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Objective: Improved pathophysiologic insight and prognostic information regarding in-hospital risk of mortality among stroke patients admitted to an intensive care unit., Design: Retrospective analysis., Setting: Neurology/neurosurgery intensive care unit in a tertiary care university medical center., Patients: A total of 63 consecutive ischemic stroke patients., Interventions: Patients were classified according to in-hospital mortality. Charts were reviewed to retrospectively generate an admitting Acute Physiology and Chronic Health Evaluation (APACHE) II score. The APACHE II score and its individual components were assessed for predicting subsequent death., Measurements and Main Results: Of 63 patients, 13 died and 50 survived to either discharge or surgical intervention. The mean admitting APACHE II score of survivors (6.9) was lower than that of patients who died (17.2; p < .0001). None of the 33 patients with a score <9 died, compared with 43% of those with a score > or =9. A score > or =18 was uniformly associated with fatal outcome (n = 8). Univariate analysis identified APACHE II total score, Glasgow Coma Scale score, temperature, pH, and white blood cell count as significant predictors of death. Among multivariate logistic regression models examining the components of the APACHE II score, the model containing white blood cells, temperature, and creatinine best predicted death., Conclusions: Several features of the APACHE II score are associated with risk of death in this patient population. The findings suggest particular physiologic derangements that are associated with, and may contribute to, increased mortality in critically ill patients with acute ischemic stroke.

Background: Treatment of giant-cell tumor of bone generally involves wide en bloc resection of the lesion and the surrounding bone or curettage with or without bone-grafting or the use of cement. Radiation therapy has been used for patients who cannot be operated on for medical reasons or who have a tumor that is technically difficult to resect or that cannot be resected because of its location. We performed the present study to evaluate the efficacy of megavoltage radiation in terms of lack of tumor progression and treatment-related morbidity., Methods: Twenty patients who had giant-cell tumor of bone were managed with a single course of megavoltage radiation (forty to seventy gray administered at 1.8 to 2.0 gray per fraction with an average total duration of treatment of five to seven weeks) between March 1973 and March 1992. We used megavoltage photons, 160-megaelectron-volt proton beams, or a combination of the two., Results: After a median duration of follow-up of 9.3 years, the tumor had not progressed in seventeen of the twenty patients. Thus, the actuarial ten-year rate for lack of progression was 85 percent. Local regrowth was evident in one patient who had received radiation alone and in two of the thirteen patients who had been managed with partial resection and radiation. Operative treatment was successful in the three patients in whom the radiation treatment had failed. No radiation-induced tumors were observed in our series., Conclusions: We concluded that giant-cell tumor of bone was effectively treated with megavoltage radiation in our series of twenty patients in whom operative resection would have been difficult or was not feasible. The rate of tumors that did not progress with this regimen of radiation is similar to that reported by investigators from several other centers. Furthermore, these results closely rival those obtained with modern curettage procedures. Malignant sarcomatous transformation was not observed in our series. A longer duration of follow-up of a larger group of patients is necessary to provide a better estimate of the risk of malignant transformation.

Mitotic index > 6, proliferating cell nuclear antigen (PCNA) index > 5%, high tumour grade and absence of progesterone receptors (PR) are significant predictors for poor outcome in meningiomas. Since MIB-1 (Ki-67) is a more specific cell proliferation marker, and overexpression of TGF-alpha is also associated with tumour progression, we compared the prognostic significance of these factors with the other indices. Intracranial meningiomas from 21 men and 36 women (age 54.5 +/- 1.7, mean +/- SEM) were classified as 24 benign, 24 atypical and nine malignant. Twenty-one of the 57 tumours recurred (mean interval to recurrence was 57.3 +/- 13.1 months). The mean follow-up period for patients without tumour recurrence was 81.9 +/- 8.7 months. MIB-1 labelling index (LI) was expressed as percentage of labelled nuclei to total tumour nuclei counted in the most densely labelled areas. Analysis of variance revealed significant differences between tumour grades for MIB-1 labelling indices (0.75 +/- 0.21 for benign, 3.2 +/- 0.57 for atypical 6.04 +/- 1.48 for malignant; P < or = 0.0066), and between malignant and non-malignant meningiomas for TGF alpha staining scores (P < or = 0.029). MIB-1 LI also correlated with mitotic and PCNA indices (P < or = 0.0001), but not with age of the patients. Male patients had higher tumour MIB-1 LI than females (P < or = 0.0128). Univariate analysis indicated that MIB-1 LI > 3%, TGF alpha score > 4 (scoring scale 0-5), mitotic index > 6, and negative PR status were significant factors for worse outcome. Higher MIB-1 LI, TGF alpha score and mitotic index as continuous variables were also significant negative predictors. With multivariate analysis, both MIB-1 LI and TGF alpha score remained significant factors when paired with all other variables: TGF alpha or MIB-1 LI, respectively, mitosis, PCNA, tumour grade, PR status, age, sex, postoperative radiation therapy. We conclude that MIB-1 LI and TGF alpha score are important independent prognostic indicators for patients with meningiomas.

The grading of glial tumors has traditionally relied on histological assessment, but the distinction between grade II and grade III gliomas is still a subject of debate. We examined the value of the monoclonal antibody MIB-1 (Ki-67) labeling index (LI) in the differentiation between grade II and grade III gliomas by either the 1993 WHO grading scheme or the St. Anne-Mayo grading scale. The MIB-1 Li in the most densely labeled areas from 80 diffuse cerebral hemispheric gliomas was determined. The tumors included 16 grade II, 31 grade III and 33 grade IV gliomas by the WHO scale. The mean LIs (%) were 0.88 +/- 0.29 for grade II, 8.75 +/- 1.71 for grade III, and 9.12 +/- 1.55 for grade IV gliomas. Analysis of variance indicated a significant difference in mean LIs between grades II and III and grades II and IV (p < or = 0.0001), but not between grades III and IV. Seven tumors were classified differently by the 2 systems (grade III by WHO, but grade 2 by St. Anne-Mayo), and all had MIB-1 LI over 3%. Univariate analysis showed that MIB-1 LI with a cut-off point at 1.5% was a significant prognostic factor (p < or = 0.0005). High tumor grade (WHO, p < or = 0.0002; St. Anne-Mayo, p < or = 0.0006) and patient age > 50 (p < or = 0.0001) were also significant factors for shorter survival. Using Cox Regression Multivariate Analysis, MIB-1 LI > 1.5% was a significant independent predictor of shorter disease survival when paired with tumor grade (p < or = 0.032), patient age (p < or = 0.0065), or gender (p < or = 0.0007). We conclude that the MIB-1 immunoreactivity is useful in distinguishing grade II from grade III gliomas, and maybe more sensitive in assigning aggressive gliomas to grade III than the St. Anne-Mayo grading system.

Purpose: To analyse the experience treating soft tissue sarcomas of the head and neck at the Massachusetts General Hospital, Boston. Detailed results have been published previously [17]., Patients and Method: Between 1972 and 1993, 57 patients were treated curatively with radiation alone (n = 13) or combined surgery and pre- and/or postoperative irradiation (n = 44). Gross complete resection was achieved in 82% of patients and margins were negative in 5 patients. Doses ranged from 36.0 to 79.2 Gy (median 64.8 Gy), usually conventionally fractionated. In 16 patients protons were used. Median follow-up time was 4.3 years (range 1.1 to 16.8 years)., Results: After 5 years, patients with angiosarcomas (n = 11) and patients with other tumor types (n = 46) had locoregional control rates of 24% and 69%, distant failure rates of 58% and 17%, and overall survival rates of (for overall survival) and T stage (for locoregional control) (p < 0.05). Particularly, gross completely resected T1 tumors had a locoregional control rate of 91%. Patients with locoregional recurrence were at an increased risk to die (p = 0.004 in multivariate analysis). Patients with and without direct tumor extension to neurovascular structures, bones, organs, or skin had distant failure rates of 27% and 0%, respectively (p = 0.031). In multivariate analysis, direct extension was additionally a negative prognosticator of overall survival (p = 0.034)., Conclusion: 1. Angiosarcomas of the head and neck have a considerably poorer prognosis than other soft tissue sarcomas of this region. 2. Head and neck sarcomas have a higher local recurrence rate than for example soft tissue sarcomas of the extremities. Optimisation of local treatment through combination of surgery and high-dose irradiation, however, can achieve improved results, especially for prognostically favourable subgroups. 3. In addition to tumor grade and size, direct tumor extension may be a useful additional staging parameter.

Meningiomas often contain steroid hormone receptors, but the correlation of receptor presence with patient outcome or mitotic index is unclear. Intracranial meningiomas from 70 patients (27 males and 43 females, mean age 52.9 + 1.7 years [mean +/- standard error of the mean], range 15-78 years) were evaluated immunocytochemically for female sex hormone receptors using specific monoclonal antibodies. Prognostic correlations were determined using statistical analyses that included clinical and histological variables. Twenty-eight tumors were benign, 27 had atypical features, and 15 were malignant. Thirty tumors were meningotheliomatous, 11 were fibroblastic, 28 were transitional, and one was secretory. Twenty-nine of the 70 primary tumors recurred (mean interval to recurrence 50.1 +/- 10 months). The mean progression-free follow-up period for patients without recurrence was 82.1 +/- 7.7 months. Nuclear staining for the progesterone receptor (PR) was found in 58 cases (83%) and PR status was scored as 0 (0% nuclei positive), 1 (< 1%), 2 (1-9%), 3 (10-49%), or 4 (> 50%). Only six tumors (8.6%) contained nuclear estrogen receptor (ER) staining, which was limited to a small number of nuclei (< 1%). Fisher's exact test (two-tailed) showed an inverse correlation between tumor grade and PR staining score (p < or = 0.001), with 96% of benign and 40% of malignant meningiomas containing PR-positive nuclei. No correlation between age or histological subtype and PR score was detected. Meningiomas from female patients had more PRs (p < or = 0.05). Analysis of variance revealed that the mitotic index (total counts of mitoses per 10 high-power fields) for tumors with 0 PR staining (18 +/- 4.4) was higher (p < or = 0.0001) than for those with PR scores of 1 to 4 (4.3 +/- 1.9, 5.1 +/- 2, 2.2 +/- 0.8, and 1.7 +/- 0.9, respectively). Univariate analysis indicated that the absence of PR, high mitotic index, and higher tumor grade were significant factors for shorter disease-free intervals. Multivariate analysis showed that a three-factor interaction model, with a PR score of 0, mitotic index greater than 6, and malignant tumor grade, was a highly significant predictor (p < or = 0.0001) for worse outcome in patients harboring meningiomas. These data indicate that the presence of PRs, even in a small number of tumor cells, is a favorable prognostic factor for meningiomas.

We performed an immunohistochemical cell kinetic study with monoclonal antibodies to proliferating cell nuclear antigen (PCNA)-PC10-and Ki-67-MIB-1-on 62 thymic epithelial tumors, to evaluate whether there is correlation between the proliferation indices of the neoplastic epithelial cells and histological subtype, stage, and risk of relapse. The 62 cases of thymic epithelial tumors were classified as medullary thymoma (4 cases), composite (mixed) thymoma (17 cases), organoid thymoma (predominantly cortical) (11 cases), cortical thymoma (10 cases), well-differentiated thymic carcinoma (18 cases), and poorly differentiated thymic carcinoma (2 cases). Labeling indices were expressed as percentage of epithelial cells with positive nuclear immunostaining by random counting of 1,000 epithelial tumor cells, using an oil immersion 100 x objective. PCNA labeling indices were consistently higher than those of Ki-67, and they correlated with each other. Well-differentiated thymic carcinoma showed higher labeling indices (3.11% +/- 3.53%) by Ki-67 antibody compared with the medullary type (0.60% +/- 0.07%) (P < .05) but there were no statistically significant differences between the other histological subtypes. Stage IV cases showed higher PCNA labeling indices (PCNA: 11.07% +/- 7.35%, Ki-67: 6.86% +/- 5.87%) than cases of the other stages (P < .05), but there were no statistically significant differences in either labeling index between the other stages. The number of patients who relapsed was too small to permit meaningful correlation between labeling indices and relapse. Our results indicate that the differences in biological behavior of the different histological subtypes of thymic epithelial tumors may be in part explained by differences in tumor growth fraction. Analysis of a larger group of patients will be required to determine whether proliferation fraction as determined by this method can be used to predict outcome in individual cases.

p16 is involved in a cell cycle regulatory cascade that includes cyclin-dependent kinase 4 (cdk4), cyclin D1, and pRb (retinoblastoma). Alterations of each of these components have been described in primary human glioblastoma multiforme (GBM) or in GBM cell lines. Because perturbation of any component in this pathway may have similar oncogenic effects, we studied the relationship between abnormalities of CDKN2/p16 and RB, the two commonly involved tumor suppressor genes, in 55 astrocytic gliomas (42 GBMs, 8 anaplastic astrocytomas, and 5 astrocytomas). By using comparative multiplex PCR, homozygous deletions of the CDKN2/p16 gene were detected in 24 GBMs (57%) and in 2 anaplastic astrocytomas. Two additional GBMs and one anaplastic astrocytoma had allelic loss of chromosome 9p, as assessed by microsatellite polymorphisms flanking the CDKN2/p16 region. Single-strand conformation polymorphism and DNA sequencing analysis of all three coding exons of CDKN2/p16 revealed a frameshift mutation (four-bp deletion) in one of the three GBMs that had lost the remaining 9p allele. Allelic loss of chromosome 13q at the RB gene, RB gene mutations, or loss of pRb expression was noted in 14 GBMs (33%) and 2 anaplastic astrocytomas. Thirty-six of 42 GBMs (86%) had alterations of either CDKN2/p16 (n = 22), RB (n = 10), or both (n = 4); these two genetic changes, however, were relatively exclusive (P = 0.003). Furthermore, of the six GBMs without either CDKN2/p16 or RB gene abnormalities, one case had CDK4 gene amplification. These data indicate that the vast majority of GBMs probably have inactivation of the p16-cdk4/cyclin D1-pRb pathway. The findings also provide corroborative evidence that CDKN2/p16 and RB are the critical glioma tumor suppressor genes on chromosomes 9p and 13q, respectively.

Chronic lymphocytic leukemia is the most common human leukemia but infrequently causes neurologic symptoms. We have reviewed all previously reported cases of chronic lymphocytic leukemia in the CNS along with three new cases; one patient was diagnosed antemortem and treated with immediate improvement and 4-year survival. In addition, we reviewed all autopsy cases since 1972 and available lumbar puncture data on patients with chronic lymphocytic leukemia admitted to the Massachusetts General Hospital. Invasion of the CNS by chronic lymphocytic leukemia often leads to confusional state, meningitis with cranial nerve abnormalities, optic neuropathy, or cerebellar dysfunction. Lumbar puncture shows a lymphocytosis consisting of monoclonal B cells, but CSF cytology studies are of limited value in establishing the diagnosis. Long-term survival may be related to the stage of chronic lymphocytic leukemia at the time of CNS disease and may be associated with intrathecal chemotherapy. A mild, asymptomatic infiltration of the brain, frequently noted in late-stage chronic lymphocytic leukemia in autopsy series, may explain the CSF lymphocytosis in some patients with late-stage chronic lymphocytic leukemia.

Little is known of the molecular genetic mechanisms contributing to meningioma tumor progression. We evaluated a total of 26 clinical cases of meningioma: twenty three patients with meningioma treated at our institution between 1978 and 1990 and three asymptomatic cases found initially at autopsy. In addition, histologically normal meninges obtained at post-mortem examination from 5 cases were evaluated. There were 13 men and 10 women in the patient group with a median age of 48.7 years, treated by surgery and/or irradiation. Median follow-up was 46 months (range 16-152 months). Archival cases and age-matched normal meningeal tissue obtained at autopsy during the same time period were obtained for study. Patients with TGF alpha scores greater than 3.0 were more likely to fail treatment and had lower overall survival times than those with immunostaining scores of 1 or 2. Three autopsy cases where meningioma had been silent clinically had overall staining scores of 0.75, while 10 samples of normal meninges harvested from 5 cases at autopsy had staining scores of 0. Two patients each underwent 3 surgeries for recurrent tumor, serial specimens showed increased TGF alpha expression over time, though all material from these procedures was consistent with the diagnosis of histologically benign meningioma.

Urokinase-type plasminogen activator (u-PA) is a 54-kd enzyme shown to participate in tissue degradation under certain normal and pathological conditions, including cancer invasion and metastasis. Increased u-PA expression has been found in cancers of the breast, lung, colon, and prostate, and correlated with worse outcome in patients with lung and breast cancer. We examined the correlation between u-PA expression in gliomas and patient survival. Seventy-seven gliomas from 41 men and 36 women (ages 2 to 73) were immunostained for u-PA using monoclonal antibody 394 directed against human urokinase. The tumors included 32 grade 4, 16 grade 3, and 20 grade 2 astrocytomas (Daumas-Duport scale), and 9 pilocytic astrocytomas. Strong cytoplasmic staining was found in tumor cells of all grade 4, most of the grade 3, and a few of the lower grade tumors. Adjacent normal brain tissue showed faint staining associated with subpial cell processes and white matter fibers. The fiber staining was stronger in brain tissue infiltrated by tumor cells. Cytoplasmic u-PA staining in tumor cells was scored from 0 (no staining) to 6 (strong and widespread staining). The mean u-PA scores were 5.08 +/- 0.19 (mean +/- SEM) for grade 4, 3.97 +/- 0.46 for grade 3, 1.65 +/- 0.39 for grade 2, and 1.22 +/- 0.60 for pilocytic astrocytomas. The statistical analysis was based on cytoplasmic staining only. Analysis of variance revealed significant differences between the mean u-PA scores of different grades (P < 0.02 between grades 4 and 3, and P = 0.0001 between grades 4 or 3 and 2, and between grades 4 or 3 and pilocytic), except between grade 2 and pilocytic astrocytomas. Univariate analysis indicated that u-PA score > or = 4 (P = 0.0001), tumor grade 4 (P = 0.01), and age > 50 (P < 0.001) were all significant predictors for shorter disease survival. A three-way interaction model by multivariate analysis indicated that u-PA score > or = 4, tumor grade 4, and age > 50, taken together, were significant factors for shorter patient survival (P < 0.02). We conclude that u-PA may be used as a prognostic tool in conjunction with tumor grade and patients' age in predicting survival for patients with gliomas.

Survival of rats harboring cerebral 9L gliosarcomas can be significantly extended by an intratumoral inoculation with a herpes simplex virus vector, designated as hrR3. This vector, which bears the lacZ reporter gene, is defective in the gene encoding ribonucleotide reductase, allowing for replication in dividing tumor cells but not in postmitotic neural cells. It also possesses an intact viral thymidine kinase (TK) gene, which confers chemosensitivity to ganciclovir. In this study, the ability of ganciclovir to potentiate the antitumor effect of hrR3 was evaluated. In culture, there was a 23% decrease in the growth of 9L cells treated with hrR3 plus ganciclovir compared to hrR3 alone (P < 0.01). The combination of hrR3 plus ganciclovir led to the long-term survival of 48% of rats harboring intracerebral 9L gliosarcomas compared to 20% survival in the hrR3 group (P < 0.05). Ganciclovir treatment had no effect on the growth of tumor cells in vitro or in vivo when a herpes simplex virus vector with a defective TK gene was used. Immunocytochemistry confirmed selective expression of the TK gene in cells within the tumor. These findings indicate that the TK gene can potentiate the antitumor effect of the hrR3 herpes simplex virus vector and provide the basis for placing additional therapeutic genes in the genome of hrR3.

Purpose: The purpose of this paper is to present local control rates of carcinoma of the larynx in relation to the total treatment course after radical radiation therapy., Methods and Materials: A total of 1350 patients with laryngeal carcinoma treated at the Massachusetts General Hospital for the past three decades were available for analysis. Treatment courses were divided into two groups: 45 days and > 45 days. The local control rates were compared and evaluated for statistical differences., Results: The data indicated that prolonged treatment course adversely affects local tumor control of both advanced glottic and supraglottic lesions, but to a lesser degree for the early tumors., Conclusion: The study indicated that for optimal local control, radiation treatment should be completed as soon as possible, preferably within 6.5 weeks, either by once- or twice-daily accelerated programs. The local control of early T1 glottic cancer has been exceedingly satisfactory by conventional once-daily radiation therapy. Further improvement by shortening of treatment time for such early lesions will be difficult to assess without a prospective randomized trial.

The prognostic value of tumor proliferative indices in meningiomas was assessed by mitotic counts and by immunocytochemistry using a monoclonal antibody against the proliferating cell nuclear antigen (PCNA) (clone 19A2), a 36-kd nuclear protein involved in DNA synthesis. Sixty-three intracranial meningiomas were classified as benign (26), with atypical features (24) or as malignant (13). The patients included 24 men and 39 women, mean age 54.2 +/- 1.7 (mean +/- SEM) (range 15-78) at initial presentation. Twenty-four of the 63 primary tumors recurred locally, including 23.1% (6/26) of the benign, 37.5% (9/24) of the atypical, and 69.2% (9/13) of the malignant meningiomas. Among tumors that recurred, 1/9 (11%) of the atypical and 5/9 (55.5%) of the malignant tumors had had macroscopical total excision at the initial surgery. The mean interval to recurrence was 52 +/- 11.8 months. The mean progression-free follow-up period for patients without tumor recurrence was 82 +/- 8.5 months. Analysis of variance revealed that significant differences existed between tumor grades for both PCNA indices (1.16 +/- 0.29% for benign; 14.14 +/- 2.07% for atypical and 21.37 +/- 5.47% for malignant) and mitotic indices (total counts per ten high power fields) (0.08 +/- 0.05 for benign, 4.75 +/- 0.91 for atypical and 19.00 +/- 4.07 for malignant). Multivariate regression analysis indicated that mitotic index > 6 was the single most important factor (p < 0.05) for shorter disease-free interval. Age, sex and total surgical excision were not significant factors. PCNA index was a significant factor in the univariate model, but not in the multivariate model.(ABSTRACT TRUNCATED AT 250 WORDS)

We studied 161 prostate cancer patients treated by radical irradiation alone without endocrine therapy in whom pretreatment and posttreatment prostate specific antigen (PSA) values were measured, and who had a minimum followup of 2 years. Outcome was analyzed in an actuarial fashion using clinical disease-free survival and biochemical disease-free survival (freedom from an increasing PSA level or a PSA level of greater than 1.0 ng./ml. 2 years following irradiation) as end points. Of the patients 54% achieved a post-irradiation nadir value in the range 0 to 1.0 ng./ml. and 29% had a nadir value that was undetectably low (less than 0.5 ng./ml.). The likelihood of achieving these values was greater among patients with early stage than locally advanced tumors. For all T stages the likelihood of being disease-free at 4 years was substantially and significantly lower when PSA was used as an end point than when clinical evaluation alone was used: stages T1 and T2 (85 patients) 41% versus 71%, and stages T3 and T4 (76 patients) 15% versus 61%. For the whole group at 4 years clinical control was 67% but biochemical control was only 26% (p < 0.05). The likelihood of being free of biochemical evidence of persistent disease at 4 years was a function of the initial PSA value (PSA less than 4.0 in 81% of the cases, 4.1 to 10.0 in 43%, 10.1 to 20.0 in 31%, 20.1 to 50.0 in 6% and greater than 50.0 in 0%). For stages T1 and T2 cancer patients with an initial PSA level of less than 15 ng./ml. (67% of all early stage cases) this value was 65% and it was even higher (73%) when poorly differentiated tumors were excluded. When the initial PSA level for stages T1 and T2 tumors was greater than 15 ng./ml. the projected 4-year rate of freedom from biochemical failure was only 7%. For stages T3 and T4 cancer patients the corresponding figures were 39% for those with an initial PSA level of less than 15 ng./ml. and 0% for those with an initial PSA level of greater than 15 ng./ml. The prognostic power of the initial PSA level was independent of stage, grade, patient age and prior transurethral resection of the prostate in a multivariate analysis. An initial serum PSA level of more than 15 ng./ml. is, therefore, a powerful predictor of probable failure with conventional radiation therapy. Serum PSA monitoring is a sensitive detector of early relapse.(ABSTRACT TRUNCATED AT 400 WORDS)

Objective: The authors investigated the combined experience of a single institution in treating bile duct carcinoma during the modern era., Summary Background Data: Bile duct carcinomas are notoriously difficult to cure, with locoregional recurrence the rule, even after radical resection. Adjuvant efforts have included various radiation modalities, with limited success. Recently, charged-particle radiotherapy has also been used in these patients., Methods: The authors performed a retrospective chart analysis of 129 patients with bile duct adenocarcinomas treated between 1977 and 1987 through the University of California at San Francisco, including 22 patients treated at Lawrence Berkeley Laboratory with the charged particles helium and neon. The minimum follow-up was 5 years. Survival, outcome, and complication results were analyzed., Results: Sixty-two patients were treated with surgery alone (S), 45 patients received conventional adjuvant x-ray radiotherapy (S + X), and 22 were treated with charged particles (S + CP). The median survival times were 6.5, 11, and 14 months, respectively, for the entire group, and 16, 16, and 23 months in patients treated with curative intent. There was a survival difference in patients undergoing total resection compared with debulking (p = 0.05) and minor resections (p = 0.0001). Patients with microscopic residual disease had increased median survival times when they were treated with adjuvant irradiation, most markedly after CP (p = 0.0005) but also with conventional X (p = 0.0109). Patients with gross residual disease had a less marked but still statistically significant extended survival (p = 0.05 for S + X and p = 0.0423 for S + CP) after irradiatio, Conclusions: The mainstay of bile duct carcinoma management was maximal surgical resection in these patients. Postoperative radiotherapy gave patients with positive microscopic margins a significant survival advantage and may be of value in selected patients with gross disease.

Background: For patients with invasive bladder cancer the usual recommended treatment is radical cystectomy, although transurethral resection of the tumor, systemic chemotherapy, and radiotherapy are each effective in some patients. We sought to determine whether these treatments in combination might be as effective as radical cystectomy and thus might allow the bladder to be preserved and the cancer cured., Methods: We enrolled 53 consecutive patients with muscle-invading bladder cancer (stages T2 through T4, NXM0) in a trial of transurethral surgery, combination chemotherapy, and irradiation (4000 cGy) with concurrent cisplatin administration. Urologic evaluation of the tumor response directed further therapy: radical cystectomy in the 8 patients who had incomplete responses, additional chemotherapy and radiotherapy (6480 cGy) in the 34 patients who had complete responses or who were unsuited for cystectomy, and alternative care in the 11 patients who could not tolerate either irradiation or chemotherapy., Results: After a median follow-up of 48 months, 24 of the 53 patients (45 percent) were alive and free of detectable tumor. In 31 patients (58 percent) the bladder was free of invasive tumor and functioning well, even though in 9 (17 percent) a superficial tumor recurred and required further transurethral surgery and intravesical drug therapy. Of the 28 patients who had complete responses after initial treatment, 89 percent had functioning tumor-free bladders., Conclusions: Conservative combination treatment may be an acceptable alternative to immediate cystectomy in selected patients with bladder cancer, although a randomized clinical trial that included a group for simultaneous comparison would be required to produce definitive results.

Purpose: Dose escalation for prostate cancer by external beam irradiation is feasible by a 160 MeV perineal proton beam that reduces the volume of rectum irradiated. We correlated the total doses received to portions of the anterior rectum to study the possible relationship of the volume irradiated to the incidence of late rectal toxicity., Methods: We have randomized 191 patients with stages T3 and T4 prostatic carcinoma to one of two treatment dose arms. These were: 1) 75.6 Cobalt-Gy-equivalent (CGE), 50.4 Gy delivered by 107-25 MV photons followed by 25.2 CGE delivered perineally by protons (Arm 1) or 2) 67.2 CGE delivered by 10-25 MV photons (Arm 2)., Results: With a median follow-up of 3.7 years, post-irradiation rectal bleeding (grades 1 and 2 only, none requiring surgery or hospitalization) from telangiectatic rectal mucosal vessels has occurred in 34% of 99 Arm-1 patients and 16% of 92 Arm-2 patients (p = 0.013). Dose-volume histograms (DVHs) for the anterior rectal wall, the posterior rectal wall and the total rectum in 41 patients treated on Arm 1 were calculated from the three dimensional dose distributions. Rectal bleeding has occurred in 14 or 34% of the 41 DVH-analyzed subset of Arm-1 patients. Both the fractional volume of the anterior rectum and the total dose received by fractional volumes of the anterior rectum significantly correlate with the actuarial probability of bleeding., Conclusions: Clinicians planning dose escalation to men with localized prostate cancer should approve with caution treatment plans raising more than 40% of the anterior rectum to more than 75 CGE without additional effort to protect the rectal mucosa because this late sequela data indicate that more than half of these men will otherwise have rectal bleeding.

Heterogeneity of response of tumor tissue to radiation clearly exists. Major parameters include histopathologic type, size (number of tumor rescue units (TRUs)), hemoglobin concentration, cell proliferation kinetics and immune rejection reaction by host. Further, normal and presumably tumor tissue response is altered in certain genetic diseases, e.g. ataxia telangiectasia. Any assessment of response of tumor tissue to a new treatment method or the testing of a new clinical response predictor is optimally based upon a narrow strata, viz., uniform with respect to known parameters of response, e.g. size, histological type. Even among tumors of such a clinically defined narrow strata, there will be residual heterogeneity with respect to inherent cellular radiation sensitivity, distributions of pO2, (SH), cell proliferation etc. The value of a response predictor of an individual tumor will be determined by the heterogeneity of values for these and or other characteristics and by the coefficient of variation (CV) of the measured values of the individual parameters. Heterogeneity of one or more parameters of response is reflected in the slope of the dose response curve for local control, viz. the greater the heterogeneity the less steep the slope. To examine for this effect, the slope of dose response curves for control of model tumors of 10(8) tumor rescue units (TRU) and the SF2 = 0.5 (survival fraction after a single dose of 2 Gy) has been used to assess the impact of inter- and intra-tumoral variation of SF2 on slope, defined as gamma 50 values. The gamma 50 is the increase in local control expressed in percent points for a one percentage increment in dose, at the mid-point on the dose-response curve. The gamma 50 was 6.5 for CV = 0.0. For inter-tumoral CVs of 10%, 20% and 40%, the gamma 50 rapidly decreased to 2.4, 1.3 and 0.7. Intra-tumoral variation was less important, viz., for CVs of 10%, 20%, and 40% the gamma 50 values were reduced to 5.3, 3.8 and 2.2. Combining inter- and intra-tumoral variation reduced the gamma 50 only slightly below that for inter-tumoral variation alone. For example, were the CV 10% for inter- and intra-tumoral variation, the gamma 50 would be 2.1 as compared to 2.4 for inter-tumoral variation alone. The number of TRUs also affects slope, viz. gamma 50 increased from 1 to 9.7 as the TRU number increased from 10(1) to 10(12).(ABSTRACT TRUNCATED AT 400 WORDS)