Diamine Functionalized Cubic Mesoporous Silica for Ibuprofen Controlled Delivery.

A diamine functionalized cubic mesostructured KIT-6 (N-KIT-6) has been prepared by post-synthetic method using calcined mesoporous KIT-6 with a diamine source, i.e., N-'[3-(tri methoxysilyl)- propyl]'ethylenediamine. The KIT-6 mesoporous silica used for N-KIT-6 was synthesized under weak acidic hydrothermal method using bitemplates, viz., Pluronic P123 and 1-butanol. The synthesized mesoporous materials, KIT-6 and N-KIT-6, have been characterized by the relevant instrumental techniques such as SAXS, N2 sorption isotherm, FT-IR, SEM, TEM and TGA to prove the standard mesoporous materials with the identification of diamine groups. The characterized mesoporous materials, KIT-6 and N-KIT-6, have been extensively used in the potential application of controlled drug delivery, where ibuprofen (IBU) employed as a model drug. The rate of IBU adsorption and release was monitored by UV vis-spectrometer. On the basis of the experimental results of controlled drug delivery system, the results of IBU adsorption and releasing rate in N-KIT-6 are higher than those of KIT-6 because of the higher hydrophobic nature as well as rich basic sites on the surface of inner pore wall silica.

Framework functionalization of periodic mesoporous organosilica with 1,2-bis[3-(triethoxysilylpropyl)ureido] cyclohexane function via basic co-condensation self-assembly.

The synthesized bis silylated long alkyl chain containing organosilicate precursor, 1,2-bis(3-(triethoxysilylpropyl)ureido)cyclohexane (BSPUCh) has been used as co-precursor with 1,2-bis (triethoxysilyl)ethane (BTSE) for the preparation of functional periodic mesoporous organosilicas (PMOs) via surfactant-mediated basic co-condensation self-assembly method. The various characterization techniques such as X-ray diffraction patterns (XRD), transmission electron microscope (TEM), N2 adsorption-desorption isotherms (BET), FT-IR, and 13C and 29Si CPMAS NMR spectroscopies were used to characterize the resulting structure of functionalized PMO mesostructures. Results obtained from XRD, TEM, and BET analysis clearly showed that the structural and pore arrangement of the functionalized PMOs were found to be dependent on the used concentration of BSPUCh. The functional PMOs showed well ordered mesophases when BSPUCh concentration was < or = 9 wt% in the initial mixtures, whereas higher concentration of the BSPUCh always produced disordered hierarchical mesostructures with bimodal pore size distributions. The incorporation of BSPUCh also reduces the surface area, pore volume, pore size, and pore wall thickness of the functionalized nanostructures, indicating that the BSPUCh is incorporated in the pore channels of the PMOs. The solid-state 13C and 29Si NMR spectra showed that the BSPUCh organosilicate with non-hydrolyzable bridging ligands propylureidocyclohexane has been successfully covalently linked in the framework of the resulting functional PMOs.

Toxicity of repeated intravenous injection of gene therapeutics for X-CGD in mice.

We made gene therapeutics for X-chronic granulomatous disease (CGD) by transducing murine bone marrow-derived stem cells with MT-gp91 retrovirus and evaluated possible toxicity in mice as a prerequisite for human clinical trials. Male C57BL/6 mice were injected intravenously with gene therapeutics for X-CGD twice at an interval of two weeks at 5 x 10(7) cells/kg and sacrificed 2 weeks after the last administration. Significant changes noted in gene therapeutics for X-CGD-treated animals were an increase in white blood cell counts and a slight decrease in albumin/globulin ratio. The red pulp hyperplasia in the spleen accompanied with an increase in organ weight was considered to result from the accumulation of gene therapeutics for X-CGD, bone marrow-derived stem cells, in the spleen. No anti-gp91 antibody was detected in the sera collected from the animals treated with gene therapeutics for X-CGD. No integration of gp91 DNA from retroviral vector was detected in chromosomal DNA of gonads in animals dosed with the test substance, indicating no potential of genomic integration. In conclusion, the repeated dose of gene therapeutics for X-CGD exerted no toxicity. The splenic red pulp hyperplasia and the increase observed in white blood cell counts and in spleen weights were considered as pharmacological changes induced by the treatment.

Total body irradiation, fludarabine, melphalan, and allogeneic hematopoietic stem cell transplantation for advanced pediatric hematologic malignancies.

We evaluated the efficacy and toxicity of adding 9 Gy of total body irradiation (TBI), in three single daily fractions of 3 Gy, to the reduced intensity regimen of fludarabine 30 mg/m2 i.v. x 4 days and melphalan 140 mg/m2 i.v. x 1 day in advanced pediatric hematologic malignancies. Twenty-two acute lymphoblastic leukemia (ALL), six acute myeloid leukemia (AML), and one non-Hodgkin lymphoma patients were transplanted. Of these, 13 were beyond second remission, and five had prior hematopoietic stem cell transplant (HSCT). Twenty-one donors were unrelated, of which 19 were from cord blood (CB) units. Three of the eight related donors were genotypically disparate. Oral mucositis and diarrhea were the most common toxicities. Twenty-seven patients achieved neutrophil engraftment (median 16 days), and 23 had platelet engraftment (median 42 days). One patient had primary graft failure. Seven patients died of non-relapse causes in the first 100 days. With a median follow-up of 52 months, seven of 22 ALL, five of six AML, and one of one lymphoma patients are alive and in remission. The regimen of TBI, fludarabine, and melphalan allows the engraftment of allogeneic hematopoietic stem cells (including mismatched CB). It was fairly well tolerated in pediatric patients, even for second transplants. Its efficacy requires further evaluation.

Allogeneic hematopoietic stem cell transplantation after rituximab-containing myeloablative preparative regimen for acute lymphoblastic leukemia.

We explored the safety and efficacy of rituximab administered in combination with the standard transplant conditioning regimen of cyclophosphamide (Cy) 120 mg/kg and total body irradiation (TBI) 12 Gy for adult patients with acute lymphoblastic leukemia (ALL). Patients were eligible if their disease expressed CD20. Rituximab was administered at 375 mg/m2 weekly for four doses beginning on day -7 of the conditioning regimen. Graft-versus-host-disease (GVHD) prophylaxis consisted of tacrolimus and methotrexate. Thirty-five patients undergoing matched sibling (n = 23) or unrelated donor (n = 12) transplantation were studied, with a median age of 30 years (range 15-55 years). At 2 years, progression-free survival, treatment-related mortality, and overall survival were 30, 24, and 47%, respectively. There was no delay in engraftment or increased incidence of infection. The cumulative incidence of grade II-IV acute GVHD was 17%, and limited and extensive chronic GVHD was 43% at 2 years. The addition of rituximab to the standard Cy/TBI transplant conditioning regimen in ALL was safe and well tolerated, and there was a suggestion of decreased incidence of acute GVHD when compared to historically reported GVHD rates for this group of patients.

Rectal and bladder dose reduction with the addition of intravaginal balloons to vaginal packing in intracavitary brachytherapy for cervical cancer.

PURPOSE: The use of intravaginal Foley balloons in addition to conventional packing during high-dose-rate (HDR) tandem and ovoids intracavitary brachytherapy (ICBT) is a means to improve displacement of organs at risk, thus reducing dose-dependent complications. The goal of this project was to determine the reduction in dose achieved to the bladder and rectum with intravaginal Foley balloons with CT-based planning and to share our packing technique. METHODS AND MATERIALS: One hundred and six HDR-ICBT procedures performed for 38 patients were analyzed for this report. An uninflated Foley balloon was inserted into the vagina above and below the tandem flange separately and secured in place with vaginal packing. CT images were then obtained with both inflated and deflated Foley balloons. Plan optimization occurred and dose volume histogram data were generated for the bladder and rectum. Maximum dose to 0.1, 1.0, and 2.0 cm(3) volumes for the rectum and bladder were analyzed and compared between inflated and deflated balloons using parametric statistical analysis. RESULTS: Inflation of intravaginal balloons allowed significant reduction of dose to the bladder and rectum. Amount of reduction was dependent on the anatomy of the patient and the placement of the balloons. Displacement of the organs at risk by the balloons allowed an average of 7.2% reduction in dose to the bladder (D0.1 cm(3)) and 9.3% to the rectum (D0.1 cm(3)) with a maximum reduction of 41% and 43%, respectively. CONCLUSIONS: For patients undergoing HDR-ICBT, a significant dose reduction to the bladder and rectum could be achieved with further displacement of these structures using intravaginal Foley balloons in addition to conventional vaginal packing.

Primary cutaneous non-Hodgkin's lymphoma of Ann Arbor stage I: preferential cutaneous relapses but high cure rate with doxorubicin-based therapy.

PURPOSE: Establish frequency, presenting features, response and relapse patterns, and outcome of primary cutaneous non-Hodgkin's lymphoma (PCNHL). PATIENTS AND METHODS: Review of untreated patients, older than 16 years, presenting between 1971 and 1993 with cutaneous lymphoma, not mycosis fungoides, and Ann Arbor stage I. RESULTS: We identified 46 patients, 27 males, with median age of 57 years. Treatment was radiotherapy in 10 patients, doxorubicin-based therapy in 33 patients that was followed by radiotherapy in 25 patients, and other combination with radiotherapy in one patient. The complete response rate was 95%. After a median follow-up of 140 months (range, 61 to 284 months), 18 patients have relapsed, and 14 have died from lymphoma. The first failure was exclusively cutaneous in 50% of relapses. For the 44 treated patients, progression-free survival (PFS; actuarial +/- SE) was 61% +/- 7% and survival was 58% +/- 9% at 12 years. For the 18 patients with diffuse large B-cell lymphoma, after doxorubicin-based regimens, PFS was 71% +/- 12% (P = .0003) versus 0% after radiotherapy; survival was 77% +/- 12% versus 25% +/- 22% (P = 004), respectively. For the nine patients with follicular center-cell lymphoma treated with combined modality, the 12-year PFS was 89% +/- 11% and survival 70% +/- 18%. CONCLUSION: PCNHL is rare, and its first relapse is exclusively cutaneous in 50% of patients. Patients with diffuse large B-cell lymphoma are curable with doxorubicin-based regimens but not with radiotherapy. Prospective studies in PCNHL should define the cytogenetics, the basis for cutaneous tropism, the prognosis of histologic subtypes, and the role of radiotherapy.

Results of treatment with hyper-CVAD, a dose-intensive regimen, in adult acute lymphocytic leukemia.

PURPOSE: To evaluate the efficacy and toxicity of Hyper-CVAD (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone), a dose-intensive regimen, in adult acute lymphocytic leukemia (ALL). PATIENTS AND METHODS: Adults with newly diagnosed ALL referred since 1992 were entered onto the study; treatment was initiated in 204 patients between 1992 and January 1998. No exclusions were made because of older age, poor performance status, organ dysfunction, or active infection. Median age was 39.5 years; 37% were at least 50 years old. Mature B-cell disease (Burkitt type) was present in 9%, T-cell disease in 17%. Leukocytosis of more than 30 x 10(9)/L was found in 26%, Philadelphia chromosome-positive disease in 16% (20% of patients with assessable metaphases), CNS leukemia at the time of diagnosis in 7%, and a mediastinal mass in 7%. Treatment consisted of four cycles of Hyper-CVAD alternating with four cycles of high-dose methotrexate (MTX) and cytarabine therapy, together with intrathecal CNS prophylaxis and supportive care with antibiotic prophylaxis and granulocyte colony-stimulating factor therapy. Maintenance in patients with nonmature B-cell ALL included 2 years of treatment with mercaptopurine, MTX, vincristine, and prednisone (POMP). RESULTS: Overall, 185 patients (91%) achieved complete remission (CR) and 12 (6%) died during induction therapy. Estimated 5-year survival and 5-year CR rates were 39% and 38%, respectively. The incidence of CNS relapse was low (4%). Compared with 222 patients treated with vincristine, doxorubicin, and dexamethasone (VAD) regimens, our patients had a better CR rate (91% v 75%, P <.01) and CR rate after one course (74% v 55%, P <.01) and better survival (P <.01), and a smaller percentage had more than 5% day 14 blasts (34% v 48%, P =.01). Previous prognostic models remained predictive for outcome with Hyper-CVAD therapy. CONCLUSION: Hyper-CVAD therapy is superior to our previous regimens and should be compared with established regimens in adult ALL.

Rapid recovery of spermatogenesis after mitoxantrone, vincristine, vinblastine, and prednisone chemotherapy for Hodgkin's disease.

PURPOSE: Because the effects of mitoxantrone on human male fertility were unknown, we determined prospectively the effects of three courses of mitoxantrone (Novantrone), vincristine (Oncovin), vinblastine, prednisone (NOVP) chemotherapy on the potential for fertility of men with Hodgkin's disease (HD). PATIENTS AND METHODS: Semen analyses were performed on 58 patients with stages I-III HD before, during, and after chemotherapy and after the sperm count recovered from the effects of abdominal radiotherapy that was given after chemotherapy. RESULTS: Before the initiation of treatment, 84% of the patients were normospermic. Sperm counts declined significantly within 1 month after the start of NOVP chemotherapy. In the month after chemotherapy, 38% of patients were azoospermic, 52% had counts < 1 million/ mL, and 10% had counts between 1 and 3 million/mL. Between 2.6 and 4.5 months after the completion of chemotherapy, sperm counts recovered rapidly to normospermic levels in 63% of patients. In the remaining patients who were followed up for at least 1 year after standard upper abdominal radiotherapy, counts also recovered to normospermic levels. CONCLUSION: NOVP chemotherapy, like most other regimens, produced marked temporary effects or spermatogenesis. However, sperm production recovered very rapidly, within 3 to 4 months after the end of NOVP chemotherapy. This pattern was caused by killing differentiating spermatogenic cells, but there was little cytotoxicity or inhibition of stem cells from mitoxantrone or the other drugs. After the combination of NOVP plus abdominal radiotherapy, sperm counts and motility were restored in most patients to pretreatment levels, which were compatible with normal fertility.

Serial determination of the bcl-2 gene in the bone marrow and peripheral blood after central lymphatic irradiation for stages I-III follicular lymphoma: a preliminary report.

Two-thirds of patients with follicular lymphoma have rearrangement of bcl-2 major breakpoint region (MBR) through t(14;18) (q32;q21). This rearrangement can serve as a sensitive marker for follicular lymphoma cells. This study was undertaken to assess the molecular complete response rate of stages I-III follicular lymphoma to central lymphatic irradiation (CLI) by detection of PCR-amplifiable bcl-2 MBR rearrangement in the bone marrow and peripheral blood before and after CLI. Twenty patients with stages I-III follicular lymphoma were treated with CLI. Twelve of them were part of a prospective randomization trial comparing CLI with multi-agent chemotherapy. Bone marrow and peripheral blood samples were obtained from the patients before the initiation of treatment. By using the PCR technique, the DNA sequences from the bone marrow and peripheral blood samples that flank the bcl-2 MBR involved in t(14;18) (q32;q21) were amplified. In PCR-positive patients, bone marrow and blood samples were followed at regular intervals during and after CLI. The results of the PCR amplification were correlated with clinical findings. All 20 patients achieved clinical complete response after CLI. Median follow-up was 22 months (range, 12-37 months), and no patient has relapsed. Pretreatment PCR results were available in all patients (19 patients for peripheral blood samples and 16 patients for bone marrow samples). Nine of 19 peripheral blood samples and 9 of 16 bone marrow samples were PCR-positive for bcl-2 MBR rearrangement. Eight PCR-positive patients converted to negative (8 of 9 blood samples and 2 of 3 bone marrow samples) 2-20 months from the first day of CLI. Bone marrow and peripheral blood with PCR-amplifiable bcl-2 MBR rearrangement can be converted from positive to negative after chemotherapy in patients with follicular lymphoma. Early results from our study show for the first time that peripheral blood and bone marrow can be converted from positive to negative after CLI. The prognostic significance of the observed conversions requires longer follow-up.

Dosimetric effect of photon beam energy on volumetric modulated arc therapy treatment plan quality due to body habitus in advanced prostate cancer.

PURPOSE: The purpose of this study was to dosimetrically compare 6- and 10-MV photon beam energies in high-risk prostate cancer patients of various body habitus using a volumetric modulated arc therapy (VMAT) radiation delivery technique. The objectives of the study were to evaluate whether dosimetric differences exist and to investigate whether differences are dependent on patient body habitus. METHODS AND MATERIALS: Forty patients with various body habitus who had previously received treatment to the prostate and pelvic lymph nodes with VMAT techniques were chosen. Patients were planned in the Pinnacle(3) treatment planning system with double or triple SmartArc plans with 6- and 10-MV photon energies. All patients were optimized with the same planning objectives and normalized such that 95% of the planning target volume (PTV) received the prescription dose. Patients were evaluated for PTV and organ at risk (OAR) parameters for the bladder, rectum, small bowel, penile bulb, and sigmoid colon. Metrics used for comparison were D2%, D98%, homogeneity, conformity, and dose falloff for the PTV and D(2%), D(mean), V(80%), V(60%), and V(40%) for OARs. Statistical differences were evaluated with a paired-sample Wilcoxon signed rank test with a significance level of .05. RESULTS: For the PTV, there were no statistically significant differences in D(mean), D(2cc), conformation number, and homogeneity index values, but the dose falloff parameters, R50 and R25, showed a median improvement of 6.7% (P<.01) and 6.2% (P<.01), respectively, with 10 MV. A correlation between patient anterior-posterior distance (d(AP)) and percentage reduction in R50 of 0.436% per centimeter (P<.01) was determined. For OARs, statistically significant reductions in dose metrics were found in the small bowel and bladder, but increases in the D(2cc) of 3.5% in the penile bulb (P<.01) and 0.2% in the rectum (P=.02) were shown with 10 MV. The use of 10 MV also demonstrated a statistically significant reduction in the total number of monitor units of 15.9% (P<.01) compared with 6 MV. CONCLUSIONS: The study showed that 10 MV provides a faster dose falloff than 6 MV for patients whose prostate and pelvic lymph nodes are treated using a VMAT technique irrespective of body habitus; however, the improvement in dose falloff is dependent on body habitus and increases as the patient body habitus increases.

Utilization of thermoluminescent dosimetry in total skin electron beam radiotherapy of mycosis fungoides.

PURPOSE: The purpose of this report is to discuss the utilization of thermoluminescent dosimetry (TLD) in total skin electron beam (TSEB) radiotherapy to: (a) compare patient dose distributions for similar techniques on different machines, (b) confirm beam calibration and monitor unit calculations, (c) provide data for making clinical decisions, and (d) study reasons for variations in individual dose readings. METHODS AND MATERIALS: We report dosimetric results for 72 cases of mycosis fungoides, using similar irradiation techniques on two different linear accelerators. All patients were treated using a modified Stanford 6-field technique. In vivo TLD was done on all patients, and the data for all patients treated on both machines was collected into a database for analysis. Means and standard deviations (SDs) were computed for all locations. Scatter plots of doses vs. height, weight, and obesity index were generated, and correlation coefficients with these variables were computed. RESULTS: The TLD results show that our current TSEB implementation is dosimetrically equivalent to the previous implementation, and that our beam calibration technique and monitor unit calculation is accurate. Correlations with obesity index were significant at several sites. Individual TLD results allow us to customize the boost treatment for each patient, in addition to revealing patient positioning problems and/or systematic variations in dose caused by patient variability. The data agree well with previously published TLD results for similar TSEB techniques. CONCLUSION: TLD is an important part of the treatment planning and quality assurance programs for TSEB, and routine use of TLD measurements for TSEB is recommended.

Gain in target dose from using Computer Controlled Radiation Therapy (CCRT) in the treatment of non-small cell lung cancer.

PURPOSE: A study was undertaken to evaluate the gain from Computer Controlled Radiation Therapy in the treatment of non-small cell lung cancer. The purpose of this study is two-fold: (a) to measure the gain in the minimum target dose provided by Computer Controlled Radiation Therapy and (b) to determine the change in the minimum target dose as a function of the lung tolerance limits. METHODS AND MATERIALS: Six cases of non-small cell lung cancer were studied by stimulating treatments with conventional and Computer Controlled Radiation Therapy techniques. For conventional treatments, a boost dose was delivered to the gross tumor volume via a pair of opposed oblique fields with a fixed gantry angle. For Computer Controlled Radiation Therapy, the gantry angle was allowed to change along the longitudinal axis of the patient. Prescriptions had to satisfy a bound on the maximum dose in the spinal cord and a limit on the amount of contralateral lung which could exceed 20 Gy. The boost dose was increased until either a tolerance limit was reached or minimum target dose of 80 Gy was delivered. RESULTS: A minimum target dose of 80 Gy could be given to three of four patients who could not receive 80 Gy with conventional therapy. A minimum target dose of 80 Gy could be given to the remaining two patients with either technique. CONCLUSION: The gain from computer controlled radiation therapy strongly depended on the chosen lung tolerance limit. A 10 to 20 Gy gain in minimum target dose could be found for some patients, but the gain was significantly reduced for a relatively small decrease in the amount of lung permitted a dose above 20 Gy.

Salvage central lymphatic irradiation in follicular lymphomas following failure of chemotherapy: a feasibility study.

PURPOSE: Management of follicular lymphoma after chemotherapy failure has been controversial and has ranged from watchful waiting to high-dose chemotherapy. High-dose chemotherapy with bone marrow reconstitution may produce clinical and molecular complete responses at the risk of serious morbidity and mortality. It has been previously reported that central lymphatic irradiation (CLI) can achieve long-term relapse-free survival in patients with Stage I, II, or III follicular lymphoma. Therefore, we investigated the feasibility of treating patients in whom front-line chemotherapy failed with salvage CLI instead of instituting more intensive chemotherapy. METHODS AND MATERIALS: Salvage CLI with curative intent for patients with follicular lymphoma was started at The University of Texas M. D. Anderson Cancer Center in 1992. Eleven patients whose disease showed poor response to or relapsed after chemotherapy were managed with this approach. The median age of the patients was 61 years. Criteria for exclusion included bone marrow involvement or other evidence of Ann Arbor Stage IV disease at any time during the course of the disease. Overall survival and relapse-free survival were calculated from the first day of CLI. RESULTS: Ten patients were alive at a median follow-up of 25 months (range 9-73 months). The treatment was well tolerated in general. Two patients could not complete CLI: one 75-year-old patient owing to prolonged platelet count depression and deterioration in general medical condition, and a 66-year-old patient because of exacerbation of preexisting pancytopenia and worsening of heart disease. Everyone who completed CLI remains in remission at the time of this report, except for one patient who had a relapse in the right lacrimal gland at 32 months. This patient was treated with local radiation therapy and is free of disease. Eventual recovery of the blood counts was observed for the patients who completed CLI. CONCLUSION: These results demonstrate for the first time that with CLI, it is possible to achieve complete remission of acceptable quality in follicular lymphoma patients who experience a chemotherapy failure. The main toxicity is limited to transient depression in hematological profiles. The treatment is fairly well tolerated and seems to carry little risk compared with high-dose chemotherapy and bone marrow rescue. Salvage CLI may not necessarily compromise future treatment with chemotherapy, including autologous bone marrow or stem cell transplantation, because the patients' blood counts recover.

The significance of molecular response of follicular lymphoma to central lymphatic irradiation as measured by polymerase chain reaction for t(14;18)(q32;q21).

BACKGROUND: More than 80% of the patients with follicular lymphoma have a characteristic chromosomal translocation, t(14;18)(q32;q21), at the major breakpoint region (MBR) or minor cluster region (MCR) involving the bcl-2 oncogene. This study was undertaken to assess the significance of the molecular response rate measured by the polymerase chain reaction (PCR) evidence of translocation among patients with Stage I to III follicular lymphoma treated with central lymphatic irradiation (CLI). METHODS AND MATERIALS: Thirty-three patients with Stage I-III follicular lymphoma were treated with CLI on a prospective protocol. Bone marrow and peripheral blood samples were obtained before CLI for PCR analysis of t(14;18)(q32; q21). PCR-positive patients were followed by PCR analysis at regular intervals during and after CLI, and the results were correlated with clinical outcome. The following pretreatment factors were also investigated for their relationship to relapse and molecular response: gender, age, lactate dehydrogenase (LDH) and beta-2 microglobulin (beta2M) levels, Ann Arbor stage, and International Prognostic Index (IPI) for malignant lymphoma. RESULTS: The subjects were 19 men and 14 women, with a median age of 52 years (range 30-69), who started CLI between January 1993 and February 1998. Median follow-up was 44 months (range 12-67), and all but 2 patients were still alive at the last follow-up. Four patients were Stage IA, 8 were Stage IIA, 19 were Stage IIIA, and 2 were Stage IIIB. Two patients had abnormal LDH levels (> 618 U/dL) and 7 patients had abnormal beta2M levels (> 2 mg/dL). Nine patients had IPI = 0, 16 had IPI = 1, and 8 had IPI = 2. All patients achieved complete response (CR). Twelve patients have relapsed to date. The median overall time to relapse was 54 months. The actuarial proportion of patients free from relapse at 3 years was 87% (95% confidence interval [CI] 69-95%). A total of 287 PCR results were available, 64 from bone marrow and 223 from peripheral blood. Pretreatment PCR data were available for 27 patients, of whom 21 were positive and 3 were unambiguously negative (in blood and bone marrow for both MBR and MCR). For the 19 PCR positive patients for whom we had post-treatment results, there was a clear and steady decreasing trend toward loss of PCR positivity (49% positive for bone marrow and 32% positive for peripheral blood at 3 years). There was a clear trend for increasing PCR positivity with increasing IPI: 10% for IPI = 0, 31% for IPI = 1, and 63% for IPI = 2 at 3 years for blood. The same trend was also observed for bone marrow. The IPI was the only statistically significant predictor for relapse with a relapse-free survival of 91% at 3 years for IPI < 2 and 75% for IPI = 2 (p = 0.024, log-rank test). CONCLUSION: Molecular response to CLI occurs gradually over years. High IPI is a negative predictor for molecular response and relapse-free survival.

Solitary bone plasmacytoma: outcome and prognostic factors following radiotherapy.

PURPOSE: To clarify the natural history of solitary plasmacytoma of bone (SBP) after radiation treatment. METHODS AND MATERIALS: Between 1965-1996, we identified 57 previously untreated patients with a SBP. A serum myeloma protein was present in 33 patients (58%) and Bence Jones proteinuria was present in an additional eight patients (14%). The median radiotherapy dose was 50 Gy (range, 30-70 Gy). Overall survival, cause-specific survival, and freedom from progression to multiple myeloma were calculated actuarially. RESULTS: Local control was achieved in 55 of 57 patients (96%). For those 29 patients (51%) who subsequently developed multiple myeloma, the median time to progression was 1.8 years. There was a direct correlation between persistence of abnormal protein following radiotherapy and the likelihood of developing multiple myeloma. Among 11 patients with disappearance of myeloma protein, only two developed multiple myeloma after 4 and 12 years, in contrast to progression in 57% of patients with a persistent protein peak and 63 % of those with nonsecretory disease (p = 0.02). Among 23 patients with thoracolumbar spine disease, 7 of 8 patients staged with plain radiographs alone developed multiple myeloma in comparison with 1 of 7 patients who also had magnetic resonance imaging (MRI) (p = 0.08). For all patients, the median survival from radiotherapy was 11.0 years. The median cause-specific survival of patients with disappearance of myeloma protein was significantly longer than that of the remaining patients (p = 0.004). CONCLUSION: Results supported the importance of precise staging that includes MRI of the spine for optimum patient selection and the application of definitive radiotherapy. Those patients with myeloma protein that disappears following radiotherapy represent a category with a high likelihood of cure.

Recovery of sperm production following radiation therapy for Hodgkin's disease after induction chemotherapy with mitoxantrone, vincristine, vinblastine, and prednisone (NOVP).

PURPOSE: The effect on human male fertility of radiotherapy following chemotherapy for the treatment of Hodgkin's disease (HD) is unknown. The impact of radiation therapy, given after mitoxantrone, vincristine, vinblastine, and prednisone (NOVP) chemotherapy, on sperm production is the focus of this study. PATIENTS: Serial semen analyses were performed on 34 patients with HD Stages I-III before NOVP chemotherapy, after chemotherapy prior to radiation, and after radiation therapy. The most inferior radiation portals for patients were: mantle, 1 patient; paraaortic-spleen, 3 patients; upper abdomen, 24 patients; abdominal spade, 4 patients; and pelvic, 2 patients. Testicular radiation dose measurements were available for 20 of these patients. RESULTS: Before the start of radiation, 90% of patients were normospermic. The magnitude of the decline in sperm counts was related to the measured testicular dose and/or radiation fields employed. The minimum postradiotherapy counts, expressed as a fraction of pretreatment counts, for the various treatment groups are as follows: paraaortic-spleen, 20%; upper abdomen, testicular dose < 30 cGy, 4%; upper abdomen, testicular dose 30-39 cGy, 0.9%; abdominal spade, 0.02%; and pelvis, 0%. The time to nadir of sperm counts averaged 4.5 months. Recovery to normospermic levels occurred in 96% of patients, with most recovering to that level within 18 months. CONCLUSION: The effect of radiation following NOVP chemotherapy on sperm counts was no greater than would be expected with radiation therapy alone. In most patients, sperm counts recovered to levels compatible with normal fertility.

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.

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.

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.