Evaluating the role of HLA-DQ polymorphisms on immune response to bacterial superantigens using transgenic mice.

Bacterial superantigens bind directly to human leukocyte antigen (HLA) class II molecules and vigorously activate T cells expressing certain T-cell receptor variable region families. As interaction with HLA class II molecules is the primary step in this process, polymorphic variations in HLA class II can determine the extent of superantigen binding to HLA class II molecules, govern the magnitude of immune activation induced by given superantigens and determine the outcome of superantigen-mediated diseases. As direct assessment of the influence of HLA class II polymorphism in humans is impossible because of expression of more than one HLA class II alleles in a given individual and toxicity of superantigens, transgenic mice expressing HLA-DQ6 (HLA-DQA1*0103 and HLA-DQB1*0601) and HLA-DQ8 (HLA-DQA1*0301 and HLA-DQB1*0302) were used to achieve this goal. HLA-DQ6 and HLA-DQ8 elicited comparable in vitro and in vivo immune response to staphylococcal enterotoxins (SE) A, SEB, SEH and SEK, toxic shock syndrome toxin-1, streptococcal pyrogenic exotoxin (SPE) A and SPEC and streptococcal mitogenic exotoxin Z (SMEZ). However, each superantigen had a unique T-cell receptor activation profile. In vivo challenge with Streptococcus pyogenes, H305, capable of elaborating SPEA and SMEZ, yielded a similar clinical outcome in HLA-DQ6 and HLA-DQ8 transgenic mice. In conclusion, HLA-DQ6 and HLA-DQ8 elicited comparable response to certain bacterial superantigens. Our report highlights the advantages of HLA class II transgenic mice in such studies.

Elderly cohort study subjects unable to return for follow-up have lower bone mass than those who can return.

Longitudinal studies of osteoporosis in older persons may underestimate bone loss because of a lack of follow-up measurements on subjects too frail to return. The authors addressed this possible bias as part of the population-based Framingham Study; in 1996-1997, they used quantitative ultrasound to assess the bone status of elderly subjects regardless of their ability to return to the clinic. Broadband ultrasound attenuation (BUA) and speed of sound of the calcaneus (heel) were measured in 433 subjects at the Framingham, Massachusetts, clinic and in 167 subjects at their homes or nursing homes. All ultrasound parameters were measured with intramachine coefficients of variation of <6.0%. The mean BUA for those subjects evaluated at the clinic was higher than for those measured at home (9.2% higher for men, p = 0.081; 8.6% higher for women, p = 0.034). After adjustment for age and weight, the differences in BUA were no longer significant. Among the elderly subjects participating in this longitudinal cohort study, those who were unable to return for follow-up were older, weighed less, and had a lower BUA than those who did return, suggesting that longitudinal studies of changes in bone mass with aging may underestimate the true population values.

An unusual cause of spinal cord injury: case report and discussion.

Traumatic spinal cord injury is a devastating condition that alters every aspect of the victim's life. Motor vehicle accidents cause about half of the cases, whereas others are the result of falls, recreational and sporting accidents, or acts of violence. We report a case of a C3 spinal fracture with a resultant Brown Sequard syndrome, which occurred in a unique manner and could have easily been prevented. There is a need for the medical community to play a more active role in educating the public to prevent accidents that lead to these catastrophic injuries.

Metastatic nonresectable fibrolamellar hepatoma: prognostic features and natural history.

Fibrolamellar hepatoma has a clinical course distinct from that of typical histologic hepatocellular carcinoma. The clinical behavior and prognostic features of nonresectable metastatic fibrolamellar hepatoma have not previously been fully addressed and are the focus of this report. Retrospective chart review of all patients (n = 17) with nonresectable metastatic fibrolamellar hepatoma referred to the Johns Hopkins Oncology Center from 1985 through 1990 was carried out. All patients had hepatic parenchymal involvement and regional node metastases at the time of referral. Metastases were limited to regional nodes in four patients. The remaining patients had lung metastases (n = 4), peritoneal metastases (n = 5), or both (n = 4). To assess the impact of the fibrolamellar variant, characteristic-matched control patients with typical histologic hepatocellular carcinoma were obtained from the Radiation Therapy Oncology Group database. Actuarial median survival from treatment was 14 months in the patients with fibrolamellar hepatoma and 7.7 months in the patients with hepatocellular carcinoma (p < 0.001). Karnofsky performance status and hepatic tumor volume at time of referral were important prognostic features. Multimodality treatment included radiation therapy and radiolabelled antibody, cisplatin-based chemotherapy, or both; results are discussed. Thirteen patients died, nine of liver failure, three of metastatic disease, and one of sepsis. Fibrolamellar histologic type, liver function tests, tumor volume, and patient performance status were significant predictors of survival. The cause of death in fibrolamellar hepatoma differs considerably from that observed in typical histologic hepatocellular carcinoma in the United States. The techniques of treatment of this uncommon disease were modeled after advances in the multimodality treatment of hepatocellular carcinoma and are discussed. Median survival was 14 months in patients with metastatic nonresectable fibrolamellar hepatoma.

Dose escalation with 3D conformal treatment: five year outcomes, treatment optimization, and future directions.

PURPOSE: To report the 5-year outcomes of dose escalation with 3D conformal treatment (3DCRT) of prostate cancer. METHODS AND MATERIALS: Two hundred thirty-two consecutive patients were treated with 3DCRT alone between 6/89 and 10/92 with ICRU reporting point dose that increased from 63 to 79 Gy. The median follow-up was 60 months, and any patient free of clinical or biochemical evidence of disease was termed bNED. Biochemical failure was defined as prostate-specific antigen (PSA) rising on two consecutive recordings and exceeding 1.5 ng/ml. Morbidity was reported by the Radiation Therapy Oncology Group (RTOG) scale, the Late Effects Normal Tissue (LENT) scale, and a Fox Chase modification of the latter (FC-LENT). All patients were treated with a four-field technique with a 1 cm clinical target volume (CTV) to planning target volume (PTV) margin to the prostate or prostate boost; the CTV and gross tumor volume (GTV) were the same. Actuarial rates of outcome were calculated by Kaplan-Meier and cumulative incidence methods and compared using the log rank and Gray's test statistic, respectively. Cox regression models were used to establish prognostic factors predictive of the various measures of outcome. Five-year Kaplan-Meier bNED rates were utilized by dose group to estimate logit response models for bNED and late morbidity. RESULTS: PSA <10 ng/ml: No dose response was demonstrated using estimated bNED rates or by analysis of PSA nadir vs. dose. PSA 10-19.9 ng/ml: A bNED dose response was demonstrated (p = 0.02) using the log rank test. The logit response model showed 5-year bNED rates of 35% at 70 Gy and 75% at 76 Gy (p = 0.0049) and illustrated the relative ineffectiveness of conventional dose treatment. PSA 20+ ng/ml: A bNED dose response was demonstrated (p = 0.02) using the log rank test. The logit response model indicated a 5-year bNED rate of 10% at 70 Gy and 32% at 76 Gy (p = 0.10). Morbidity: Dose response was demonstrated for FC-LENT grade 2 and grade 3,4 GI morbidity and for LENT grade 2 GU sequelae. RTOG grade 3,4 GI morbidity at 5 years was <1%. Factors associated with bNED, cause-specific survival, and metastasis were studied using Cox multivariate analysis. Pretreatment PSA (p = 0.0001), Gleason score 7-10 (p = 0.0001), and dose (p = 0.017) were significantly predictive of bNED. For each 1 Gy increase in dose, the hazard of bNED failure decreased by 8%. Palpation stage was associated with cause-specific survival (p = 0.002) and distant metastasis (p = 0.0004). Gleason score was also predictive of distant metastasis (p = 0.02). CONCLUSIONS: A dose response was observed for patients with pretreatment PSA >10 ng/ml based on 5-year bNED results. No dose response was observed for patients with pretreatment PSA < 10 ng/ml. Dose response was observed for FC-LENT grade 2 and grade 3,4 GI sequelae and for LENT grade 2 GU sequelae. Optimization of treatment was made possible by the results in this report. The improvement in 5-year bNED rates for patients with PSA levels > 10 ng/ml strongly suggests that clinical trials employing radiation should investigate the use of 3DCRT and prostate doses of 76-80 Gy.

Population nutrient intake approaches dietary recommendations: 1991 to 1995 Framingham Nutrition Studies.

OBJECTIVE: To estimate population nutrient intake levels and to assess adherence to current dietary recommendations for health promotion and disease prevention. DESIGN: Cross-sectional analysis of nutrient intake estimated from 3-day food records. Median macronutrient and micronutrient intake levels for men, women, and the total population are reported along with the proportions of men and women who achieved intakes compatible with nutrient goals defined by published guidelines. SETTING: Adult participants (2,520: 1,375 women and 1,145 men) in the Framingham Offspring-Spouse Study surveyed between 1991 and 1995. STATISTICAL ANALYSES: chi 2 Analyses were used to test for gender differences in the proportions of persons who had intakes that met nutrient guidelines. RESULTS: Population intake levels of certain key nutrients, including total and saturated fat, appear to be approaching recommended levels. High proportions of the Framingham population (70% or more) met current recommendations for intakes of protein, polyunsaturated and monounsaturated fat, cholesterol, alcohol, vitamins C and B-12, and folacin. About half or fewer met guidelines for carbohydrate; total and saturated fat; fiber; beta carotene; vitamins A, E, and B-6; calcium; and sodium. Important gender differences in the proportion of those meeting nutrient guidelines were observed for 12 of the 18 nutrients examined, including carbohydrate; total, saturated, and monounsaturated fat; cholesterol; fiber; sodium; calcium; and several vitamins. CONCLUSIONS: Although progress has been made toward achieving population adherence to preventive nutrition recommendations, large proportions of adults fall short of guidelines for some key nutrients. Differences in adherence rates between men and women suggest areas for gender-specific, targeted nutrition messages and behavioral interventions.

Optimization of conformal radiation treatment of prostate cancer: report of a dose escalation study.

PURPOSE: The development of conformal radiation technique including improved patient immobilization has allowed us to test the value of dose escalation in optimizing the radiation treatment of prostate cancer. METHODS AND MATERIALS: Outcome is reported for 233 consecutive patients treated with conformal technique between March 1989 and October 1992. Dose was escalated from 68 Gy to 79 Gy. Patient status is reported at 3 years follow-up, which is available in all alive patients. Pretreatment and serial posttreatment prostate specific antigen (PSA) values are available for all patients. Biochemical freedom of disease (bNED) defines failure as PSA > 1.5 ngm/ml and rising on two consecutive measures. Dose response for bNED control of cancer and late morbidity are represented by logit response models fitted to the data. Kaplan-Meier methods, the log rank test, and Cox Regression models are also used. RESULTS: No dose response is observed for bNED survival for patients with pretreatment PSA <10 ngm/ml comparing patients treated above or below 71.5 Gy or on multivariate analysis. Dose response is observed for bNED survival for pretreatment PSA groups of 10-19.9 ngm/ml and 20+ ngm/ml. The dose associated with 50% bNED survival at 3 years is 64 Gy and 76 Gy, respectively. The slope of the dose responses are 13 and 9%, respectively. Dose response is demonstrated for Grade 2 gastrointestinal (GI), Grade 2 genitourinary (GU), and Grade 3,4 combined GI and GU late morbidity. The slopes of the morbidity responses are steeper than for cancer control (19 to 21%). CONCLUSIONS: Patients with pretreatment PSA < 10 ngm/ml do not benefit from dose escalation, and the serious late morbidity of conformal radiation at 70 Gy is < 3%. Patients with PSA values 10-19.9 ngm/ml and 20+ ngm/ml benefit from dose escalation beyond 70 Gy. Treatment beyond 75 Gy results in > 10% serious morbidity unless special precautions are taken to protect the rectal mucosa. All levels of severity of radiation morbidity show a dose response and combined with the dose response for bNED survival these data allow the optimization of treatment.

Conformal technique dose escalation for prostate cancer: biochemical evidence of improved cancer control with higher doses in patients with pretreatment prostate-specific antigen > or = 10 NG/ML.

PURPOSE: Conformal radiation technology results in fewer late complications and allows testing of the value of higher doses in prostate cancer. METHODS AND MATERIALS: We report the biochemical freedom from disease (bNED) rates (bNED failure is Prostate Specific Antigen (PSA) > or = 1.5 ng/ml and rising) at 2 and 3 years for 375 consecutive patients treated with conformal technique from 66 to 79 Gy. Median follow-up was 21 months. Biochemical freedom from disease was analyzed for patients treated above and below 71 Gy as well as above and below 73 Gy. Each dose group was subdivided by pretreatment PSA level (< 10, 10-19.9, and > or = 20 ng/ml). Dose was stated to be at the center of the prostate gland. RESULTS: There was significant improvement in bNED survival for all patients divided by a dose above or below 71 Gy (p = 0.007) and a marginal improvement above or below 73 Gy (p = 0.07). Subdividing by pretreatment PSA level showed no benefit to the PSA < 10 ng/ml group at the higher dose but there was a significant improvement at 71 and 73 Gy for pretreatment PSA 10-19.9 ng/ml (p = 0.03 and 0.05, respectively) and for pretreatment PSA > or = 20 ng/ml (p = 0.003 and 0.02, respectively). CONCLUSIONS: Increasing dose above 71 or 73 Gy did not result in improved bNED survival for patients with pretreatment PSA < 10 ng/ml at 2 or 3 years. Further dose escalation studies may not be useful in these patients. A significant improvement in bNED survival was noted for patients with pretreatment PSA > or = 10 ng/ml treated above 71 or 73 Gy; further dose escalation studies are warranted.

Prostatic-specific antigen doubling times in patients with prostate cancer: a potentially useful reflection of tumor doubling time.

PURPOSE: This study was undertaken to investigate the relationship of prostatic specific antigen doubling time with disease progression in irradiated patients whose only sign of failure was an abnormal prostatic specific antigen. METHODS AND MATERIALS: Post irradiation patients whose only sign of failure was an elevated prostatic specific antigen were followed without treatment. The prostatic specific antigen doubling time was determined and compared to original characteristics of disease, time to elevation of prostatic specific antigen after treatment and time to a second sign of failure. RESULTS: The prostatic specific antigen doubling times varied from 1.2 months to 36 months. The original grade and stage correlated with the doubling time as did the intervals to elevation of prostatic specific antigen and to a second sign of failure. CONCLUSION: We recommended delaying intervention until the prostatic antigen doubling time can be calculated for patients with prostatic specific antigen elevation as the only sign of failure. Patients with short doubling times (< 9 months) can be promptly treated while those with longer doubling times (> 1 year) may have androgen suppression delayed avoiding the cost and morbidity of that treatment.

Improved survival duration in patients with unresected solitary brain metastasis using accelerated hyperfractionated radiation therapy at total doses of 54.4 gray and greater. Results of Radiation Therapy Oncology Group 85-28.

BACKGROUND: Although there have been occasional reports of improved response with greater doses of irradiation for unresected brain metastases, dose escalation has not been systematically studied in a cohort of patients with solitary brain metastasis. The current study examines this group of patients to evaluate dose escalation using accelerated hyperfractionated radiation therapy (XRT) with regard to survival, patterns of failure, and toxicity. METHOD: Radiation Therapy Oncology Group (RTOG) 85-28, a Phase I/II randomized trial of accelerated hyperfractionated XRT for patients with unresected supratentorial brain metastases, enrolled 153 patients with solitary brain metastasis. Whole brain dose was 32 Gray (Gy) administered in 1.6 Gy fractions twice a day with an interfraction interval of 4-8 hours. Boost dose was escalated to total doses of 48.0, 54.4, 64.0, and 70.4 Gy. RESULTS: Acute and late toxicities were acceptable. The median survival time and 1-year survival rates were 4.9 months and 20% at 48 Gy; 5.4 months and 33% at 54.4 Gy; 7.2 months and 28% at 64 Gy; and 8.2 months and 37% at 70.4 Gy, respectively. Comparison of the upper three dose treatment arms to the 48 Gy treatment arm revealed a superior survival time with doses of 54.4 Gy and greater (P = 0.05). Improvement in neurologic function appeared to increase with dose escalation, with 25% of patients experiencing improvement at doses of 48 Gy, 38% at 54.4 Gy, 50% at 64 Gy, and 63% at 70.4 Gy (P = not significant). CONCLUSION: A radiation dose response for survival time appears to exist with the use of accelerated hyperfractionated XRT for patients with unresected solitary brain metastasis.

Conformal static field radiation therapy treatment of early prostate cancer versus non-conformal techniques: a reduction in acute morbidity.

Patients with early prostate cancer have been definitively treated using our previously described technique of CT-based 3D treatment planning and beam's eye view techniques with patients immobilized in alpha cradle casts. An average of 14% bladder (range 6-31%) and 14% rectal (range 7-25%) volume receiving a given dose was eliminated using four conformally blocked fields, with a 1.5 cm margin around the prostate contour, when compared to stage matched controls. Treatment-related acute morbidity was compared for 26 patients treated by the conformal techniques (CG) since April 1989 and 20 consecutive patients treated immediately prior to the conformal techniques with prostate only fields from May 1985-March 1989 (NCG). Acute urinary symptoms (frequency, dysuria, hematuria) or acute rectal symptoms (diarrhea, tenesmus, blood) occurred in 77% (20/26) of the CG versus 80% (16/20) of the NCG patients. Only 31% (8/26) of the CG versus 60% (12/20) of the NCG patients (p < .05) experienced symptoms to a degree which prompted physician intervention (medication and/or interruption of treatment). Two of 26 CG patients (8%) required medication for both bladder and rectal symptoms compared to 5/20 (25%) NCG patients (p = .09). Symptoms persisted for an average of 2.5 weeks versus 3.5 weeks in the CG and NCG groups, respectively. Persistent symptoms at or beyond the 1 month follow-up were present in 3/26 (11%) CG patients (average duration 1.5 months) and were present in 4/20 (20%) of the NCG patients (average duration 2.5 months). Thus, although the percentage of patients who experience acute irritation of the bladder and/or rectum is similar in the two groups, it appears that the percentage requiring medication and/or interruption of treatment is significantly less when 3D treatment planning, rigid immobilization, and conformal blocks are used. The amount of bladder and rectal tissue that is eliminated by our conformal technique is important as shown clinically by the lesser severity and shorter duration of acute symptomatology.

Stage T1 glottic carcinoma: results of radiation therapy or laser excision.

A retrospective analysis was made of the data on 60 patients with stage T1 glottic carcinoma (43 T1a, 17 T1b) who received radiation therapy and 17 patients with T1a disease who underwent laser excision as the primary treatment modality. Patients who received radiation therapy achieved 3- and 5-year actuarial local control rates of 92% and 89% for T1a and 77% and 77% for T1b disease, respectively. In patients who underwent laser excision (all with T1a disease), the 3-year local control rate was 77%. Of the 42 evaluable irradiated T1a patients, 31 (74%) had a normal to near-normal voice, eight (19%) had mild or intermittent hoarseness, and three (7%) had persistent hoarseness. Of the 13 evaluable patients in the laser-excision group, four (31%) had a normal to near-normal voice, five (38%) had mild or intermittent hoarseness, and four (31%) had persistent hoarseness. The difference in the quality of voice between these two groups is statistically significant (P = .012), although the ultimate local control rate after salvage therapy for irradiated patients (97%) was similar to that for laser-excision patients (94%).

Staging, treatment, and results in testicular seminoma. A 12-year report.

Sixty-one patients with histologically confirmed seminoma of the testis were treated by radiotherapy at The Johns Hopkins Hospital from 1975 to 1987. Fifty-seven patients remain disease-free, three patients died of intercurrent disease, and one patient (Stage IIB) died of widespread seminoma. Median follow-up for these patients is 5.5 years. Using a modified M.D. Anderson Hospital clinical staging system, 42 (69%) were Stage I, 16 (26%) were Stage IIA, and three (5%) were Stage IIB. Radiologic staging included both lymphangiogram (LAG) and abdominal computed tomography (CT) scan. Among Stage I disease, nine patients had false-positive CT scans, determined by negative LAG. Six patients had false-negative CT scans and were upstaged to Stage IIA by LAG. Treatment portals were altered in 15 of the 39 patients (38%) who had both LAG and CT scan. Overall actuarial survival (Kaplan-Meier method) was 97% at 5 years and 92% at 10 years. Five-year survival corrected for intercurrent disease was 100% for Stage I, 100% for Stage IIA, and two of three in Stage IIB patients. There were two distant treatment failures among the entire cohort. One patient who had Stage I disease was salvaged with local-field radiation and chemotherapy and is now without evidence of disease for 6 years. The second patient with Stage IIB seminoma receiving the same treatments disseminated and died. There were no significant acute toxicities or serious complications. In summary, proper staging with information gained from LAG and adequate radiation dose led to a 92% 10-year disease-free survival.

Relationship of dose to local control in advanced stage III and IV head and neck cancer treated by surgery and postoperative radiotherapy.

Retrospective analysis of 76 patients with locally advanced squamous cell carcinoma of multiple head and neck sites, who were treated by surgical resection and either 4,000-5,000, 6,000, or 6,600 rad postoperative external beam radiotherapy, revealed reduced local recurrence rates with increasing postoperative radiation dose.

Outcome of locally advanced stage III and IV head and neck cancer treated by surgery and postoperative external beam radiotherapy.

An uncontrolled retrospective analysis of 76 patients with locally advanced Stage III and Stage IV squamous cell carcinoma of the oral cavity, oropharynx, pyriform sinus, supraglottic larynx, glottic larynx, and hypopharynx, who were treated in a uniform manner by surgical resection and 6,600 rad postoperative external beam radiotherapy, revealed relatively high 2-year and 4-year adjusted survival rates of 76% and 68%, respectively. Complication rates were acceptable (8%). The advantages of this treatment approach for locally advanced head and neck cancers compared to treatment by surgery alone are discussed.

Fluoroscopy guided transperineal percutaneous permanent 125iodine implantation of prostate cancer.

The transperineal percutaneous template permanent iodine interstitial brachytherapy under "C-arm" fluoroscopic guidance is a simple, easily-learned, accurate and rapid procedure which can be performed without subjecting the patient to celiotomy. We have treated 58 patients by the transperineal percutaneous permanent interstitial brachytherapy. The use of transperineal percutaneous technique with C-arm fluoroscopic guidance improves the symmetry and dosimetry of the implant. This results in reduction of the incidence of chronic radiation-induced complications. In the group of 22 patients who underwent brachytherapy without celiotomy and lymphadenectomy and without adjuvant external-beam radiotherapy, there were no major complications.