Isaac R. Francis

Radioimmunotherapy of B-Cell Lymphoma with [131I]Anti-B1 (Anti-CD20) Antibody

BACKGROUND Many patients with non-Hodgkins lymphomas are not cured by current therapies, and new approaches to treatment are needed. As part of an ongoing phase 1 study, we examined the effect of radioimmunotherapy with 131I-labeled B-cell-specific anti-CD20 monoclonal antibody in 10 patients with CD20-positive B-cell lymphomas in whom primary chemotherapy had failed. METHODS AND RESULTS Anti-B1 (anti-CD20) mouse monoclonal antibody trace-labeled with 131I (15 mg containing 5 mCi) was given intravenously at approximately one-week intervals: first, without pretreatment with unlabeled anti-B1 antibody, to all 10 patients; then, with pretreatment with 135 mg of unlabeled antibody, to 8 patients; and then, with pretreatment with 685 mg, to 2 patients. Serial quantitative gamma-camera images and measures of whole-body radioactivity were obtained after each tracer dose. All known disease sites larger than 2 cm could be imaged. The effect of a pretreatment dose of unlabeled anti-B1 antibody on targeting of the tumor with the radiolabeled antibody was variable. The pretreatment dose of unlabeled antibody that produced the highest ratio of the tumor dose to the whole-body dose in tracer studies was then used to deliver higher doses of radioactivity for radioimmunotherapy in nine patients. Three patients received doses designed to deliver 25 cGy to the whole body (two patients treated twice, six to eight weeks apart), four patients received 35 cGy (one patient treated twice), and two patients received 45 cGy (one patient treated twice); each dose contained 34 to 66 mCi of activity. Six of the nine treated patients had tumor responses, including patients with bulky or chemotherapy-resistant disease: four patients had complete remissions, and two had partial responses. Three patients had objective responses to tracer infusions before they received radioimmunotherapeutic doses. Of the four patients with complete remissions, one remained in remission for eight months and the other three continue to have no disease progression (for 11, 9, and 8 months). There was mild or no myelosuppression. CONCLUSIONS Radioimmunotherapy with [131I]anti-B1 antibody is a promising new treatment for lymphoma.

Poor CD4 T cell restoration after suppression of HIV-1 replication may reflect lower thymic function.

ObjectiveTo characterize immune phenotype and thymic function in HIV-1-infected adults with excellent virologic and poor immunologic responses to highly active antiretroviral therapy (HAART). MethodsCross-sectional study of patients with CD4 T cell rises of ⩾ 200 × 106 cells/l (CD4 responders; n = 10) or < 100 × 106 cells/l (poor responders; n = 12) in the first year of therapy. ResultsPoor responders were older than CD4 responders (46 versus 38 years;P < 0.01) and, before HAART, had higher CD4 cell counts (170 versus 35 × 106 cells/l;P = 0.11) and CD8 cell counts (780 versus 536 × 106 cells/l ; P = 0.02). After a median of 160 weeks of therapy, CD4 responders had more circulating naive phenotype (CD45+CD62L+) CD4 cells (227 versus 44 × 106 cells/l ; P = 0.001) and naive phenotype CD8 cells (487 versus 174 × 106 cells/l ; P = 0.004) than did poor responders (after 130 weeks). Computed tomographic scans showed minimal thymic tissue in 11/12 poor responders and abundant tissue in 7/10 responders (P = 0.006). Poor responders had fewer CD4 cells containing T cell receptor excision circles (TREC) compared with CD4 responders (2.12 versus 27.5 × 106 cells/l ; P = 0.004) and had shorter telomeres in CD4 cells (3.8 versus 5.3 kb ; P = 0.05). Metabolic labeling studies with deuterated glucose indicated that the lower frequency of TREC-containing lymphocytes in poor responders was not caused by accelerated proliferation kinetics. ConclusionPoor CD4 T cell increases observed in some patients with good virologic response to HAART may be caused by failure of thymic T cell production.

Distribution of distant metastases from newly diagnosed non-small cell lung cancer

BACKGROUND The purpose of our study was to determine the incidence and locations of M1 disease at presentation in patients with non-small cell lung cancer to help design appropriate preoperative imaging algorithms. METHODS All patients with non-small cell lung cancer seen between 1991 and 1993 were identified, and records were reviewed. For patients with M1 disease, the sites of distant metastases and the methods of diagnosis were recorded. RESULTS Of 348 patients identified, 276 (79%) had M0 disease and 72 (21%) had M1 disease. In 40 of 72 patients (56%), M1 disease was detected via chest or abdominal computed tomography (CT). Brain, bone, liver, and adrenal glands were the most common sites of metastatic disease, in decreasing order. Brain metastases often occurred as an isolated finding, although isolated liver metastases were uncommon. CONCLUSIONS M1 disease was common at presentation, and was often detectable via chest CT. The incremental yield of abdominal CT over chest CT was very small, and therefore abdominal CT is not an effective method of screening for metastases if chest CT has been performed.

Dose escalation for non-small cell lung cancer using conformal radiation therapy

PURPOSE Improved local control of non-small cell lung cancer (NSCLC) may be possible with an increased dose of radiation. Three-dimensional radiation treatment planning (3D RTP) was used to design a radiation therapy (RT) dose escalation trial, where the dose was determined by (a) the effective volume of normal lung irradiated, and (b) the estimated risk of a complication. Preliminary results of this trial were reviewed. METHODS AND MATERIALS A graph of the iso-normal tissue complication probability (NTCP) levels associated with a dose and effective volume (V(eff)) was derived, using normal tissue parameters derived from the literature. This led to a dose escalation schema, where patients were sorted into 1 of 5 treatment bins, determined by the V(eff) of the best possible treatment plan. The starting doses ranged from 63 to 84 Gy. Each treatment bin was then escalated separately, as in Phase I dose escalation fashion, with Grade > or = 3 radiation pneumonitis defined as dose limiting. To allow for dose escalation, we required patient follow-up to be > or = 6 months for at least three patients. 3D treatment planning was used to irradiate only the radiographically abnormal areas, with 2.1 Gy (corrected for lung inhomogeneity)/day. Clinically uninvolved lymph nodes were not treated prophylactically. RESULTS A total of 48 NSCLC patients have been treated (Stage I/II: 18 patients; Stage III: 28 patients; mediastinal recurrence postsurgery: 2 patients). No radiation pneumonitis has been observed in the 30 patients currently evaluable beyond the 6-month time point. All treatment bins have been escalated at least once. Current doses in the five treatment bins are 69.3, 69.3, 75.6, 84, and 92.4 Gy. None of the 15 evaluable patients in any bin with > or = 30% NTCP experienced clinical radiation pneumonitis, implying that the actual risk is < 20% (beta error rate 5%). Despite the observation of the clinically negative lymph nodes at high risk, there has been no failure in the untreated mediastinum as the sole site of first failure. Three of 10 patients receiving > or = 84 Gy have had biopsy proven residual or locally recurrent disease. CONCLUSION Successful dose escalation in a volume-dependent organ can be performed using this technique. By incorporating the effective volume of irradiated tissue, some patients have been treated to a total dose of radiation over 50% higher than traditional doses. The literature-derived parameters appear to overestimate pneumonitis risk with higher volumes. There has been no obvious negative effect due to exclusion of elective lymph node radiation. When completed, this trial will have determined the maximum tolerable dose of RT as a single agent for NSCLC and the appropriate dose for Phase II investigation.

Frequency, outcome, and appropriateness of treatment of nonionic iodinated contrast media reactions

OBJECTIVE The objective of our study was to evaluate the frequency, outcome, and appropriateness of treatment of adults with acute allergiclike reactions related to IV-administered nonionic iodinated contrast media. MATERIALS AND METHODS For IV injections of nonionic iodinated contrast media between January 1, 1999, and December 31, 2005, contrast reaction reports and medical records of patients in whom contrast reactions occurred were reviewed. Data collected included patient sex and age, symptoms, reaction manifestations, treatment, and long-term sequelae. The appropriateness and efficacy of patient management were assessed. RESULTS Allergic-type reactions occurred in 545 (0.6%) of patients injected with nonionic iodinated contrast media: 418 (77%) reactions were mild, 116 (21%) were moderate, and 11 (2%) were severe. Two hundred twenty-one patients (41%) received treatment. The most commonly administered medication was diphenhydramine (145 patients or 27%). Corticosteroids were administered to 17 patients, nebulized albuterol to 16, and epinephrine to 15. Although 99% of the treatments did not result in any complication, three patients may have had short-term sequelae as a result of receiving a nonrecommended treatment. CONCLUSION Patients usually do well after developing acute allergiclike reactions to nonionic iodinated contrast media. Fortunately, in our series, this was true even in the rare cases in which the instituted treatment was considered to be inappropriate. Reacting patients rarely develop serious long-term sequelae.

Thymic Size and Lymphocyte Restoration in Patients with Human Immunodeficiency Virus Infection after 48 Weeks of Zidovudine, Lamivudine, and Ritonavir Therapy

Human immunodeficiency virus (HIV) infection is associated with progressive loss of circulating CD4+ lymphocytes. Treatment with highly active antiretroviral therapy (HAART) has led to increases in CD4+ T lymphocytes of naive (CD45RA+62L+) and memory (CD45R0+RA-) phenotypes. Thymic computerized tomography scans were obtained on 30 individuals with HIV disease to investigate the role of the thymus in cellular restoration after 48 weeks of HAART. Individuals with abundant thymic tissue had higher naive CD4+ T lymphocyte counts at weeks 2-24 after therapy than individuals with minimal thymic tissue. Individuals with abundant thymic tissue had significantly larger increases in naive CD4+ cells during the first 4 weeks of therapy. These individuals were also more likely to experience viral rebound despite comparable initial declines in plasma HIV-1 RNA. These findings suggest that there is a complex relationship among the thymus, viral replication, and lymphocyte restoration after application of HAART in HIV disease.

Imaging, dosimetry, and radioimmunotherapy with iodine 131-labeled anti-CD37 antibody in B-cell lymphoma.

PURPOSE This study was undertaken to evaluate the tumor targeting, toxicity, and therapeutic potential of the anti-B-cell-reactive monoclonal antibody MB-1 (anti-CD37) labeled with iodine 131 given in a nonmarrow ablative dose range in B-cell lymphoma patients who relapsed after chemotherapy. PATIENTS AND METHODS Twelve patients with MB-1-reactive tumors were infused first with 40 mg of trace-labeled (3 to 7 mCi) MB-1. Ten patients who had no serious toxicity postinfusion and who had successful tumor imaging on serial gamma scans then received at least one 40-mg radioimmunotherapy (RIT) dose (25 to 161 mCi). Tracer estimates of delivered whole-body dose (WBD) were used in prescribing a millicurie RIT dose for seven patients. RESULTS Eleven patients had positive tumor imaging after a tracer dose, including patients with bulky tumors and/or large tumor burdens (> or = 1 kg) +/- splenomegaly. However, overall sensitivity for the detection of known tumor sites was only 39%. In six of eight patients with dose-assessable tumors, the radiation dose to at least one tumor was 1.1 to 3.1 times higher than to any normal organ, excluding the spleen for a 40-mg tracer dose. Tracer-dose toxicities included reversible glossal edema in one patient, grade 3 hepatic transaminasemia in another, and early drops in both circulating B and T cells (with decreases in B cells more pronounced) in nearly all patients. RIT toxicity was primarily myelosuppression (especially thrombocytopenia), which had a delayed onset and protracted recovery (without significant recovery until at least 2 months post-RIT). Grade 3 myelosuppression in two of two patients who were treated at a tracer-projected 50-cGy WBD level (133 and 149 mCi) precluded further planned RIT dose escalation. Less myelosuppression was generally observed in patients who were treated at < or = 40-cGy WBD levels. Antimouse antibodies developed in two patients. Six patients had tumor responses post-RIT. Four had responses that lasted more than 1 month (2 to 6 months), which included one complete response, one partial response, one minor response, and one mixed response. Responses seemed to occur more frequently in imaged tumors than in nonimaged tumors. The most durable response occurred in a patient who had the best antibody targeting to tumor. CONCLUSIONS Although 131I-MB-1 has limited diagnostic value, it can produce tumor responses at nonmarrow ablative RIT doses. Further studies that focus on improving tumor targeting with this or other B-cell-reactive radiolabeled antibodies and on ameliorating the myelosuppression associated with the RIT-dosing approach used in this trial are warranted.

Crohn's disease evaluation: Comparison of contrast-enhanced MR imaging and single-phase helical CT scanning

The purpose of this study was to evaluate the use of gadolinium and barium‐enhanced magnetic resonance (MR) imaging in detecting intestinal and extraintestinal Crohns disease and compare MRI with contrast‐enhanced helical computed tomography (CT). Twenty‐six patients with Crohns disease underwent imaging examinations, including gadolinium‐enhanced, fat suppressed fast multiplanar spoiled gradient‐recalled (FMPSPGR) MR imaging with oral 2% barium sulfate and rectal water and with helical CT using IV and positive (13) or negative (13) intestinal contrast material. MR images and CT scans were reviewed separately by two radiologists for bowel wall thickness and enhancement, presence of abscess, phlegmon, and fistula. MR images and CT scans were then compared side by side. Surgical, endoscopic, and histopathologic findings and results of barium studies were reviewed to determine the location and severity of involvement of intestinal Crohns disease. Depiction of mural thickening and/or enhancement was superior on the MR images, which showed 55 (85%) and 52 (80%) of 65 abnormal bowel segments for the two observers, compared with helical CT, which showed 39 (60%) and 42 (65%; P < 0.001, P < 0.05) of bowel segments affected by Crohns disease. Segments of bowel with moderate or marked mural thickening were depicted equally on MR imaging and helical CT. In mildly diseased segments of bowel, with only slight thickening and enhancement, MR imaging depicted 22 (79%) and 19 (68%) of 28 segments, compared with helical CT, which depicted 9 (32%; P < 0.01), and 13 (46%; P > 0.05) of 28 segments. In the side‐by side comparison, MR imaging was preferred over helical CT for depicting normal bowel wall (MR 71%, CT 4%, equal 25%; P < 0.001), mural thickening (MR 41%, CT 11% equal 48%; P < 0.01), mural enhancement (MR 89%, equal 11%; P < 0.001), and overall GI tract evaluation (MR 52%, CT 10%, equal 38%; P < 0.001). Gadolinium‐enhanced MR imaging with oral dilute barium sulfate and rectal water depicts intestinal and extraintestinal changes of Crohns disease and shows promise as a clinically useful tool. J. Magn. Reson. Imaging 2000;11:127–135.

Imaging Manifestations of Meckel's Diverticulum

OBJECTIVE Meckels diverticulum is the most common congenital anomaly of the gastrointestinal tract, found in 2% of the population in autopsy studies. Most patients remain asymptomatic during their lifetime. Complications of Meckels diverticulum are reported to occur in approximately 4-40% of patients and include inflammation (diverticulitis), hemorrhage, intussusception, small-bowel obstruction, stone formation, and neoplasm. The purpose of this article is to familiarize the radiologist with the current imaging of Meckels diverticulum and its presenting complications. The spectrum of diagnostic findings on various imaging techniques will be reviewed. CONCLUSION Meckels diverticulum and its complications are a serious health problem. Familiarity of the radiologist with the appearance of this pathologic entity enables an accurate diagnosis in emergent settings.

Age-Related Immune Dysfunction in Health and in Human Immunodeficiency Virus (HIV) Disease: Association of Age and HIV Infection with Naive CD8+ Cell Depletion, Reduced Expression of CD28 on CD8+ Cells, and Reduced Thymic Volumes

Older age is a strong predictor of accelerated human immunodeficiency virus (HIV) disease progression. We investigated the possible immunologic basis of this interaction by comparing older (>/=45 years) and younger (</=30 years) HIV-infected adults with simultaneously enrolled, aged-matched, healthy volunteers. Cross-sectional comparisons suggested age-associated reductions in naive CD8(+) cells and in the expression of CD28(+) on CD8(+) cells among both HIV-infected subjects and control subjects. Opposite patterns of CD4(+) and CD8(+) cell differences were apparent between these subject groups. HIV infection, but not age, was associated with impairments in delayed-type hypersensitivity responses, lymphoproliferation, and spontaneous apoptosis and with alterations in expression of chemokine receptors CCR5 and CXCR4. Reduced thymic volumes were associated with age and with HIV infection among younger, but not older, subjects. Because of their common association with age and HIV disease, naive CD8(+) cell depletion, diminished CD28 expression on CD8(+) cells, and reduced thymic volumes are possible correlates of the interaction of age with HIV disease.