A 50-year-old woman with a history of sick sinus syndrome presented acutely with cough, hemoptysis, and pleuritic left-sided chest pain. Her past history was significant for an atrioventricular sequential pacemaker insertion at age 24 and chronic paroxysmal atrial fibrillation (AF) managed with warfarin, acetylsalicylic acid, and propafenone. Seven months prior to presentation, the patient underwent pulmonary vein ablation to treat her AF. A physical examination revealed normal sinus rhythm, and the lungs were clear on auscultation. Basic laboratory investigations were noncontributory. A chest radiograph revealed peripheral consolidation in the left upper lobe with heterogeneous opacities in the left upper and lower zones (Fig 1). Findings suggestive of a small left pleural effusion were also noted. Contrast-enhanced CT scan pulmonary angiography, performed on a 64-slice Lightspeed volumetric VCT XT scanner (GE Healthcare; Waukasha, WI) to evaluate for pulmonary embolus, demonstrated nonopacification of the left lower and left upper lobe pulmonary veins. Increased soft tissues at the hilum without focal discrete mass were noted. Follow-up CT scan with a delayed-phase series with a delay of 90 s was remarkable for the persistent absence of pulmonary vein enhancement. Ground-glass change and more confluent consolidation were demonstrated in the apical posterior segment of the left upper lobe, suggestive of pulmonary hemorrhage. Septal thickening and changes consistent with pulmonary edema were also evident, most marked in the left upper lobe (Fig 2A).Figure 2Axial high-resolution CT scan of the left upper lobe. Ground-glass opacities with thickened interlobular septae (short arrow) and more confluent airspace consolidation in the apical posterior segment (long arrow) (A). Section of the left upper lobe corresponding to axial CT image. Interconnecting pale tan and red linear abnormalities corresponding to secondary lobular septae and paraseptal parenchyma (white arrows) enclose regions of relatively normal lung parenchyma. Bar = 1.0 cm (B).View Large Image Figure ViewerDownload Hi-res image Download (PPT) The patient underwent bronchoscopy, and the hemoptysis was found to be arising from the left lung. The entire left mainstem bronchus was edematous and highly distorted as the result of mucosal engorgement. The mucosa was friable and bled easily. Cardiac catheterization with transseptal atrial puncture confirmed markedly reduced flow velocities in the left superior and inferior pulmonary veins. Balloon dilation was performed, with only transient improvement. A subsequent urgent left thoracotomy performed for ongoing hemoptysis showed the superior pulmonary vein had a diameter of only 1 to 2 mm and was thrombosed from the pericardium to the parenchyma of the left upper lobe. The left upper lobe was congested and heavy, while the lower lobe had relatively normal parenchyma. The inferior pulmonary vein measured approximately 5 mm and had some flow through it. Attempts to mobilize and perform a patch angioplasty of the left superior vein were unsuccessful, as the vein was completely thrombosed. A left upper lobectomy was subsequently performed for lung necrosis. The patient had an uneventful recovery and was discharged home. In follow-up, she required treatment of the left inferior pulmonary vein stenosis; this was stented with a 10 × 19 Genesis (Cordis; Miami, FL) bare metal stent following limited benefit from multiple balloon angioplasties. A follow-up ECG-gated contrast-enhanced chest CT scan displayed a patent stent without focal stenosis of the left lower lobe pulmonary vein. Axial sections of the fixed lobectomy specimen demonstrate a relatively uniform congested parenchyma, with diffuse coarse linear bands involving immediate subpleural and deeper lung (Fig 3A) that demonstrate contiguous bridging enclosing roughly hexagonal areas of less involved lung parenchyma. The bands appear variably broad and hemorrhagic or slightly narrower and tan-white. Histologically, these bands represent paraseptal alveolar parenchymal necrosis with loss of nuclei, fibrinoid necrosis, and organized airspace exudates (Fig 3A). Other sections (Fig 3B) demonstrate similar anatomic regions in which the necrotic alveolar septae contain engorged and dilated capillaries that are often progressively attenuated toward the centrilobular bronchovascular structures. Widespread pulmonary arterial thickening, manifested as muscularization of arterioles, medial hypertrophy, and intimal hyperplasia, involves centrilobular and intraacinar arteries (Fig 3C). Plexiform lesions are not identified. Other findings include lymphatic dilation, pleural thickening, and fibrinous pleuritis. What is the diagnosis? Diagnosis: Pulmonary venous occlusion and lobar infarction as a complication of radiofrequency ablation of arrhythmogenic foci This case illustrates the radiologic, surgical, and pathologic correlation of an iatrogenic pathology that is of increasing importance (Figs 1-4). Catheter-directed radiofrequency ablation of focal arrhythmogenic triggers arising from the ostea or muscular sleeves of pulmonary veins1Haïssaguerre M Jaïs P Shah DC et al.Right and left atrial radiofrequency catheter therapy of paroxysmal atrial fibrillation.J Cardiovasc Electrophysiol. 1996; 7: 1132-1144Crossref PubMed Scopus (519) Google Scholar has been shown to be an effective long-term treatment of AF.2Haïssaguerre M Jaïs P Shah DC et al.Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins.N Engl J Med. 1998; 339: 659-666Crossref PubMed Scopus (6375) Google Scholar As the clinical practice of radiofrequency ablation has expanded, however, complications are increasing. A well-recognized and potentially life-threatening complication is pulmonary vein occlusion (PVO), defined as greater than 95% stenosis or complete loss of patency of the pulmonary vein on CT scan. PVO, likely due to scarring and contraction of vein walls due to thermal injury, occurs in up to 2.1% of cases and can lead to pulmonary venous hypertension and pulmonary venous infarction (PVI).3Ravenel JG McAdams HP Pulmonary venous infarction after radiofrequency ablation for atrial fibrillation.AJR Am J Roentgenol. 2002; 178: 664-666Crossref PubMed Scopus (45) Google Scholar, 4Di Biase L Fahmy TS Wazni OM et al.Pulmonary vein total occlusion following catheter ablation for atrial fibrillation: clinical implications after long-term follow-up.J Am Coll Cardiol. 2006; 48: 2493-2499Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar As the ablation technique has evolved, refocusing the ablation target toward the pulmonary vein antrum or left atrium, stenotic complications have been minimized.5Okada T Yamada T Murakami Y et al.Prevalence and severity of left atrial edema detected by electron beam tomography early after pulmonary vein ablation.J Am Coll Cardiol. 2007; 49: 1436-1442Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar, 6Saad EB Marrouche NF Saad CP et al.Pulmonary vein stenosis after catheter ablation of atrial fibrillation: emergence of a new clinical syndrome.Ann Intern Med. 2003; 138: 634-638Crossref PubMed Scopus (217) Google Scholar, 7Shah DC Haïssaguerre M Jaïs P et al.Electrophysiologically guided ablation of the pulmonary veins for the curative treatment of atrial fibrillation.Ann Med. 2000; 32: 408-416Crossref PubMed Scopus (51) Google Scholar Multidetector CT scan mapping can provide useful noninvasive information on the number, size, location, and branching anomalies of the pulmonary veins, allowing the selection of catheter size and a reduction in ablation procedure times.8Scharf C Sneider M Case I et al.Anatomy of the pulmonary veins in patients with atrial fibrillation and effects of segmental ostial ablation analyzed by computed tomography.J Cardiovasc Electrophysiol. 2003; 14: 150-155Crossref PubMed Scopus (201) Google Scholar, 9Cronin P Sneider MB Kazerooni EA et al.MDCT of the left atrium and pulmonary veins in planning radiofrequency ablation for atrial fibrillation: a how-to guide.AJR Am J Roentgenol. 2004; 183: 767-778Crossref PubMed Scopus (83) Google Scholar MRI with time-resolved angiographic sequences and phase-contrast imaging can be used for evaluation of pulmonary vein stenosis, but it is significantly more time intensive. Common immediate symptoms of the procedure have included cough, burning chest pain, and tachycardia. Other observed complications include pericardial effusions, peripheral vascular complications, pericardial tamponade, cerebrovascular accident, pulmonary vein stenosis, systemic emboli, pulmonary dysfunction, and severe bleeding, often secondary to the intense anticoagulation required.10Robbins IM Colvin EV Doyle TP et al.Pulmonary vein stenosis after catheter ablation of atrial fibrillation.Circulation. 1998; 98: 1769-1775Crossref PubMed Scopus (406) Google Scholar Presentation varies greatly and largely depends on the number of veins involved and the severity of involvement.11Holmes Jr, DR Monahan KH Packer D Pulmonary vein stenosis complicating ablation for atrial fibrillation: clinical spectrum and interventional considerations.JACC Cardiovasc Interv. 2009; 2: 267-276Crossref PubMed Scopus (177) Google Scholar In the initial published series of 23 patients from the Mayo Clinic, the time to presentation was 103 ± 100 days.11Holmes Jr, DR Monahan KH Packer D Pulmonary vein stenosis complicating ablation for atrial fibrillation: clinical spectrum and interventional considerations.JACC Cardiovasc Interv. 2009; 2: 267-276Crossref PubMed Scopus (177) Google Scholar Symptoms may progress rapidly or may be quite indolent, and, as a result, some advocate for an immediate postprocedural CT scan as a baseline assessment. PVO, however, is often asymptomatic, especially if it is isolated to a single vein. Symptoms, when present, tend to present weeks to months postprocedure and are underrecognized. In fact, past studies have reported that up to 44% of patients with severe stenosis remained asymptomatic.6Saad EB Marrouche NF Saad CP et al.Pulmonary vein stenosis after catheter ablation of atrial fibrillation: emergence of a new clinical syndrome.Ann Intern Med. 2003; 138: 634-638Crossref PubMed Scopus (217) Google Scholar The spectrum of symptoms caused by PVO may include dyspnea on exertion, cough, orthopnea, hemoptysis, and recurrent pulmonary infections. Development of such symptoms after catheter ablation should immediately raise suspicion for PVO, because, if unrecognized, this complication is often fatal, with most patients succumbing to right heart failure.10Robbins IM Colvin EV Doyle TP et al.Pulmonary vein stenosis after catheter ablation of atrial fibrillation.Circulation. 1998; 98: 1769-1775Crossref PubMed Scopus (406) Google Scholar Radiographically, the findings favored significant venous congestion in the left upper lobe and mild to moderate venous congestion in the left lower lobe with areas of acute pulmonary hemorrhage and possible edema from venous congestion (Figs 1, 2A). The increased peribronchovascular soft tissues at the left hilum (Fig 4) raised the possibility of a primary lung neoplasm with hilar adenopathy; however, given the clinical history, the possibility of vein occlusion with associated hemorrhage was suggested. Follow-up CT scans may be useful to enable early detection of pulmonary vein stenosis, because early intervention has been shown to predict improvement in lung perfusion postintervention. Transesophageal echocardiography has a limited role in the evaluation of pulmonary vein stenosis and its severity owing to the inability to image deeply into all four pulmonary veins. Studies have shown a positive correlation between the number of interventions and improvement in lung perfusion, underscoring the frequency of restenosis and indicating that perseverance has a beneficial effect on outcome.4Di Biase L Fahmy TS Wazni OM et al.Pulmonary vein total occlusion following catheter ablation for atrial fibrillation: clinical implications after long-term follow-up.J Am Coll Cardiol. 2006; 48: 2493-2499Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar Treatment options include balloon angioplasty and/or endovascular stenting in incomplete pulmonary venous stenosis. The use of balloon angioplasty in pulmonary venous stenosis has often led to unsatisfactory results, with a high incidence of restenosis. Stenting as a treatment option is still in its early stages, with guarded optimism concerning results.12Packer DL Keelan P Munger TM et al.Clinical presentation, investigation, and management of pulmonary vein stenosis complicating ablation for atrial fibrillation.Circulation. 2005; 111: 546-554Crossref PubMed Scopus (244) Google Scholar There have been no reports of successful surgical reconstruction of the pulmonary vein for this condition. Although surgical resection of the affected lobe is extremely rare, it remains the only option for patients with persistent PVO following failed balloon angioplasty or pulmonary venous stenting. It was required in this case to control ongoing hemoptysis. Prior to the recent emergence of catheter-directed radiofrequency ablation, the most frequent reported cause of PVI was sclerosing mediastinitis; other causes included left atrial myxoma, left atrial clot from mitral stenosis, and squamous cell carcinoma.13Williamson WA Tronic BS Levitan N Webb-Johnson DC Shahian DM Ellis Jr, FH Pulmonary venous infarction.Chest. 1992; 102: 937-940Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar Two pathologic patterns have been described: hemorrhagic necrosis and diffuse interstitial fibrosis. Hemorrhagic necrosis is characterized by multifocal subpleural infarcts, paraseptal necrosis, venular occlusion, arterial medial hypertrophy, and ectasia of lymphatic channels, and likely results from an acute severe insult.14Katzenstein AL Mazur MT Pulmonary infarct: an unusual manifestation of fibrosing mediastinitis.Chest. 1980; 77: 521-524Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar, 15Mendelson EB Mintzer RA Hidvegi DF Venoocclusive pulmonary infarct: an unusual complication of fibrosing mediastinitis.AJR Am J Roentgenol. 1983; 141: 175-176Crossref PubMed Scopus (13) Google Scholar Bronchi distal to the obstruction demonstrate prominent submucosal venous and lymphatic channel ectasia.16Bindelglass IL Trubowitz S Pulmonary vein obstruction: an uncommon sequel to chronic fibrous mediastinitis.Ann Intern Med. 1958; 48: 876-891Crossref PubMed Scopus (23) Google Scholar Diffuse interstitial fibrosis, possibly representing a more chronic, low-grade response, is characterized by capillary proliferation, alveolar septal thickening, fibrous thickening of venous adventitia, venous dilation, and arteriolar intimal hypertrophy. In our case, there was exquisite paraseptal alveolar necrosis with acute hemorrhage, airspace hemosiderin-containing histiocytes, alveolar capillary dilation, and capillary proliferative changes consistent with PVI in various stages of development (Figs 3A, 3B). Although interlobular septal veins were typically engorged, very few examples of thrombosis were identified and, when present, were more suggestive of a necrotizing vasculopathy secondary to being incorporated in the infarct rather than a primary thrombotic process. The lobar pulmonary vein stump demonstrated nonocclusive fibrointimal proliferation and patchy mural changes consisting of smooth muscle atrophy and fibrosis. The pathologic differential diagnosis of pulmonary venous infarct includes (arterial) thromboembolic infarcts17Tsao M-S Schraufnagel D Wang N-S Pathogenesis of pulmonary infarction.Am J Med. 1982; 72: 599-606Abstract Full Text PDF PubMed Scopus (65) Google Scholar, 18Dalen JE Pulmonary embolism: what have we learned since Virchow? Natural history, pathophysiology, and diagnosis.Chest. 2002; 122: 1440-1456Abstract Full Text Full Text PDF PubMed Scopus (236) Google Scholar and the uncommon conditions of pulmonary venoocclusive disease and pulmonary capillary hemangiomatosis.19Stewart S Rassl D Advances in the understanding and classification of pulmonary hypertension.Histopathology. 2009; 54: 104-116Crossref PubMed Scopus (18) Google Scholar, 20Frazier AA Franks TJ Mohammed T-LH Ozbudak IH Galvin JR From the archives of the AFIP: pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis.Radiographics. 2007; 27: 867-882Crossref PubMed Scopus (130) Google Scholar Pulmonary venous infarcts characteristically manifest as lobar or whole-lung processes,13Williamson WA Tronic BS Levitan N Webb-Johnson DC Shahian DM Ellis Jr, FH Pulmonary venous infarction.Chest. 1992; 102: 937-940Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar in contradistinction to arterial thromboembolic infarcts, which are typically multiple, pleural-based, wedge-shaped or rounded lesions.21Yousem SA The surgical pathology of pulmonary infarcts: diagnostic confusion with granulomatous disease, vasculitis, and neoplasia.Mod Pathol. 2009; 22: 679-685Crossref PubMed Scopus (29) Google Scholar Microscopically, alveolar capillary congestion, alveolar hemorrhage, and necrosis with airspace organization may be common features. A distinct septal distribution of necrosis is characteristic of venous infarction, with possible sparing of the central bronchovascular region.17Tsao M-S Schraufnagel D Wang N-S Pathogenesis of pulmonary infarction.Am J Med. 1982; 72: 599-606Abstract Full Text PDF PubMed Scopus (65) Google Scholar, 18Dalen JE Pulmonary embolism: what have we learned since Virchow? Natural history, pathophysiology, and diagnosis.Chest. 2002; 122: 1440-1456Abstract Full Text Full Text PDF PubMed Scopus (236) Google Scholar Although histologic features may be similar and the distribution of changes may be irregular, pulmonary venoocclusive disease is typically diffuse and bilateral. Pulmonary capillary hemangiomatosis is panlobular in distribution and consists of patchy foci of proliferating capillaries within alveolar septae, but with extension in and around bronchovascular structures and septal veins. Occlusive venous changes are noted, but infarcts are not a recognized feature.22Lantuéjoul S Sheppard MN Corrin B Burke MM Nicholson AG Pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis: a clinicopathologic study of 35 cases.Am J Surg Pathol. 2006; 30: 850-857Crossref PubMed Scopus (199) Google Scholar In summary, PVO with venous infarction is an important and potentially life-threatening complication of ablation techniques for AF. Complete occlusions may be asymptomatic or have trivial respiratory complaints, and a high clinical suspicion must be in place when dealing with symptomatic postpulmonary vein ablation patients.

UNLABELLED Biodistribution studies demonstrate that intralesional administration of radiolabeled IgM results in high retention of radioactivity with little normal tissue uptake. This study examines the therapeutic potential of this modality. MATERIALS AND METHODS Nude mice bearing subcutaneous human head and neck squamous cell carcinoma xenografts were treated with single intralesional (IL) injections of tumor-reactive human monoclonal IgM (CR4E8) labeled with 25-394 microCi of yttrium-90 (90Y). Untreated mice, mice treated with IL unlabeled immunoconjugate or IL 90Y-aggregate, 160-400 microCi, served as controls. Mice were monitored for tumor growth and toxicity. RESULTS Mice received 80 Gy per 100 microCi of 90Y-labeled IgM and 110 Gy per 100 microCi of 90Y-aggregate. All tumors treated with 90Y-labeled IgM responded. In mice that received > or = 100 microCi, tumors macroscopically disappeared within three weeks from treatment with seventy-six percent tumor-free at 216 days. Acute toxicities associated with high activity 90Y-labeled IgM and 90Y-aggregate were moist skin desquamation and reduced blood counts. Late radiation damage to connective tissue was observed in mice treated with > 100 microCi of 90Y-labeled IgM. CONCLUSIONS Intralesional administration of 90Y-labeled IgM can ablate tumors in nude mice with modest acute or late toxicity. Further development of this modality for loco-regional therapy is warranted.

The development of cancer-selective therapies, in particular radiolabeled immunoglobulin therapy (RIT), has stalled. RIT limitations/opportunities are identified in translational research in nude mice, beagles and rhesus monkeys, and in patients with Hodgkin's disease, neurological paraneoplastic syndromes or small vessel vasculitis. Intravenous RIT is most successful in patients with hematological malignancies due to high tumor uptake and long tumor retention of radiolabeled immunoglobulins. Patients with solid tumors are only expected to benefit from RIT by the administration of radiolabeled immunoglobulins directly into the tumor. Tumor-reactive IgG is the best vehicle for i.v. RIT. Tumor-reactive IgM is the best vehicle for intratumoral RIT. The authors do not intend to review the whole clinical RIT experience, but instead analyze the current limitations to success and how they can be circumvented. When the scientific community can reach a consensus on the development and use of these promising and economical radiopharmaceuticals, increasing numbers of patients with recurrent cancer will start to benefit from RIT.

Translational research supports the use of radiolabeled antiferritin for recurrent Hodgkin's disease. A 60% tumor response rate is obtained after treatment of out-patients with polyclonal radiolabeled antiferritin, Hodgkin's disease masses shrink after radiolabeled antiferritin treatment due to the radiation delivered by the radioimmunoconjugate. Unlabeled antiferritin does not cause tumor shrinkage. Hodgkin's disease provides unique opportunities for the development and optimization of radiolabeled immunoglobulin therapy for other malignancies as well.Radiolabeled Immunoglobulin Therapy is a useful addition to the cancer treatment armamentarium due to its high therapeutic ratio: high tumor response rates with side effects limited to hematopoetic tissues.

UNLABELLED:In an effort to improve loco-regional control of ovarian cancer, intraperitoneal (i.p.) administration of an yttrium-90 (90Y) labeled human IgM was studied in a nude mouse model of the disease.METHODS:Athymic nude mice bearing i.p. nodules of SKOV3 NMP2, a human ovarian carcinoma cell line, received single (50-400 microCi) or fractionated (150-510 microCi) administrations of 90Y-labeled 2B12. Untreated mice and mice treated with unlabeled immunoconjugate served as controls. Mice were monitored for weight loss, blood counts and survival.RESULTS:Mice that received at least 300 microCi of 90Y-labeled 2B12 in a single administration lost more than 10% of their body weight with some early deaths, both of which were prevented with fractionated administration. Granulocytes and lymphocytes declined with treatment while red blood cell counts were relatively stable. Untreated mice and mice treated with unlabeled immunoconjugate had a median survival time of 20 and 17 days respectively. Treatment with 90Y-labeled 2B12 increased median survival by 11-12 days per 100 microCi for single (50-300 microCi) and fractionated administrations (150-510 microCi). The highest fractionated activity produced over three logs of tumor cell kill without significant toxicity.CONCLUSION:Intraperitoneal RIT with 90Y-labeled 2B12 appears to be an attractive modality to treat peritoneal carcinomatosis and warrants further development.

The objective was to identify pharmacokinetic parameters predictive for tumor response and normal tissue side effects after i.v. administered radiolabeled rabbit antihuman ferritin IgG. Twenty-eight patients with recurrent Hodgkin's disease received 2 mg of rabbit antihuman ferritin i.v., labeled with 4-7 mCi of In-111 followed by two doses of 0.25, one dose of 0.3, or one dose of 0.4 mCi of Y-90-labeled antiferritin per kg of body weight 1 week later. Radioactivity and HPLC measurements of blood and urine samples and liver and tumor volumes identified on sequential whole-body scans provided the data for a pharmacokinetic analysis covering the first 6 days after the administration of the radioimmunoconjugate. Side effects and tumor response were recorded. Temporary hematological toxicity was noted in all patients. Sixteen patients showed a tumor response. The Y-90 blood level at 1 h after administration correlated with the severity of subsequent hematological toxicity. The rapid blood elimination half-life of radioactivity was 4.4 h. Less than 5% of the administered radioactivity was eliminated in the first 24 h urine. The slow blood elimination half-life was 44 and 37 h for In-111 and Y-90, respectively. One of 12 retreated patients produced anti-rabbit IgG antibodies. The volume of distribution was larger for Y-90 than for In-111-labeled antiferritin (160 versus 110% of estimated blood volume). Accidentally extravasated rabbit IgG was rapidly catabolized in perivascular tissues with an effective half-life of less than 35 h. Slower catabolism was noted for rabbit IgG in blood (t(1/2) = 40 h), liver (t(1/2) = 62 h) or tumor (t(1/2) = 40-80 h). Twelve of 13 patients with an effective tumor half-life > 57 h showed a tumor response. I.v. administered polyclonal rabbit antihuman ferritin, labeled with In-111 or Y-90 is stable in vivo and targets Hodgkin's disease. Intravascular Y-90 causes a vascular leak and a larger volume of distribution for antiferritin. Elevated Y-90 blood levels at 1 h and a tumor half-life of >57 h predict for hematological toxicity and tumor response, respectively.

The objective of this study was to determine the therapeutic ratio of fractionated radiolabeled immunoglobulin therapy (RIT) for patients with recurrent Hodgkin's disease. Ninety patients with recurrent Hodgkin's disease received 2 mg of yttrium-90-labeled polyclonal rabbit antihuman ferritin IgG i.v. Fifty-seven patients received a single (unfractionated) administration per treatment cycle; 11 of them were treated with 0.3 mCi/kg body weight, 39 were treated with 0.4 mCi/kg body weight, and 7 received 0.5 mCi/kg body weight per treatment cycle. Thirty-three patients had their radiolabeled immunoglobulin administration separated (fractionated) in 2 x 0.25 mCi/kg body weight (total activity, 0.5 mCi/kg). The interval between fractions was 1 week. Radioimmunoconjugates did not cause serious acute side effects. In vivo radioimmunoconjugates were stable. Human antirabbit IgG antibodies were found in 2 of 50 retreated patients (<5%). Hematological toxicity was the only side effect noted in all patients, and it was usually temporary. Response rates (RRs) were 20%, 61%, and 86% after 0.3, 0.4, or 0.5 mCi/kg unfractionated yttrium-90-labeled antiferritin. The RR for patients treated with fractionated RIT was 42%. In the fractionated RIT group, complete responses were decreased, and progressive disease increased (P < 0.05). Complete responses had a medium duration of 6 months. Median survival times were 390 days for 1 x 0.4 mCi/kg and 300 days for the 2 x 0.25 mCi/kg patient group. Fractionation did not provide the expected decrease in hematological toxicity or the expected increase in tumor RRs.

Radiolabeled monoclonal antibodies reactive with tumor associated antigens can selectively deliver cytotoxic or diagnostic isotopes to malignant cells in vivo. To achieve maximum retention of radiolabel iu. tumor and a more rapid clearance of radioisotope from normal tissues, six Linker immunoconjugates were evaluated in studies using nude mice and beagle dogs. All radioimmunoconjugates contained a mouse monoclonal IgG (QCI) reactive with human ferritin, Different chemical Linkages mere inserted between immunoglobulins and the radiolabeled chelate (DTPA), Three Linkers (ITCB, DSS and BSOCOES) were stable in in vitro and in vivo studies. Three Linkers (EGS, DST and DSP) mere labile in in vitro and in vivo studies. Indium-111 labeled antiferritin-containing ITCB or DSS Linker showed high uptake in human hepatoma xenografts in nude mice. In addition, long blood half-lives and higher normal Liver uptakes were noted. Studies of whole body retention of radioimmunoconjugates showed approximately three-fold faster elimination of radioimmunoconjugates containing a labile linker (EGS), EGS linker is the labile linker with the highest therapeutic ratio: higher tumor uptake, but low normal liver uptake and a shortened blood half-life of the radioimmunoconjugate. The differences in normal tissue uptake (liver) between EGS and ITCB were confirmed in beagle dogs. Urine elimination studies and incubation of radioimmunoconjugates in serum or tissue homogenates of tumor, liver or muscle, showed that enzymes in serum and liver homogenates were able to cleave the labile Linkers, which led to a more rapid elimination of low molecular weight radioactive metabolites in urine. The metabolism of linker radioimmunoconjugates in tumor was less effective, The labile linker DSP appears less useful because sulphydryl groups that are generated by cleavage of cause higher uptake radioactivity in normal kidney. Biodistribution studies in nude mice were confirmed by serial immunoscintigraphy studies on individual mice. The immunoscintigraphy studies are semi-quantitative only, but enable the use of lower numbers of experimental animals, This is of particular significance in large experimental animals such as beagle dogs. The labile linker approach can reduce normal tissue radiation exposure. The study also provides an example of preclinical optimization of radioimmunoconjugates. Continued use of the appropriate preclinical animal models will accelerate more successful applications of radioimmunoconjugates in cancer patients.

The promise of radiolabelled immunoglobulin therapy (RIT) for selective, patient friendly, cancer treatment has not yet been fulfilled. Only patients with haematological malignancies show sizable response rates after RIT. With solid tumours, intravenous administration of radiolabelled antibodies does not provide sufficient tumour targeting. However, intracompartmental administration may solve this problem, particularly if tumour reactive IgM is used. Clinical progress in RIT depends on understanding the important RIT variables: antigen, antibody, radioisotope, conjugation chemistry, activity escalation, fractionation and protein dose. These are reviewed and a new translational decision tree/flow diagram is presented that can limit analysis to the most important RIT variables for a particular disease. These variables may differ depending on the type and stage of cancer, but the guiding principles in RIT development remain the same: selectivity and accountability. The proper application of these principles leads to the definition of a new series of phase I, II, III studies. These studies are more appropriate for the clinical exploration of RIT and place an emphasis on therapeutic ratio rather than toxicity.

UNLABELLED:Most patients with ovarian cancer have disease in the peritoneal cavity. Treatment of this region is inadequate because recurrences are frequent. Increased radiation doses to tumor and, hence, greater tumor control may be possible with intraperitoneal (i.p.) administration of radiolabeled human monoclonal immunoglobulin M (IgM), which is reactive with tumor-associated antigens.METHODS:Biodistribution studies were performed in nude mice bearing i.p. nodules of human ovarian cancer after administration of human monoclonal IgMlambda (AC6C3-2B12), labeled with 111In or 90Y. Irrelevant 111In-labeled human IgMlambda (CH-1B9) and 90Y-aggregate served as specificity controls.RESULTS:Intravenous administration of 111In-labeled AC6C3-2B12 produced low tumor and high liver and spleen uptake. Intraperitoneal administration of AC6C3-2B12 labeled with 111In or 90Y resulted in rapid, high tumor uptake (>45% of injected dose per gram of tumor at 3 hr) that was at least three-fold higher than any normal organ. Biodistribution results were similar for 111In- and 90Y-labeled IgM. Tumor uptake of 111In-labeled AC6C3-2B12 was two-fold greater than that of 111In-labeled CH-1B9. Normal organ uptakes were similar for tumor-reactive and irrelevant IgM. Radioimmunoconjugates were retained in the peritoneal cavity for a prolonged period of time. Yttrium-90 aggregate demonstrated high tumor and bone uptake.CONCLUSION:Higher tumor uptake was observed after i.p. administration of tumor-reactive IgM than after irrelevant IgM. The in vivo behavior of tumor-reactive IgM was similar when it was radiolabeled with either 111In or 90Y. Therefore, 111In-based imaging studies can be used to predict the biodistribution of subsequently administered 90Y-labeled IgM. Further development of radiolabeled AC6C3-2B12 as a diagnostic and therapeutic agent for patients with advanced ovarian carcinoma is warranted.

BACKGROUND:Unlabeled murine monoclonal anti-GD2 immunoglobulin (Ig)G (14G2a) reactive with nervous system diganglioside and neuroblastoma, melanoma, and small cell lung carcinoma produces tumor regression. However, serious acute abdominal pain, paresthesia, hypotension and hypertension, syndrome of inappropriate secretion of antidiuretic hormone (SIADH), and occasional motor weakness occur. Studies in preclinical animal models can elucidate the mechanism of the observed neurotoxicity and lead to anti-GD2 antibody treatment with a higher therapeutic ratio. METHODS:One mg of 14G2a or control IgG was labeled with 1-2 mCi of indium-111 and administered intravenously to beagles (n = 8). In 2 dogs, additional high dose (200 mg) unlabeled 14G2a was given over 5 days. Whole body gamma camera images and SPECT scans were obtained repeatedly over 7 days. On Day 7, sciatic nerve conduction studies were performed, and after euthanasia radioactivity was determined in major organs. RESULTS:Unlabeled high dose 14G2a administered to mice, rats, or rabbits did not cause neurotoxicity within 3 weeks. GD2 antigens were shown by immunochemistry to be present in brain and peripheral nerve tissues of rodents and beagles. After in vivo administration of radiolabeled 14G2a, canine lymph nodes showed specific uptake, but only minimal radioactivity was found in the nervous system. Dogs that received additional high dose unlabeled 14G2a showed much higher lymph node uptake and follicular lymph node hyperplasia. Low motor response amplitudes on nerve conduction studies were noted. CONCLUSIONS:A radioisotope label on IgG and its visualization in a large series of animal models indicate that a low protein dose of anti-GD2 IgG will not cause neurologic side effects in patients. High protein dose anti-GD2 IgG may enhance antineoplastic effects and contribute to neurotoxicity through stimulation of normal lymphocytes with subsequent release of cytokines.

BACKGROUND. Indium-111 labeled antiferritin targets 95% of all Hodgkin's disease lesions with a diameter of 1 cm or more. Subsequent treatment with yttrium-90 labeled antiferritin secures a high response rate in patients with recurrent Hodgkin's disease.METHODS. A total of 87 patients were entered on one of three different yttrium-90 labeled antiferritin protocols. Recurrences after yttrium-90 treatment were analyzed. Nine patients were retreated with involved external beam radiation fields, selected with the help of indium-111 labeled antiferritin.RESULTS. In single-agent yttrium-90 antiferritin studies, a response rate of more than 60% was found, with an average response duration of 6 months. One-third of the patients had recurrences in previously uninvolved areas. Repeat indium antiferritin scintigraphy allowed for the selection of new radiation fields for recurrences. In-field disease control was obtained for a median of 8 months, but new recurrences in new areas occurred. Chemotherapy or radiation therapy given immediately before antiferritin decreased tumor targeting with indium-111 labeled antiferritin.CONCLUSIONS. Recurrences after radiolabeled antiferritin treatment are not due to radioresistant Hodgkin's disease. In contrast, Hodgkin's disease less than 1 cm in diameter is not targeted and not controlled by radiolabeled antiferritin. New multimodality regimens with a higher therapeutic ratio are needed for treatment of Hodgkin's disease with curative intent. Radiolabeled antiferritin can be incorporated in such regimens to secure better control of bulky Hodgkin's disease (> 1 cm in diameter), but it should be given before chemotherapy or radiation therapy. (C) 1997 American Cancer Society.

BACKGROUND AND PURPOSE:Intralesional (i.l.) administration of radiolabeled human monoclonal IgM could provide a new method for increasing the radiation dose delivered to a tumor without exceeding normal tissue tolerance. MATERIALS AND METHODS:Nude mice with subcutaneous human head and neck squamous cell carcinoma nodules were injected either intralesionally or intravenously with a tumor-reactive human monoclonal IgM (CR4E8) labeled with indium-111 (111In) or yttrium-90 (90Y). Groups of mice were sacrificed at different time points and their tumors and major organs were excised and counted for radioactivity. Additional mice that were treated with i.l. 90Y-labeled CR4E8 were sacrificed at the same time points for tumor autoradiography. Serial whole-body gamma camera images were obtained from additional mice treated with i.l. 111In-labeled CR4E8. Intralesionally administered 111In-labeled irrelevant IgM (CH-1B9) and 90Y-aggregate served as specificity controls. RESULTS:Intralesional administration of radiolabeled IgM resulted in prolonged high tumor radioactivity with little normal tissue uptake, with kidney and liver having the highest values. The biodistribution of i.l. CR4E8 was similar whether labeled with 111In or 90Y. Tumor uptake of i.l. irrelevant IgM appeared to be lower and tumor retention appeared to be shorter. Intravenous administration of tumor-reactive IgM resulted in very low tumor radioactivity with high liver and moderate spleen uptake. The i.l. administration of 90Y-aggregate produced prolonged high tumor radioactivity with little normal tissue uptake, with bone having the highest value. Tumor autoradiographs demonstrated that the radiolabeled IgM diffused through the tumor over time while the 90Y-aggregate remained localized at the injection site. Gamma camera scintigraphy corroborated the results of the biodistribution studies. CONCLUSIONS:Intralesional but not intravenous administration of 111In- or 90Y-labeled human IgM results in high tumor radioactivity with low normal tissue exposure. Myelotoxicity is not anticipated to be the dose-limiting normal tissue toxicity of this treatment. Further development of human IgM for the i.l. treatment of human malignancies appears to be warranted.

This study was aimed at developing a hydrophilic diethyl-enetriaminepentaacetic acid–tamoxifen (DTPA–Tam) analogue for use in imaging estrogen receptor positive (ER+) lesions. In rat uterine cytosol, the IC50 of DTPA-Tam conjugate was 1 µM and of tamoxifen, 2 µM. Biodistribution, autoradiography, and radionuclide imaging of 111In–DTPA–Tam in breast-tumor-bearing rats showed that tumor-to-tissue ratios increased steadily between 30min and 48h. The in vivo response of MCF-7 breast cancer xenografts to tamoxifen and DTPA–Tam in nude mice demonstrated that DTPA–Tam could reduce tumor growth rate. These results indicate that DTPA–Tam, a new hydrophilic ER+ ligand, might be useful in diagnosing ER+ lesions.