Obesity and outcomes in patients treated with chemoradiotherapy for esophageal carcinoma.

Body mass index (BMI) is a risk factor for comorbid illnesses and cancer development. It was hypothesized that obesity status affects disease outcomes and treatment-related toxicities in esophageal cancer patients treated with chemoradiotherapy (CRT). From March 2002 to April 2010, 405 patients with non-metastatic esophageal carcinoma at MD Anderson Cancer Center treated with either definitive or neoadjuvant CRT were retrospectively analyzed. Patients were categorized as either obese (BMI ≥ 25 kg/m(2) ) or nonobese (BMI < 25 kg/m(2) ). Progression-free survival and overall survival times were examined using the Kaplan-Meier method and Cox proportional hazards regression analysis. One hundred fifteen (28.4%) patients were classified as nonobese and 290 (71.6%) as obese. Obese patients were more likely than others to have several comorbid diseases (P < 0.001), adenocarcinoma located distally (P < 0.001), and have undergone surgery (P = 0.004). Obesity was not associated with either worse operative morbidity/mortality (P > 0.05) or worse positron emission tomography tumor response (P = 0.46) on univariate analysis, nor with worse pathologic complete response (P = 0.98) on multivariate analysis. There was also no difference in overall survival, locoregional control, or metastasis-free survival between obese and nonobese patients (P = 0.86). However, higher BMI was associated with reduced risk of chemoradiation-induced high-grade esophagitis (P = 0.021), esophageal stricture (P < 0.001), and high-grade hematologic toxicity (P < 0.001). In esophageal cancer patients treated with CRT, obesity is not predictive of poorer disease outcomes or operative morbidities; instead, data suggest it may be associated with decreased risk of acute chemotherapy- and radiotherapy-related treatment toxicities.

Risk factors for local and regional recurrence in patients with resected N0-N1 non-small-cell lung cancer, with implications for patient selection for adjuvant radiation therapy.

BACKGROUND: The purpose of this study was to evaluate the actuarial risk of local and regional failure in patients with completely resected non-small-cell lung cancer (NSCLC), and to assess surgical and pathological factors affecting this risk. PATIENTS AND METHODS: Between January 1998 and December 2009, 1402 consecutive stage I-III (N0-N1) NSCLC patients underwent complete resection without adjuvant radiation therapy. The median follow-up was 42 months. RESULTS: Local-regional recurrence was identified in 9% of patients, with local failure alone in 3% of patients, regional failure alone in 4% of patients, and both local and regional failure simultaneously in 2% of patients. Patients who had local failure were found to be at increased risk of mortality. By multivariate analyses, three variables were shown to be independently significant risk factors for local [surgical procedure (single/multiple wedges+segmentectomy versus lobectomy+bilobectomy+pneumonectomy), tumor size>2.7 cm, and visceral pleural invasion] and regional (pathologic N1 stage, visceral pleural invasion, and lymphovascular space invasion, LVI) recurrence, respectively. CONCLUSION: Patients with N0-N1 disease have low rates of locoregional recurrence after surgical resection. However, several prognostic factors can be identified that increase this risk and identify patients who may benefit from adjuvant treatment.

Switching in polaritonic-photonic crystal nanofibers doped with quantum dots.

We have studied the acousto-optic effect in polaritonic nanofibers made by embedding a cylindrical polaritonic nanowire within a photonic crystal. Here the nanowire consists of either a phonon-polaritonic or an exciton-polaritonic material. The nanowire is doped with ensemble of noninteracting quantum dots. Quantum dots interact with the nanofiber via the exciton-polariton interaction. It is found that for the certain acoustic strain intensity the nanofiber has a localized-to-delocalized polariton transition similar to the metal-to-insulator transitions in doped semiconductors. It is also found that nanofiber has a transparent state due to the exciton-bound polariton coupling. The transparent state can be switched ON or OFF by the external acoustic strain intensity. These are very useful discoveries that can be used to fabricate new types of polaritonic nanoswitches and nanosensors.

Postoperative radiotherapy increases locoregional control of patients with stage IIIA non-small-cell lung cancer treated with induction chemotherapy followed by surgery.

PURPOSE: To determine the effectiveness of postoperative radiotherapy (RT) in patients with Stage IIB and Stage IIIA non-small-cell lung cancer (NSCLC) treated with induction chemotherapy followed by surgery. METHODS AND MATERIALS: We retrospectively reviewed the treatment records of 98 patients (58 men and 40 women; median age 61 years, range 31-91) with Stage IIB and Stage IIIA NSCLC who were treated with induction chemotherapy followed by surgery at our institution between January 1990 and December 2000. Patients were grouped by treatment (chemotherapy/surgery alone vs. chemotherapy/surgery/RT), by disease stage and nodal classification. The rates of local control (LC), disease-specific survival, disease-free survival, and overall survival (OS) were calculated using the Kaplan-Meier method. RESULTS: Of the 98 patients, 40 had Stage IIB and 58 had Stage IIIA. The clinical disease stage and N stage were significantly greater in those patients who underwent RT than in those who did not; however, no statistically significant differences were identified in the additional characteristics between those receiving and not receiving RT within each stage or nodal group. The overall 5-year actuarial LC rate was 81% in the RT group and 54% in the chemotherapy/surgery-alone group (p = 0.07). Postoperative RT significantly improved the 5-year LC rate in patients with Stage IIIA disease (from 35% to 82%, p = 0.01). Postoperative RT did not significantly improve the 5-year OS rate (30% with RT vs. 49% without) for all patients or for patients with Stage IIIA disease. The disease-specific survival and disease-free survival rates did not differ between the treatment groups. Patients who responded to induction chemotherapy had a significantly greater 5-year OS rate (49%) than did those with stable or progressive disease (22%, p = 0.003). CONCLUSION: Postoperative RT in patients with Stage IIIA NSCLC treated with induction chemotherapy followed by surgery significantly improved LC without improving OS. Significantly improved survival was observed in all patients who responded to induction chemotherapy compared with those with stable or progressive disease.

Biocompatible semiconductor optoelectronics.

We investigate optoelectronic properties of integrated structures comprising semiconductor light-emitting materials for optical probes of microscopic biological systems. Compound semiconductors are nearly ideal light emitters for probing cells and other microorganisms because of their spectral match to the transparency wavelengths of biomolecules. Unfortunately, the chemical composition of these materials is incompatible with the biochemistry of cells and related biofluids. To overcome these limitations, we investigate functionalized semiconductor surfaces and structures to simultaneously enhance light emission and the flow of biological fluids in semiconductor microcavities. We have identified several important materials problems associated with the semiconductor/biosystem interface. One is the biofluid degradation of electroluminescence by ionic diffusion into compound semiconductors. Ions that diffuse into the active region of a semiconductor light emitter can create point defects that degrade the quantum efficiency of the radiative recombination process. In this paper we discuss ways of mitigating these problems using materials design and surface chemistry, and suggest future applications for these materials.

Randomized phase III study of chemoradiation with or without amifostine for patients with favorable performance status inoperable stage II-III non-small cell lung cancer: preliminary results.

A prospective randomized study was conducted to determine whether amifostine (Ethyol) reduces the rate of severe esophagitis and hematologic and pulmonary toxicity associated with chemoradiation or improves control of non-small cell lung cancer (NSCLC). Sixty patients with inoperable stage II or III NSCLC were treated with concurrent chemoradiotherapy. Both groups received thoracic radiation therapy (TRT) with 1.2 Gy/fraction, 2 fraction per day, 5 days per week for a total dose 69.6 Gy. All patients received oral etoposide (VP-16), 50 mg Bid, 30 minutes before TRT beginning day 1 for 10 days, repeated on day 29, and cisplatin 50 mg/m(2) intravenously on days 1, 8, 29, and 36. Patients in the study group received amifostine, 500 mg intravenously, twice weekly before chemoradiation (arm 1); patients in the control group received chemoradiation without amifostine (arm 2). Patient and tumor characteristics were distributed equally in both groups. Of the 60 patients enrolled, 53 were evaluable (27 in arm 1, 26 in arm 2) with a median follow-up of 6 months. Median survival times were 26 months for arm 1 and 15 months for arm 2, not statistically significantly different. Morphine intake to reduce severe esophagitis was significantly lower in arm 1 (2 of 27, 7.4%) than arm 2 (8 of 26, 31%; P =.03). Acute pneumonitis was significantly lower in arm 1 (1 of 27, 3.7%) than in arm 2 (6 of 26, 23%; P =.037). Hypotension (20 mm Hg decrease from baseline blood pressure) was significantly more frequent in arm 1 (19 of 27, 70%) than arm 2 (1 of 26, 3.8%; P =.0001). Only 1 patient discontinued treatment because of hypotension. These preliminary results showed that amifostine significantly reduced acute severe esophagitis and pneumonitis. Further observation is required to assess long-term efficacy.

Comparison of two total body irradiation fractionation regimens with respect to acute and late pulmonary toxicity.

BACKGROUND: Total body irradiation (TBI) is commonly used with autologous bone marrow transplantation (BMT) for treatment of hematologic malignancies. Pulmonary complications of TBI can cause long-term morbidity and mortality. The authors have compared the pulmonary toxicity and efficacy of two different TBI fractionation regimens in otherwise identical autologous BMT protocols. METHODS: Between 1990 and 1997 patients younger than 60 years of age with low-grade lymphoma at high risk of treatment failure were enrolled on one of two sequential protocols for autologous BMT differing only in their TBI regimens. The preoperative chemotherapy regimens were identical and consisted of intravenous etoposide (1500 mg/m(2)) for 1 day, intravenous cyclophosphamide (60 mg/kg) for 2 days, and mesna (10 mg/kg). The TBI used in protocol A consisted of twice-daily fractions of 1.7 grays (Gy) for 3 days to a total of 10.2 Gy through lateral fields, with no lung shielding. In protocol B, the TBI consisted of 3 Gy once daily for 4 days to a total of 12 Gy through anteroposterior fields, with lung shielding (5 half-value layers) during the third dose. Fifty-eight patients were treated on protocol A and 24 on protocol B. The groups were equivalent with regard to age, performance status (PS) and gender. Lung function was assessed objectively by pulmonary function tests (PFTs) before and at intervals after TBI. The pulmonary function parameters assessed included forced vital capacity (FVC), forced expiratory volume in 1 second (FEV(1)), forced expiratory flow between 25% and 75% of vital capacity (FEF(25-75)), diffusing capacity for carbon monoxide (DL(CO)), and total lung capacity (TLC). Each patient's post-TBI PFTs were normalized to the corresponding pre-TBI values and analyzed using a random effects model. Clinical pulmonary function status was scored according to Radiation Therapy Oncology Group criteria for acute and late lung toxicity. All clinical pulmonary toxicities such as pneumonitis, pneumonia, and diffuse alveolar hemorrhage, whether specifically related to TBI or not, were scored. Toxicity was classified as either acute (i.e., occurring within 90 days of TBI) or late (i.e., occurring more than 90 days after TBI). The endpoints of analysis were overall survival (OS), freedom from progression, and chronic pulmonary toxicity. Survival, progression, and complication free survival were computed using the method of Kaplan and Meier. RESULTS: Three-year actuarial OS rates were 66% and 67% for protocols A and B, respectively. Patients 50 years of age or older had a hazard ratio of death 3.5 times higher than younger patients. Freedom from progression was significantly different for the 2 TBI regimens (P < 0.001; log-rank test): 31% at 3 years in the protocol A group compared with 82% in protocol B group. Patients on protocol A had a rate of progression 4.7 times higher than patients on protocol B. The TBI protocols did not differ significantly in their effects on FVC, FEV(1), FEF(25-75), DL(CO), and TLC. Patients 45 years of age or older had lower average posttransplant values of FEV(1), FVC, and DL(CO) than younger patients. There was no significant difference in acute or late toxicity rates between patients on the two protocols. Seven of the 57 patients in the twice-daily TBI (protocol A) group had acute pulmonary events (Grade 3 or greater), compared with 6 of the 24 patients in the once-daily (protocol B) group (P = 0.19). The 3-year freedom from late complications rate was 80% in the protocol A group and 70% in the protocol B group (P = 0.45). Patients with a PS of 1 had a hazard ratio of late complications 3.2 times greater than patients with a PS of 0 (P < 0.001). CONCLUSIONS: It is possible to intensify TBI from a total dose of 10.2 Gy delivered in 6 twice-daily fractions to 12 Gy delivered in 4 once-daily fractions without significantly increasing the risk of pulmonary toxicity. The increased dose may contribute to a decrease in the recurrence rate in these patients. (c) 2001 American Cancer Society.

Long-term results with radiotherapy for Stage I-II follicular lymphomas.

PURPOSE: To analyze the long-term results with radiotherapy (RT) for early-stage, low-grade follicular lymphomas. METHODS AND MATERIALS: From 1960 to 1988, 80 patients with Stage I (n = 33) or II (n = 47), World Health Organization Grade 1 (n = 50) or 2 (n = 30) follicular lymphoma were treated with RT. The lymph nodes or spleen were involved in 97% of cases. The maximal tumor sizes ranged from 0.5 to 11.0 cm (median 2.0). The RT fields encompassed only the involved Ann Arbor nodal region (involved-field RT) in 9% of the patients. The fields also included 1-3 adjacent, grossly uninvolved nodal regions (regional RT) in 54% of patients but were smaller than mantle or whole abdominopelvic fields. Mantle or whole abdominopelvic fields encompassing up to 6 grossly uninvolved regions (extended-field RT) were used in the remaining 37% of patients. The total RT doses ranged from 26.2 to 50.0 Gy given in daily 1.0-3.0-Gy fractions. RESULTS: The follow-up of the surviving patients ranged from 3.5 to 28.7 years (median 19.0). No recurrences were found >17.0 years after RT, with 13 patients free of disease at their last follow-up visit 17.6-25.0 years after treatment. In 58% of cases, death was not from follicular lymphoma. The 15-year local control rate was 100% for 44 lymphomas <3.0 cm treated with only 27.8-30.8 Gy (median 30.0 in 20 fractions). Progression-free survival was affected by the maximal tumor size at the start of RT (15-year rate 49% vs. 29% for lymphomas <3.0 cm vs. > or =3.0 cm, respectively, p = 0.04) and Ann Arbor stage (15-year rate 66% vs. 26% for Stages I and II, respectively, p = 0.006). Ann Arbor stage also affected the cause-specific survival (15-year rate 87% vs. 54% for Stages I and II, respectively, p = 0.01). No significant difference was found in overall survival between those treated with extended-field RT and those treated with involved-field RT or regional RT (15-year rate 49% and 40%, respectively, p = 0.51). The 15-year incidence rate of Grade 3 or greater late complications according to the Subjective, Objective, Management, and Analytical scale in patients treated with 26.2-30.8 Gy vs. 30.9-50.0 Gy was 0% and 6%, respectively. CONCLUSIONS: RT can cure approximately one half of Stage I and one quarter of Stage II, World Health Organization Grade 1 or 2 follicular lymphomas. Follicular lymphomas <3.0 cm can be controlled locally with doses of 27.8-30.8 Gy, and there is a trend toward a higher incidence of late complications with doses of >30.8 Gy. Doses of 25-30 Gy delivered in 15-20 fractions should be examined prospectively in patients with follicular lymphomas of <3.0 cm.

Correlation between lung fibrosis and radiation therapy dose after concurrent radiation therapy and chemotherapy for limited small cell lung cancer.

PURPOSE: To evaluate the relationship between physician-identified radiographic fibrosis, lung tissue physical density change, and radiation dose after concurrent radiation therapy and chemotherapy for limited small cell lung cancer. MATERIALS AND METHODS: Fibrosis volumes of different severity levels were delineated on computed tomography (CT) images obtained at 1-year follow-up of 21 patients with complete response to concurrent radiation therapy and chemotherapy for limited small cell lung carcinoma. Delivered treatments were reconstructed with a three-dimensional treatment planning system and geometrically registered to the follow-up CT images. Tissue physical density change and radiation dose were computed for each voxel within each fibrosis volume and within normal lung. Patient responses were grouped per radiation and chemotherapy protocol. RESULTS: A significant correlation was noted between fibrosis grade and tissue physical density change and fibrosis grade. For doses less than 30 Gy, the probability of observing fibrosis was less than 2% with conventional fractionation and less than 4% with accelerated fractionation. Physical lung density change also showed a threshold of 30-35 Gy. For doses of 30-55 Gy and cisplatin and etoposide (PE) chemotherapy, fibrosis probability was 2.0 times greater for accelerated fractionation compared with conventional fractionation (P < .005) and was correlated to increasing dose for both fractionation schedules. CONCLUSION: Lung tissue physical density changes correlated well with fibrosis incidence, and both increased with increasing dose greater than a threshold of 30-35 Gy. With concurrent PE chemotherapy, fibrosis probability was twice as great with accelerated fractionation as with once-daily fractionation.

Hematologic recovery after central lymphatic irradiation for patients with stage I-III follicular lymphoma.

BACKGROUND: The authors previously reported that central lymphatic irradiation (CLI) can induce molecular remission in patients with Stage I-III follicular lymphoma, as measured by polymerase chain reaction analysis for t(14;18) (q32;q21). Hematologic toxicity has been considered a major consequence of CLI. This study was undertaken to analyze the patterns of hematologic recovery after CLI. METHODS: Thirty-three patients with Stage I-III follicular lymphoma were treated with CLI between January 1993 and February 1998. CLI consisted of irradiation to mantle, upper two-thirds of abdomen, and pelvic fields. Each field was treated to 30.0-30.6 grays (Gy) at 1.5-1.8 Gy per fraction, with a boost to 36.0-39.6 Gy at the same rate to the sites of macroscopic disease. A break of approximately 4 weeks was given after treatment of each field. Twenty-four patients who were followed for a minimum of 1 year from the end of CLI form the basis of this analysis. Fourteen patients were male. Three patients had Stage I disease, 6 patients had Stage II disease, and 15 patients had Stage III disease. The International Prognostic Index (IPI) for malignant lymphoma was 0 for 5 patients, 1 for 13 patients, and 2 for 6 patients. The Eastern Cooperative Oncology Group performance status was 0 for 21 patients and 1 for 3 patients. The median values for their pretreatment characteristics were as follows: age, 60 years (range, 34-73 years); height, 173 cm (range, 155-193 cm); weight, 79 kg (range, 57-107 kg); body surface area (BSA), 1.95 m(2) (range, 1.61-2.31 m(2)); bone marrow cellularity, 27%(range, 2-75%), platelet count, 233,000/mm(3) (range, 139,000-339,000/mm(3)), white blood cell (WBC) counts, 6400/mm(3) (range, 4200-10,900/mm(3)); and hemoglobin, 14.5 mg/dL (range, 11.8 -16.6 mg/dL). The median duration of CLI was 159 days (range, 137-345 days). Ten patients had cardiovascular disease. The number of sites receiving a boost dose of > or = 36.0 Gy was 0 sites in 1 patient, 1 site in 6 patients, 2 sites in 11 patients, 3 sites in 5 patients, and 4 sites in 1 patient. The platelet, hemoglobin, and WBC counts were followed every 3 months after completion of CLI. These counts were normalized to the pretreatment counts for statistical analyses. Univariate and multivariate analyses were performed to investigate the correlations between patient factors and hematologic status at 1 year posttreatment. Pearson correlation analysis was used for the continuous factors (patient age, height, weight, BSA, bone marrow cellularity, and duration of CLI), and the Mann-Whitney test was used for categoric factors (IPI, gender, performance status, stage, number of sites receiving > or = 36.0 Gy, and presence or absence of cardiovascular disease). RESULTS: There was continued recovery, essentially approaching the pretreatment levels, over 3 years for platelet, WBC, and hemoglobin counts. Factors that were associated significantly with normalized platelet counts at 1 year by univariate analyses were age (P = 0.015) and cardiovascular disease (P = 0.041). Age was the only significant factor by multivariate analyses, with older patients having lower platelet counts at 1 year posttreatment. No factors were found that were associated significantly with 1-year normalized WBC or hemoglobin levels by either univariate or multivariate analyses. CONCLUSIONS: All three of the hematologic components (platelets, WBC, and hemoglobin) essentially recover after patients undergo CLI over a 3-year period. Older age was the only significant adverse factor that affected the platelet recovery, as detected by multivariate analysis. (c) 2001 American Cancer Society.

Treatment of unicentric and multicentric Castleman disease and the role of radiotherapy.

BACKGROUND: Although surgery is considered standard therapy for unicentric Castleman disease, favorable responses to radiotherapy also have been documented. The authors undertook this study to analyze the clinical factors, treatment approaches, and outcomes of patients with unicentric or multicentric Castleman disease, and to report the outcomes of patients with unicentric Castleman disease treated with radiotherapy. METHODS: The authors reviewed the medical records of 22 patients who had received a histologic diagnosis of Castleman disease at the University of Texas M. D. Anderson Cancer Center between 1988 and 1999. One patient with a concurrent histopathologic diagnosis of nonsecretory multiple myeloma was excluded from the study. In all patients, the diagnosis of Castleman disease was based on the results of lymph node biopsies. Disease was categorized as being either unicentric or multicentric and further subdivided into hyaline vascular, plasma cell, or mixed variant histologic types. Clinical variables and outcomes were analyzed according to treatment, which consisted of surgery, chemotherapy, or radiotherapy. RESULTS: Records from 21 patients were analyzed: 12 had unicentric disease, and 9 had multicentric disease. The mean follow-up time for the entire series was 51 months (median, 40 months). Four patients with unicentric disease were treated with radiotherapy alone: 2 remain alive and symptom free, 2 died of causes unrelated to Castleman disease and had no evidence of disease at last follow-up. Eight patients with unicentric disease were treated with complete or partial surgical resection, and all are alive and asymptomatic. All nine patients with multicentric disease were treated with combination chemotherapy: five are alive with no evidence of disease, and four are alive with progressive disease. CONCLUSIONS: Surgery results in excellent rates of cure in patients with unicentric Castleman disease; radiotherapy can also achieve clinical response and cure in selected patients. Multicentric Castleman disease is a more aggressive clinical entity and is most effectively treated with combination chemotherapy, whereas the role of radiotherapy in its treatment remains unclear.

Bulky disease is an adverse prognostic factor in patients treated with chemotherapy comprised of cyclophosphamide, doxorubicin, vincristine, and prednisone with or without radiotherapy for aggressive lymphoma.

BACKGROUND: In the current study, the authors analyzed prognostic factors in patients with aggressive lymphoma treated with a chemotherapy regimen comprised of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) with or without radiotherapy. METHODS: Between September 1988 and December 1996, 294 patients with newly diagnosed, clinical Ann Arbor Stage I-IV, aggressive lymphoma were enrolled on 2 protocols at The University of Texas M. D. Anderson Cancer Center. Patients on these studies had a relatively favorable prognosis; 100% had M. D. Anderson tumor scores 1 extranodal site of disease (P < 0.001), bulky disease (>or= 7 cm) (P = 0.005), and an at least 10% elevation in the serum lactate dehydrogenase (LDH) level (P = 0.007). Patient age > 60 years (P = 0.001), bulky disease (P = 0.016), and an at least 10% elevation in the serum LDH level (P = 0.040) also were found to be independent prognostic factors for overall survival. CONCLUSIONS: The independent prognostic factors in the current study suggest that either the M. D. Anderson tumor score system or the IPI can be used to select which aggressive lymphoma patients are at high risk for disease recurrence based on their having more than two adverse factors and who consequently are candidates for more intensive frontline therapy. Involved-field radiotherapy should be considered in those patients with bulky lymphomas.

Radiation therapy after a partial response to CHOP chemotherapy for aggressive lymphomas.

PURPOSE: To analyze the results with involved-field radiotherapy after aggressive lymphomas had decreased in size by 50-99% in response to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)-based chemotherapy. METHODS AND MATERIALS: From 1988 through 1996, 294 previously untreated patients with Working Formulation intermediate-grade or large-cell immunoblastic lymphomas underwent CHOP-based chemotherapy on 2 consecutive protocols at the M. D. Anderson Cancer Center. Forty-four (15%) of these patients achieved, based on international working group guidelines, a partial (50-75%) response (n = 25), or unconfirmed complete (76-99%) response (n = 19) to a median of 6 cycles of chemotherapy. These patients were treated with salvage involved-field radiotherapy (n = 32) or chemotherapy (n = 12), e.g., MINE-ESHAP, without autologous stem-cell rescue (ASCR). RESULTS: Median follow-up was 43 months. Partial responders experienced similar outcomes to unconfirmed complete responders. Local control (4-year rates: 86% vs. 53%, p = 0.009) and progression-free survival (4-year rates: 67% vs. 8%, p < 0.0001), but not overall survival (4-year rates: 70% vs. 50%, p = 0.067) were significantly better in those who received salvage radiotherapy, which was well tolerated. CONCLUSION: Progression-free and overall survival in aggressive lymphoma patients who underwent salvage radiotherapy were similar to results reported for high-dose chemotherapy with ASCR. The role of salvage radiotherapy in partial and unconfirmed complete responders to CHOP chemotherapy justifies examination in a large, cooperative group trial.

Mantle irradiation alone for pathologic stage I and II Hodgkin's disease: long-term follow-up and patterns of failure.

PURPOSE: We performed a retrospective study to determine the long-term outcome, patterns of failure, and prognostic factors for patients with pathologic Stage I or II Hodgkin's disease (HD) who were treated with mantle irradiation alone. METHODS AND MATERIALS: The medical records of 145 patients with pathologic Stage I or II supradiaphragmatic Hodgkin's disease treated with mantle irradiation alone between June 1967 and June 1991 were reviewed. Patterns of failure, overall survival (OS) rate, and progression-free survival (PFS) rate were determined. Univariate and multivariate analyses were performed to identify adverse prognostic factors for OS and PFS. The number of adverse prognostic factors per patient was counted, and a prognostic score was assigned to each patient. The log-rank test was used to compare the OS or PFS rates among patients with prognostic scores 0, 1, and 2. RESULTS: The median patient age was 27 years (range 10-66), with almost even male to female distribution. Every patient had splenectomy and negative laparotomy (LAP). Fifty-one patients had Stage I disease (IA-49, IB-2) and 94 Stage II (IIA-89, IIB-5). The histologic subtypes were nodular sclerosing in 110, mixed cellularity in 28, lymphocyte predominance in 5, lymphocyte depleted in 1, and unclassified in 1. Twelve patients with Stage II disease had >/= 3 sites of nodal involvement. Fifty-four patients had a prognostic score of 0, 70 of 1, and 21 of 2. The median follow-up time for the 109 surviving patients was 146 months (range 25-381). The 10- and 20-year actuarial OS rates for the whole group were 87.6% and 65.3%, respectively. The corresponding actuarial PFS rates were 75.3% and 74.2%, respectively. Thirty-six patients (9 Stage I, 27 Stage II) had relapses in a total of 41 sites. Failures by histology were 29 patients with nodular sclerosing, 6 with mixed cellularity, and 1 with lymphocyte predominance. Failures by sites were: trans-diaphragmatic, 22 (para-aortic nodes, 15; as the only site of progression in 12; visceral, 7; as the only site of progression in 5); within radiation field, 8; marginal miss, 8 (as the only site of failure in 2); and unknown, 3. The majority of the failures occurred within 5 years of diagnosis. Long-term side effects of radiation included cardiac complications in 30 patients, with 10- and 20-year actuarial cardiac complication rates of 12.6% and 35.1%, respectively; secondary solid tumors in 14, with 10- and 20-year actuarial rates of 2.3% and 25.7%, respectively; leukemia in 4; non- Hodgkin's lymphoma in 4, with the 10- and 20-year actuarial rates for leukemia and non-Hodgkin's lymphoma of 4.0% and 13.9%; and hypothyroidism in 38. Four adverse prognostic factors were identified for PFS: age > or = 40 years, > or = 3 sites of involvement, male sex, and constitutional symptoms. The prognostic score correlated with patients' outcome as indicated by PFS and OS rates. Patients with a prognostic score of 0 did significantly better than those with a score of 1 or 2. CONCLUSION: In this select group of patients with pathologic Stage I and II Hodgkin's disease treated with mantle irradiation alone, the OS and PFS rates at 10 and 20 years were comparable to those reported in the literature. The major pattern of disease progression was relapse below the diaphragm, therefore close surveillance of the abdomen is warranted. The prognostic score used in our series may predict the patient's outcome, and might be worth testing in a prospective trial. In our series, patients with a prognostic score of 0 had excellent long-term survival, indicating adequate treatment with mantle irradiation alone. Late complications of the treatment pose a significant threat for the patient's survival with long-term follow-up.

Biology-based combined-modality radiotherapy: workshop report.

PURPOSE: The purpose of this workshop summary is to provide an overview of preclinical and clinical data on combined-modality radiotherapy. METHODS AND MATERIALS: The 8th Annual Radiation Workshop at Round Top was held April 13-16, 2000 at the International Festival Institute (Round Top, TX). RESULTS: Presentations by 30 speakers (from Germany, Netherlands, Australia, England, and France along with U.S. participants and M. D. Anderson Cancer Center faculty) formed the framework for discussions on the current status and future perspectives of biology-based combined-modality radiotherapy. CONCLUSION: Cellular and molecular pathways available for radiation modification by chemical and biologic agents are numerous, providing new opportunities for translational research in radiation oncology and for more effective combined-modality treatment of cancer.

Clinical stage IEA-IIEA orbital lymphomas: outcomes in the era of modern staging and treatment.

BACKGROUND AND PURPOSE: The present study examines outcomes in patients with primary orbital lymphomas who underwent complete staging. MATERIALS AND METHODS: From 1978 to 1997, 21 adult patients at the M.D. Anderson Cancer Center had stage IEA-IIEA orbital non-Hodgkin's lymphomas based on staging that included computed tomography scans. Sixteen (76%) patients had working formulation low-grade lymphomas, and five (24%) had aggressive lymphomas. Fourteen of 16 (88%) patients with low-grade lymphomas were treated with radiotherapy alone, and four of five (80%) patients with aggressive lymphomas were treated using combination chemotherapy with or without radiotherapy. Total radiotherapy doses ranged from 30.0 to 40.0 Gy using daily 1.5-2.0 Gy fractions. RESULTS: The median follow-up was 84 months. For the low-grade lymphomas, the 5-year local control, progression-free survival, and overall survival rates were 100, 100, and 92%, respectively. For the seven low-grade lymphomas treated with radiotherapy alone to 30.0 Gy in 20 fractions, the 5-year local control, progression-free, and overall survival rates were 100, 100, and 75%, respectively. The 5-year incidence of complications, which were typically mild, in eyes irradiated to 30 Gy in 20 fractions versus higher biologically effective doses were 25 and 38%, respectively (P = 0.62). Of the five patients with aggressive lymphomas, none of the four who underwent chemotherapy with or without radiotherapy relapsed (all four remain alive), whereas the one treated with radiotherapy alone for stage IEA disease experienced a distant relapse. CONCLUSIONS: In patients with low-grade lymphomas, a good therapeutic ratio was obtained with low-dose radiotherapy alone. In patients with aggressive lymphomas, chemotherapy with or without radiotherapy resulted in excellent local control, progression-free survival, and overall survival; however, the statistical power was limited.

Subunit-subunit interactions in trimeric arginase. Generation of active monomers by mutation of a single amino acid.

The structure of the trimeric, manganese metalloenzyme, rat liver arginase, has been previously determined at 2.1-A resolution (Kanyo, Z. F., Scolnick, L. R., Ash, D. E., and Christianson, D. W., (1996) Nature 383, 554-557). A key feature of this structure is a novel S-shaped oligomerization motif at the carboxyl terminus of the protein that mediates approximately 54% of the intermonomer contacts. Arg-308, located within this oligomerization motif, nucleates a series of intramonomer and intermonomer salt links. In contrast to the trimeric wild-type enzyme, the R308A, R308E, and R308K variants of arginase exist as monomeric species, as determined by gel filtration and analytical ultracentrifugation, indicating that mutation of Arg-308 shifts the equilibrium for trimer dissociation by at least a factor of 10(5). These monomeric arginase variants are catalytically active, with k(cat)/K(m) values that are 13-17% of the value for wild-type enzyme. The arginase variants are characterized by decreased temperature stability relative to the wild-type enzyme. Differential scanning calorimetry shows that the midpoint temperature for unfolding of the Arg-308 variants is in the range of 63.6-65.5 degrees C, while the corresponding value for the wild-type enzyme is 70 degrees C. The three-dimensional structure of the R308K variant has been determined at 3-A resolution. At the high protein concentrations utilized in the crystallizations, this variant exists as a trimer, but weakened salt link interactions are observed for Lys-308.

Localized non-Hodgkin lymphoma involving the thyroid gland.

BACKGROUND: The current study was undertaken to define the natural history and patterns of failure of localized non-Hodgkin lymphoma (NHL) involving the thyroid gland. METHODS: A retrospective review of 51 patients with Ann Arbor Stage I or II NHL involving the thyroid gland was performed. The median age of the patients was 59 years. There were 33 females. There were 21 patients with Stage I disease and 30 patients with Stage II disease. The International Prognostic Index (IPI) was known for 43 patients (it was 0 in 16 patients and > or = 1 in 27 patients). Fifteen patients had mediastinal involvement. Four patients underwent thyroidectomy, 18 patients received radiation therapy, 5 patients received chemotherapy, and 24 patients received combined modality therapy (CMT) with chemotherapy and radiation therapy. Treatment modality, patient gender, IPI, disease stage, and mediastinal involvement were examined for significance with regard to overall survival (OS) and failure free survival (FFS). RESULTS: The 5-year OS and FFS rates were 64% and 76%, respectively. The 5-year FFS rates by treatment regimen were 76% for radiation therapy, 50% for chemotherapy, and 91% for CMT (P = 0.15). IPI was found to be the only significant predictor of OS. The 5-year OS rates were 86% and 50%, respectively, for IPIs of 0 and > or = 1 (P = 0.02). None of the 5 variables were found to correlate significantly with FFS, although the 5-year FFS rates were 93% and 68%, respectively, for IPIs of 0 and > or = 1 (P = 0.08). Eleven patients failed treatment. Nine patients had a component of distant failure across the diaphragm. CONCLUSIONS: The prognosis of patients with localized NHL involving the thyroid gland appears to be very good, especially when CMT is used. Distant recurrences appear to account for the majority of treatment failures. The IPI was found to be a significant prognostic factor for OS and a marginal one for FFS.

Probing erectile function: S-(2-boronoethyl)-L-cysteine binds to arginase as a transition state analogue and enhances smooth muscle relaxation in human penile corpus cavernosum.

The boronic acid-based arginine analogue S-(2-boronoethyl)-L-cysteine (BEC) has been synthesized and assayed as a slow-binding competitive inhibitor of the binuclear manganese metalloenzyme arginase. Kinetic measurements indicate a K(I) value of 0.4-0.6 microM, which is in reasonable agreement with the dissociation constant of 2.22 microM measured by isothermal titration calorimetry. The X-ray crystal structure of the arginase-BEC complex has been determined at 2.3 A resolution from crystals perfectly twinned by hemihedry. The structure of the complex reveals that the boronic acid moiety undergoes nucleophilic attack by metal-bridging hydroxide ion to yield a tetrahedral boronate anion that bridges the binuclear manganese cluster, thereby mimicking the tetrahedral intermediate (and its flanking transition states) in the arginine hydrolysis reaction. Accordingly, the binding mode of BEC is consistent with the structure-based mechanism proposed for arginase as outlined in Cox et al. [Cox, J. D., Cama, E., Colleluori D. M., Pethe, S., Boucher, J. S., Mansuy, D., Ash, D. E., and Christianson, D. W. (2001) Biochemistry 40, 2689-2701.]. Since BEC does not inhibit nitric oxide synthase, BEC serves as a valuable reagent to probe the physiological relationship between arginase and nitric oxide (NO) synthase in regulating the NO-dependent smooth muscle relaxation in human penile corpus cavernosum tissue that is required for erection. Consequently, we demonstrate that arginase is present in human penile corpus cavernosum tissue, and that the arginase inhibitor BEC causes significant enhancement of NO-dependent smooth muscle relaxation in this tissue. Therefore, human penile arginase is a potential target for the treatment of sexual dysfunction in the male.