighty-one eligible patients were equally balanced for all known prognostic variables. Pion patients started radiation 7 days earlier on average than photon patients, but other treatment-related variables did not differ. There were no significant differences for either early or late radiation toxicity between treatment arms. Actuarial survival analysis shows no differences in terms of time to local recurrence or overall survival where median survival was 10 months in both arms (p = 0.22). The physician-assessed KPS and patient-assessed quality of life (QOL) measurements were generally maintained within 10 percentage points until shortly before tumor recurrence. There was no apparent difference in the serial KPS or QOL scores between treatment arms. CONCLUSION: In contrast to high linear energy transfer (LET) therapy for central nervous system tumors, such as neutron or neon therapy, the safety of pion therapy, which is of intermediate LET, has been reaffirmed. However, this study has demonstrated no therapeutic gain for pion therapy of glioblastoma.

Immune reaction induced by X-rays and pions and its stimulation by schizophyllan (SPG).

Female C57BL/6 mice aged 6-8 weeks with transplanted Lewis lung cancer cells were used to investigate the anti-tumour effects and immune reactions in tumour tissue induced by X-ray and pion irradiation and their modification by schizophyllan (SPG). The effect of SPG on the rate of lung metastasis and the survival time of the mice was also studied using the same tumour system. These studies showed that in this tumour system the "practical' relative biological effectiveness (RBE) of pions was 1.33 in the dose ranges used (3 Gy x 4 = P3; 6 Gy x 4 = P6). SPG increased the suppression of tumour growth associated with moderate doses of radiation: X-rays (4 Gy x 4 = X4) or P3. SPG also decreased the number of lung metastases and prolonged the life span of the mice, these effects being independent of radiation. The addition of SPG to radiation increased both the macrophage infiltration and T-lymphocyte infiltration in the local tumour and the lung nodules. There did not appear to be any major differential effect of SPG on the pion-treated mice compared with those treated with X-rays.

Cardiac tamponade caused by central venous catheter perforation of the heart: a preventable complication.

BACKGROUND: Pericardial tamponade caused by central venous catheter perforation of the heart is a catastrophic complication that can be prevented by attention to proper positioning of the catheter tip proximal to the cardiac silhouette. This study was performed to determine awareness of this potential complication among physicians and to suggest measures to minimize the incidence of this problem. STUDY DESIGN: Clinical and radiologic features of 11 cases were evaluated. House officers and attending staff who frequently pass central venous catheters and train junior physicians to place these catheters were questioned specifically to test their awareness of this complication and their knowledge of optimal catheter tip positioning. Attending radiology staff physicians were questioned similarly. The written protocols of local community hospitals with respect to central venous catheter placement were reviewed to determine their criteria for optimal catheter placement. RESULTS: Ten of the 11 cases reviewed resulted in death; the 11th case resulted in severe anoxic brain insult with a persistent vegetative state. In the ten cases that had radiologic studies available for review, the central venous catheter tip was seen to lie malpositioned within the cardiac silhouette. Questioning of house officers and attending staff as well as attending radiology staff revealed a lack of awareness of this problem generally and a lack of knowledge of optimal catheter tip positioning specifically. The protocols of area hospitals revealed similar findings with respect to this potential complication. CONCLUSIONS: Pericardial tamponade resulting from central venous catheter perforation of the heart can be avoided by adherence to proper technique in the placement of these catheters, ensuring that the catheter tip lies proximal to the cardiac silhouette, optimally in the superior vena cava, 2 cm proximal to the pericardial reflection. Physicians who place these catheters and train others to do so must be aware of this issue and they must educate their trainees as well. Radiologists responsible for interpreting the roentgenographs of the chest obtained after catheter placement should be alert to catheter malposition and communicate this information promptly. Hospital protocols should deal with this issue explicitly and insist on repositioning of catheters if catheter tips are seen to lodge in suboptimal positions.

The treatment of adult supratentorial high grade astrocytomas.

From 1 January, 1982 until 31 December, 1987 260 adult patients were referred to the Cancer Control Agency of B.C. with high grade supratentorial astrocytomas. Multifocal disease on presentation was present in 17 cases (6.5%). Their survival is poor and whole brain radiotherapy is required. All other cases had unifocal disease, but eight did not receive radiotherapy. The 235 cases who received radiotherapy were subject to univariate and multivariate analyses according to extent of surgery, age, Kernohan and WHO grading, Karnofsky performance status, whole brain treatment, partial brain treatment, total dose and neuroret. Age is an extremely important predictor of survival (P approximately equal to 0). The pathologic appearance of glioblastoma (WHO grade) as well as the Karnofsky performance status were also important independent factors in predicting survival (P = 0.016, 0.027 respectively) on Cox multivariate analysis. Dose and neurorets were significant factors only in cases where the performance status was not recorded, suggesting that dose was selected according to the patient's condition and age. In this analysis it was found that localized radiation fields may be used rather than whole brain without jeopardizing survival.

Acute silicosis responding to corticosteroid therapy.

The course of acute silicosis usually is relentlessly progressive. Death results from cor pulmonale and respiratory failure, with mycobacterial infection a frequent serious complication. Attempts to treat the illness generally have been unavailing. We report an unusual case of acute silicosis in which improvement in clinical status, chest x-ray film findings and pulmonary function occurred following therapy with corticosteroids. To our knowledge, this is the first such case reported in the medical literature.

The response of murine B-16 melanoma to fractionated doses of pions.

The relative biological effectiveness (RBE) of pions has been studied in mouse B-16 melanoma transplanted into C57BL/6 mice. To determine the RBE at both high and low doses per fraction, a range of fractionation schedules was used, with 1, 4 and 10 fractions. The reference 250 kV X ray dose rate was 1.5 Gy/min which was much higher than the dose rate of pions (0.25 Gy/min). The RBE varied depending on the number of fractions and, within the same fractionation schedule, also on the dose per fraction. The RBE ranged from 1.15 for single fractions at 12.5 days of growth delay, to 1.80 for 10 fractions at 5 days of growth delay, which was determined by the time taken for the tumors to reach 5 times the average of their original volume. RBEs at the iso-effect level of 10 days growth delay were 1.20, 1.29 and 1.62 for single, 4 fractions and 10 fractions, respectively. RBE values were influenced by both the number of fractions and the dose per fraction, that is, the larger the number of fractions and the smaller the dose per fraction, the larger the value of RBE. In comparison with RBE of normal mouse skin, it was suggested that pion therapy may provide advantage over conventional photontherapy for radioresistant tumors such as this melanoma with the maximum therapeutic gain factor of 1.2. alpha/beta ratios for B-16 melanoma were also obtained from the 10 day growth delay iso-effect curve, and were 10.5 Gy and 32.6 Gy for X ray and pions, respectively.

Pions--the potential for therapeutic gain in locally advanced prostate cancer: dose escalation and toxicity studies.

Since 1982, 49 patients with locally advanced carcinoma of the prostate have been treated with pion radiotherapy in tolerance and tumor response studies. The relative biological effectiveness (RBE) was confirmed as 1.5 for both acute and late effects, a figure expected on the basis of animal and human studies. The radiation dose has been safely escalated to tolerance, which is estimated to be 37.5 Gy pi in 15 fractions (volume less than 500 cc), and 36 Gy pi in 15 fractions (volume 500-800 cc). Severe acute toxicity occurred in 6% and severe chronic toxicity in 4%, figures comparable to those seen with conventional radiotherapy. The equivalent photon doses are approximately 78 Gy in 39 fractions and 73 Gy in 36 fractions, respectively. That this high dose can be delivered with no increase in toxicity is a reflection of smaller volume radiotherapy achieved by exploiting the dose distribution and biological characteristics of pions. Local response rates of 94% are reported. A Phase III study is now under way.

The response of mouse tumours to fractionated doses of pions: determination of therapeutic gain factor.

Using the same experimental system which had been used to determine the pion relative biological effectiveness (RBE) for skin of mouse foot by Chaplin et al., we have determined the pion RBE for KHT sarcoma and SCCVII tumour transplanted in the foot of C3H mice. The pion RBE obtained by the tumour growth delay time method in comparison with 250 kVp X-rays at a dose rate of 150 cGy per min was determined to be 1.20, 1.28 and 1.50 with single, 4 and 10 fractions, respectively, for KHT sarcoma. As for SCCVII tumour, it was determined to be 1.17, 1.45 and 2.05 with single, 4 and 10 fractions respectively. Therefore, it has been concluded that pions have various values of RBE depending on the tumour system involved. KHT sarcoma is a tumour which grows very rapidly, on the contrary, SCCVII tumour shows somewhat slower growth characteristics. These differences of RBE between these two tumour systems possibly stem from differences in the amount of hypoxic cells and/or their rates of reoxygenation. As for therapeutic gain factor, a maximum value of 1.45 was obtained with 10 fractions using the SCCVII tumour. Pions seem to be most effective (in multiple fractions) against tumours of relatively slow growth.

Combination therapy of pions and SPG (Sonifilan, Schizophyllan), a biological response modifier for mouse tumor systems.

Female C3H mice aged 8-10 weeks with transplanted KHT sarcoma or SCCVII tumor were used to investigate the antitumor effect of SPG (Sonifilan, Schizophyllan) alone and in combination with local irradiation of pions with 4 fractions of 400 cGy (total 1600 cGy). Daily doses of 10 mg/kg of SPG were given intramuscularly to the mice bearing KHT sarcoma for 14 consecutive days from day 7, and to mice bearing SCCVII tumor for 20 consecutive days from day 7 and thereafter three times a week for another 2 weeks. The antitumor effect was evaluated by the changes in tumor volume, survival curves, and the number of pulmonary metastatic nodules on the surface of the lungs. SPG failed to exert any antitumor effect and any life-prolonging effect for the KHT sarcoma. As for SCCVII tumor, in the group treated with pions and SPG, tumor growth decreased significantly (p less than 0.01) compared with the group treated with pion only, and life prolonging effect and metastasis-suppressing effect were also observed (p less than 0.04). In conditions of minimal residual disease brought about by pion irradiation, the adjuvant effect of a Biological Response Modifier (BRM) SPG may prove to be a promising method of cancer therapy for some tumors.

Pion therapy at TRIUMF. Treatment results for astrocytoma grades 3 and 4: a pilot study.

At TRIUMF, (located on the University of B.C. Campus), 53 patients with supratentorial astrocytoma grades 3 and 4 were treated with pions between 1982 and 1985. A 3-dimensional spot-scanning treatment technique has proven to be practical. The accuracy of the beam alignment system used for treatment was reproducible daily within 2 mm. Low pion flux has hindered optimal beam shaping but this will soon be remedied as flux improves. The overall median survival observed (53 patients) is 262 days from date of first radiation treatment. Younger (less than 49 years) patients have significantly better survival than older (greater than 50 years) patients (p = 0.001). From a base line dose of 40 Gy photons whole brain and 17.5 Gy pion boost, doses were escalated to 33 Gy pions localised to the primary tumour and the median survival improved from 198 to 436 days. Survival curves for patients treated with localised pion techniques to doses above 30 Gy are significantly better than for those treated with schedules of pions mixed with photons (p = 0.04). It appears that optimal pion dose for brain tumours is 33 Gy minimum with a possible maximum of 36 Gy and doses delivered in 15 fractions in 3 weeks. Requirements for future trials are discussed.

Detection of pion-induced radioactivity by autoradiography and positron emission tomography.

An autoradiographic technique incorporating a new imaging system was used to detect pion-induced radioactivity in Plexiglass and the results were compared with aluminium activation and PET imaging. The activity distribution in the region of the pion-stopping peak was similar in all three cases. Another large signal in the entrance region due to in-flight interactions [12C(pi-, pi- n) 11C] was detected by autoradiography and by PET but was not reflected in the aluminium activation measurements. This new technique is capable of defining the stopping region in phantoms with a better resolution than PET scanning and is useful as a complementary technique to other methods of pion dosimetry.

Superfractionated radiotherapy in grade III, IV intracranial gliomas.

Preliminary results of superfractionation in the treatment of glioblastoma led to a randomized trial consisting of 76 patients. All patients received whole brain irradiation followed by a 1000 cGy boost to the primary site. Thirty-four patients received standard daily treatment to 4000 cGy, whereas 42 patients received superfractionated radiation, treating three times a day to a total dose of 4760 cGy. No significant difference was found between the 5-year survival of the superfractionated group and the standard treatment group. Early reactions were greater for superfractionation whereas late effects were less.

The use of positron emission tomography in pion radiotherapy.

The radioactive debris produced by pion radiotherapy can be imaged by the technique of Positron Emission Tomography (PET) as a method of non-invasive in situ verification of the pion treatment. This paper presents the first visualization of the pion stopping distribution within a tumor in a human brain using PET. Together with the tissue functional information provided by the standard PET scans using radiopharmaceuticals, the combination of pion with PET technique can provide a much better form of radiotherapy than the use of conventional radiation in both treatment planning and verification.

Preparatory clinical studies of Pi-mesons at TRIUMF.

Eighty patients have been treated with Pi-mesons (pions) at TRIUMF between 1979-1984. The patients had tumors rarely curable by standard methods and had no prior radiotherapy. The distribution by site included skin, metastatic nodules (13), brain, glioblastoma multiforme (32), pelvis, rectosigmoid (15), prostate (12), bladder (7), and ovary (1). The studies involve serial escalations of pion dose until maximum tissue tolerance is reached, monitoring the response at each dose increment. Sites were chosen for study where lack of local control is a significant cause of treatment failure with conventional radiation therapy. The low dose rate and the available beam access at TRIUMF limit the number of patients treated and the volume treatable. A 3-D treatment planning program is in use, and a 3-D display of the dose distribution delivered in brain tumor treatments has been developed using the PET scanner. In practice, new methods introduced for measurement of tissue response include tumor growth delay curves, fine-needle biopsy mapping, and PET scanning of brain tumors. The use of endoscopic assessment of the rectosigmoid region is emphasized. Treatment results of glioblastoma multiforme show that the median survival for patients treated to 125 pion cGy/fx is in the range of 187-198 days; for patients receiving 170 cGy per dose/fraction (fx) the range is 290-315 days, and for those receiving 200-220 cGy/fx the median survival is in excess of 290 days. For pelvic malignancies the local control obtained with doses of 2500 cGy or less was 50% in 12 assessable patients; it was 75% in 20 patients who had 3000 cGy or more.(ABSTRACT TRUNCATED AT 250 WORDS)

Pions, Vancouver.

Clinical treatments at TRIUMF started in November, 1979. Ten patients with malignant subcutaneous nodules had 14 lesions treated with pions and 37 other nodules treated with 280 kV X rays. Three different fractionation regimens were used with X ray doses spanning the expected RBE range of pions. The RBE for pions for acute skin reaction for 10 fractions had a mean value about 1.5, while for 3 fractions it was 1.3 maximum. No dissociation of acute and late skin effects was seen with follow-up to 27 months after treatment. Phase 1-2 studies of Pion-Boost Therapy for patients with glioblastoma multiforme will begin in May, 1982. These will be followed in August with treatments of advanced pelvic malignancies using pions only. The existing beam line at TRIUMF will be upgraded and commitments have been given to go to higher beam currents. As a result, the dose rate should increase by a factor of at least two, allowing treatment of clinically relevant volumes in acceptable times by 1983-1984.

Conservation of bladder function in patients with invasive bladder cancer treated by definitive irradiation and selective cystectomy.

Four hundred seventy patients with invasive bladder cancer treated by definitive irradiation (5000 rad or more) and selective systectomy were followed to assess their survival status and bladder function status. (90% were followed for at least 10 years or to death.) The survival rates for these patients were similar to those obtained in studies of preoperative irradiation with compulsory systectomy: 5 and 10 year survival rates were 38 and 22% respectively. Sixty-five to 70% of these survivors lived with healthy, functioning bladders to at least 10 years after treatment. Seventy-five had a selective cystectomy, usually for recurrent desease, with an operative mortality rate of 11%. Pre-irradiation catheterization, used to control bladder distension and to reduce the possibility of geopraphic miss in irradiating the tumour, had no effect on the control of local disease or on the long-term survival of patients. Therefore, definitive irradiation with selective cystectomy warrants serious consideration in treating patients with invasive bladder cancer, especially considering the quality of life and the high proportion of patients who retain functioning bladders.