Citations

Purpose To compare low-dose (30 Gy) radiotherapy (RT) with observation (OBS) in limited-stage aggressive lymphoma patients achieving complete remission (CR) after chemotherapy, and to measure conversion from partial response (PR) to CR with high-dose (40 Gy) RT. Patients and Methods From 1984 to 1992, stage I (with risk factors) and II adults with diffuse aggressive lymphoma in CR after eight cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) were randomly assigned to 30 Gy involved-field RT or OBS. PR patients received 40 Gy RT. Results Among 172 CR patients, the 6-year disease-free survival (DFS) was 73% for low-dose RT versus 56% for OBS (two-sided P = .05). Failure-free survival (two-sided P = .06), and time to progression (two-sided P = .06) also favored RT. Intent-to-treat analyses yielded similar results. No survival differences were observed. Three RT versus 15 OBS patients relapsed in initial disease sites. At 6 years, failure-free survival was 63% in PR patients; conversion to CR did not significantly influence clinical outcome. Conclusion For patients in CR after CHOP, low-dose RT prolonged DFS and provided local control, but no survival benefit was observed. The majority of PR patients were event-free at 6 years despite residual radiographic abnormalities. Future efforts should be directed toward improved imaging and more effective systemic therapies.

AbstractRadioligand binding assays can be used to characterize receptors in their natural environment (wild type) as well as those transfected into cell lines. They can be used to study receptor dynamics and localization, to identify novel chemical structures that interact with receptors, and to define ligand activity and selectivity. The technique thus serves as a valuable adjunct to other pharmacological and molecular biological approaches. This unit describes the major issues involved in developing a binding assay, such as selecting a radioligand, tissue preparation, optimization of assay parameters, and separation of bound from free ligand. Methods for analysis of the binding data are carefully considered, and tips for troubleshooting a binding assay are also provided.

Abstract One hundred fifty‐six arthroscopic transglenoid multiple suture repairs were performed for chronic anterior shoulder instability. In 150 shoulders (96% follow‐up), the outcome with respect to recurrence of instability and the Bankart Score was determined a minimum of 2 years and a mean of 4.1 years after surgery (range, 2 to 8.2 years). During the follow‐up interval, 11 shoulders (7.3%) redislocated. Fourteen other shoulders (9.3%) had at least one episode that we interpreted as recurrent subluxation. Shoulders with a Bankart lesion and younger patients had a higher probability of recurrent instability ( P < .05). We concluded that this method is most effective in shoulders without a Bankart lesion and in patients older than 25 years of age (regardless of pathology).

OBJECTIVESThere are options available to patients newly diagnosed with vestibular schwannoma. Our institution employs stereotactic radiosurgery, microsurgical removal, and watchful waiting. There are no studies in the literature examining which of these treatment options patients are choosing.STUDY DESIGN AND SETTINGUsing retrospective chart review from January 2000 through December 2001, we noted several variables and patients’ initial treatment choices.RESULTSDuring the 24‐month study period, 139 patients were seen at our institution with a new diagnosis of vestibular schwannoma and made a clear initial treatment choice. Of these, 32 (23%) patients elected watchful waiting; 51 (36%) underwent stereotactic radiosurgery, and 56 (40%) underwent surgical removal. Surgical excision correlated with younger age and larger tumor size.CONCLUSIONSOur initial hypothesis, that patients choosing treatment would choose stereotactic radiosurgery more than 50% of the time, was untrue for the time course studied.SIGNIFICANCEThis is the first study to examine patient choice in treatment of vestibular schwannoma.

AbstractWe compared the angiogenic potential of bone marrow plasma and the expression of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and their receptors on plasma cells from patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), and newly diagnosed multiple myeloma (NMM). Cytokine and cytokine-receptor expression was studied by bone marrow immunohistochemistry, quantitative reverse transcription-polymerase chain reaction (RT-PCR) on sorted plasma cells, and quantitative Western blot analysis. Bone marrow angiogenic potential was studied using a human in vitro angiogenesis assay. The expression levels of VEGF, bFGF, and their receptors were similar among MGUS, SMM, and NMM. Sixty-one percent of NMM samples stimulated angiogenesis in the in vitro angiogenesis assay compared with SMM (0%) and MGUS (7%) (P &lt; .001). Importantly, 63% of MGUS samples inhibited angiogenesis compared with SMM (43%) and NMM (4%) (P &lt; .001). The inhibitory activity was heat stable, not overcome by the addition of VEGF, and corresponded to a molecular weight below 10 kd by size-exclusion chromatography. Our results suggest that increasing angiogenesis from MGUS to NMM is, at least in part, explained by increasing tumor burden rather than increased expression of VEGF/bFGF by individual plasma cells. The active inhibition of angiogenesis in MGUS is lost with progression, and the angiogenic switch from MGUS to NMM may involve a loss of inhibitory activity. (Blood. 2004; 104:1159-1165)

Purpose Molecular studies of colon cancer have provided insights into pathogenesis, yet it is unclear how important these markers are in predicting prognosis. This study investigated the prognostic significance of TUNEL, bcl-2, p53, proliferation marker Ki-67 and DNA mismatch repair (MMR) status in patients with Dukes' stage B2 and C colorectal adenocarcinomas. Patients and Methods Tumor tissue from 366 patients (75% Dukes' C, 25% Dukes' B2) from four randomized North Central Cancer Treatment Group phase III surgical adjuvant trials were used. Eighty-one percent of patients received adjuvant treatment, which was primarily fluorouracil (FU) based (90%). Tumor location was predominantly (87%) the colon. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL), Ki-67, p53, bcl-2, and MMR were assayed using immunohistochemistry. Stage, grade, MMR, Ki-67, and previously determined flow cytometry markers (ploidy and S phase) were explored for associations with each other and with overall survival (OS) and disease-free survival (DFS). Results Univariately, stage B2, low grade, diploid, Ki-67 more than 27%, normal p53, and FU-based adjuvant treatment were significantly associated with improved OS and DFS (P < .05). After adjusting for stage, grade, and ploidy in multivariate analysis, Ki-67 remained significantly related to both OS and DFS (P < .01). Active FU-based adjuvant treatment was significant only for OS in this multivariate model. Neither bcl-2 nor TUNEL were significant. Conclusion This retrospective study indicates that Ki-67 and ploidy may have stronger prognostic impact on OS and DFS than other parameters investigated after adjusting for stage and tumor grade. Prospective studies to elucidate the mechanism and prognostic significance of these findings are necessary.

The authors evaluated the relationship between blood lactate accumulation and hemodynamics in a prospective controlled animal study. Seven healthy pigs were anesthetized and mechanically ventilated with a 0.6 fraction of inspired oxygen to achieve a normal PaCO 2 . Catheters for blood sampling, lactate infusion, and hemodynamic assessment were inserted into the femoral vein and femoral artery. Bolus infusions (466 µmol • kg — 1 over 1 minute) of a neutral solution of sodium lactate were given at 0, 30, 60, and 90 minutes. Each bolus was followed by continuous infusion of the same lactate solution (31.7 µmol • kg — 1 • min —1 after the first, with the rate doubled after each subsequent bolus). Arterial blood samples were drawn at baseline and at 30, 60, 90, and 120 minutes, with simultaneous hemodynamic assessment. Significant increases were seen in blood lactate (from 1.6 ± 0.4 mmol/L at baseline to 4.4 ± 0.8 at 30 minutes, 8.0 ± 1.0 at 60 minutes, and 14.4 ± 2.1 at 90 minutes), pH (from 7.40 ± 0.03 to 7.44 ± 0.05 at 30 minutes, 7.50 ± 0.05 at 60 minutes, and 7.56 ± 0.04 at 90 minutes), and HCO 3 — (from 28 ± 1.4 mmol/L to 30 ± 0.7 at 30 minutes, 34 ± 0.9 at 60 minutes, and 37 ± 1.2 at 90 minutes). PaCO 2 decreased significantly from 44 ± 3 torr at baseline to 40 ± 4.7 torr at 90 minutes. Blood pressure decreased after each lactate bolus, recovering within 2 minutes initially but not after later injections. Cardiac output, heart rate, and glucose increased significantly, mean arterial pressure and systemic vascular resistance decreased, and stroke volume did not change. Thus, the accumulation of blood lactate due to exogenous administration of a neutral solution of sodium lactate was associated with significant systemic vasodilation, increased cardiac output, increased heart rate, and metabolic alkalosis.

Purpose To determine the effectiveness of an infusional chemotherapy regimen in patients with HIV-associated lymphoma treated before and after the use of highly active antiretroviral therapy (HAART) in routine clinical practice. Patients and Methods Ninety-eight assessable patients with HIV-associated intermediate- or high-grade non-Hodgkin’s lymphoma received cyclophosphamide 200 mg/m2/d, doxorubicin 12.5 mg/m2/d, and etoposide 60 mg/m2/d (CDE) given by continuous intravenous infusion for 4 days (96 hours) every 4 weeks plus filgrastim. Concurrent antiretroviral treatment consisted of the nucleoside analog didanosine in the first 43 patients enrolled before December 1996 (pre-HAART group), or HAART in the remaining 55 patients enrolled after that time (HAART group). Results Complete response occurred in 44 patients (45%; 95% CI, 35% to 55%). Failure-free survival and overall survival (OS) at 2 years was 36% (95% CI, 26% to 46%) and 43% (95% CI, 33% to 53%), respectively. At the time of the analysis, 30% in the pre-HAART group were alive compared with 47% in the HAART group; when adjusted for varying length of follow-up, patients in the HAART group had improved OS (P = .039). Patients in the HAART group experienced less grade 4 nonhematologic toxicity (22% v 42%; P = .037), thrombocytopenia (31% v 52%; P = .033), and anemia (9% v 27%; P = .021), and had fewer treatment-associated deaths (0% v 10%; P = .013). Conclusion Infusional CDE is an effective and potentially curative regimen for patients with HIV-associated lymphoma. Patients treated in the HAART era have less chemotherapy-associated toxicity and improved survival.

Purpose To determine survival and relapse rates by T and N stage and treatment method in five randomized phase III North American rectal adjuvant studies. Patients and Methods Data were pooled from 3,791 eligible patients enrolled onto North Central Cancer Treatment Group (NCCTG) 79-47-51, NCCTG 86-47-51, US Gastrointestinal Intergroup 0114, National Surgical Adjuvant Breast and Bowel Project (NSABP) R01, and NSABP R02. Surgery alone (S) was the treatment arm in 179 patients. The remaining patients received adjuvant treatment as follows: irradiation (RT) alone (n = 281), RT + fluorouracil (FU) ± semustine bolus chemotherapy (CT; n = 779), RT + protracted venous infusion CT (n = 325), RT + FU ± leucovorin or levamisole bolus CT (n = 1,695), or CT alone (n = 532). Five-year follow-up was available in 94% of surviving patients, and 8-year follow-up, in 62%. Results Overall (OS) and disease-free survival were dependent on TN stage, NT stage, and treatment method. Even among N2 patients, T substage influenced 5-year OS (T1-2, 67%; T3, 44%; T4, 37%; P < .001). Three risk groups of patients were defined: (1) intermediate (T1-2/N1, T3/N0), (2) moderately high (T1-2/N2, T3/N1, T4/N0), and (3) high (T3/N2, T4/N1, T4/N2). For intermediate-risk patients, those receiving S plus CT had 5-year OS rates of 85% (T1-2/N1) and 84% (T3/N0), which was similar to results with S plus RT plus CT (T1-2/N1, 78% to 83%; T3/N0, 74% to 80%). For moderately high-risk lesions, 5-year OS ranged from 43% to 70% with S plus CT, and 44% to 80% with S plus RT plus CT. For high-risk lesions, 5-year OS ranged from 25% to 45% with S plus CT, and 29% to 57% with S plus RT plus CT. Conclusion Different treatment strategies may be indicated for intermediate-risk versus moderately high- or high-risk patients based on differential survival rates and rates of relapse. Use of trimodality treatment for all patients with intermediate-risk lesions may be excessive, since S plus CT resulted in 5-year OS of approximately 85%; however, 5-year disease-free survival rates with S plus CT were 78% (T1-2/N1) and 69%(T3/N0), indicating room for improvement.