Review of treatment strategies after lymphadenectomy: from molecular therapeutics to immediate microsurgical lymphatic reconstruction.

OBJECTIVE: Lymphedema is a common complication of cancer treatment, such as lymphadenectomy and radiation therapy. It is a debilitating condition with pathologic tissue changes that hinder effective curative treatment and jeopardize patients' quality of life. Various attempts to prevent the development of lymphedema have been made, with improvements in the incidence of the pathology. However, it is still prevalent among survivors of cancer. In this paper, we review both molecular therapeutics and immediate surgical lymphatic reconstruction as treatment strategies after lymphadenectomy. Specifically, we discuss pro-lymphangiogenic molecules that have proved efficient in animal models of lymphedema and clinical trials, and review currently available microsurgical techniques of immediate lymphatic reconstruction. METHODS: A literature search was conducted in PubMed, Embase, Cochrane Library, and Google Scholar through May 2022. Searches were done separately for molecular therapeutics and microsurgical techniques for immediate lymphatic reconstruction. Search terms used for (1) non-surgical methods include 'lymphangiogenesis,' 'lymphedema,' 'growth factor,' and 'gene therapy.' Search terms used for (2) surgical methods include 'lymphedema,' 'lymph node excision,' 'lymphatic vessels,' 'primary prevention,' and 'microsurgery.' RESULTS: Various pro-lymphangiogenic factors with therapeutic potential include VEGF-C, VEGF-D, HGF, bFGF, PDGF, IGF, Retinoic acid, Ang-1, S1P, TLR4, and IL-8. Microsurgical lymphatic reconstruction for prevention of secondary lymphedema includes lymphovenous anastomosis, vascularized lymph node flap transfer, and lymph-interpositional flap transfer, with promising clinical outcomes. CONCLUSIONS: With growing knowledge of the lymphangiogenic pathway and lymphedema pathology and advances in microsurgical techniques to restore lymphatic channels, molecular and surgical approaches may represent a promising method for primary prevention of lymphedema.

Lymphatic endothelial cell RXRα is critical for 9-cis-retinoic acid-mediated lymphangiogenesis and prevention of secondary lymphedema.

Secondary lymphedema is a debilitating disease characterized by abnormal soft tissue swelling and caused by lymphatic system dysfunction. Despite a high prevalence of secondary lymphedema after cancer treatments, current management is supportive and there are no approved therapeutic agents that can thwart disease progression. We have previously demonstrated that 9-cis-retinoic acid (9-cisRA) has the potential to be repurposed for lymphedema as it mitigates disease by promoting lymphangiogenesis at the site of lymphatic injury. Although the efficacy of 9-cisRA has been demonstrated in previous studies, the mechanism of action is not completely understood. In this study, we demonstrate that when RXRα is specifically deleted in lymphatic endothelial cells, 9-cisRA fails to induce lymphangiogenesis in vitro and prevent pathologic progression of postsurgical lymphedema in vivo. These findings demonstrate that downstream nuclear receptor RXRα plays a critical role in the therapeutic efficacy of 9-cisRA in postsurgical lymphedema.

Does plastic surgery need a rewiring? A survey and systematic review on robotic-assisted surgery.

Background: This is a paucity of data regarding plastic surgeons' opinions on robotic-assisted surgery (RAS). We developed a questionnaire aimed to survey plastic surgeons regarding training in robotics, concerns about widespread implementation, and new research directions. Methods: A survey was created using Google Forms and sent to practicing plastic surgeons and trainees. Responses regarding desired conference proceedings about robotics, robotic residency training, and perceived barriers to implementation were elicited. Survey responses were utilized to direct a systematic review on RAS in plastic surgery. Results: The survey received 184 responses (20.4%; 184/900). The majority (92.8%) of respondents were/are plastic surgery residents, with the most common fellowships being microsurgery (39.2%). Overall, 89.7% of respondents support some integration of robotics in the future of plastic surgery, particularly in pelvic/perineum reconstruction (56.4%), abdominal reconstruction (46.5%), microsurgery (43.6%), and supermicrosurgery (44.2%). Many respondents (66.1%) report never using a robot in their careers. Respondents expressed notable barriers to widespread robotic implementation, with cost (73.0%) serving as the greatest obstacle. A total of 10 studies (pelvic/perineum = 3; abdominal = 3; microsurgery = 4) were included after full-text review. Conclusions: Evidence from our survey and review supports the growing interest and utility of RAS within the plastic and reconstructive surgery (PRS) and mirrors the established trend in other surgical subspecialties. Cost analyses will prove critical to implementing RAS within PRS. With validated benefits, plastic surgery programs can begin creating dedicated curricula for RAS.

Is HLA-B*58:01 genotyping cost effective in guiding allopurinol use in gout patients with chronic kidney disease?

Aim: Concerns for fatal severe cutaneous adverse reactions (SCARs) hamper allopurinol use. Methods and material: We adopted a health system perspective to evaluate the cost-effectiveness of HLA-B*58:01 genotyping before allopurinol initiation. A decision tree compared three treatment strategies in gout patients with chronic kidney disease who have higher risk for SCAR. They were standard allopurinol treatment followed by febuxostat in nonresponders, test-positive patients receive febuxostat while test-negative receive allopurinol and universal use of febuxostat. Results: The first strategy was the most cost effective. Genotyping dominated universal febuxostat use. Time horizon and SCAR incidence were the most influential factors on the incremental cost-effectiveness ratio. Conclusion: HLA-B*58:01 genotyping compared with standard allopurinol-febuxostat sequential treatment does not provide good value for money in gout with chronic kidney disease.

Prevention of postsurgical lymphedema via immediate delivery of sustained-release 9-cis retinoic acid to the lymphedenectomy site.

BACKGROUND AND OBJECTIVES: Previously, we have shown that 9-cis retinoic acid (9-cis RA) stimulates lymphangiogenesis and limits postsurgical lymphedema in animal models when administered via daily intraperitoneal injections. In this study, we investigate whether a single-use depot 9-cis RA drug delivery system (DDS) implanted at the site of lymphatic injury can mitigate the development of lymphedema in a clinically relevant mouse limb model. METHODS: Hind limb lymphedema was induced via surgical lymphadenectomy and irradiation. Animals were divided into two treatment groups: (1) 9-cis RA DDS, (2) placebo DDS. Outcomes measured included paw thickness, lymphatic clearance and density, epidermal thickness, and collagen deposition. RESULTS: Compared with control animals, 9-cis RA-treated animals had significantly less paw swelling from postoperative week 3 (P = .04) until the final timepoint at week 6 (P = .0007). Moreover, 9-cis RA-treated animals had significantly faster lymphatic clearance (P < .05), increased lymphatic density (P = .04), reduced lymphatic vessel size (P = .02), reduced epidermal hyperplasia (P = .04), and reduced collagen staining (P = .10). CONCLUSIONS: Animals receiving 9-cis RA sustained-release implants at the time of surgery had improved lymphatic function and structure, indicating reduced lymphedema progression. Thus, we demonstrate that 9-cis RA contained within a single-use depot DDS has favorable properties in limiting pathologic responses to lymphatic injury and may be an effective strategy against secondary lymphedema.

A Pre-clinical Animal Model of Secondary Head and Neck Lymphedema.

Head and neck lymphedema (HNL) is a disfiguring disease affecting over 90% of patients treated for head and neck cancer. Animal models of lymphedema are used to test pharmacologic and microsurgical therapies; however, no animal model for HNL is described in the literature to date. In this study we describe the first reproducible rat model for HNL. Animals were subjected to two surgical protocols: (1) lymphadenectomy plus irradiation; and (2) sham surgery and no irradiation. Head and neck expansion was measured on post-operative days 15, 30 and 60. Magnetic resonance imaging (MRI) was acquired at the same time points. Lymphatic drainage was measured at day 60 via indocyanine green (ICG) lymphography, after which animals were sacrificed for histological analysis. Postsurgical lymphedema was observed 100% of the time. Compared to sham-operated animals, lymphadenectomy animals experienced significantly more head and neck swelling at all timepoints (P < 0.01). Lymphadenectomy animals had significantly slower lymphatic drainage for 6 days post-ICG injection (P < 0.05). Histological analysis of lymphadenectomy animals revealed 83% greater subcutis thickness (P = 0.008), 22% greater collagen deposition (P = 0.001), 110% greater TGFß1+ cell density (P = 0.04), 1.7-fold increase in TGFß1 mRNA expression (P = 0.03), and 114% greater T-cell infiltration (P = 0.005) compared to sham-operated animals. In conclusion, animals subjected to complete lymph node dissection and irradiation developed changes consistent with human clinical postsurgical HNL. This was evidenced by significant increase in all head and neck measurements, slower lymphatic drainage, subcutaneous tissue expansion, increased fibrosis, and increased inflammation compared to sham-operated animals.

Detecting adverse drug reactions in discharge summaries of electronic medical records using Readpeer.

BACKGROUND: Hospital discharge summaries offer a potentially rich resource to enhance pharmacovigilance efforts to evaluate drug safety in real-world clinical practice. However, it is infeasible for experts to read through all discharge summaries to find cases of drug-adverse event (AE) relations. PURPOSE: The objective of this paper is to develop a natural language processing (NLP) framework to detect drug-AE relations from unstructured hospital discharge summaries. BASIC PROCEDURES: An NLP algorithm was designed using customized dictionaries of drugs, adverse event (AE) terms, and rules based on trigger phrases, negations, fuzzy logic and word distances to recognize drug, AE terms and to detect drug-AE relations. Furthermore, a customized annotation tool was developed to facilitate expert review of discharge summaries from a tertiary hospital in Singapore in 2011. MAIN FINDINGS: A total of 33 trial sets with 50 to 100 records per set were evaluated (1620 discharge summaries) by our algorithm and reviewed by pharmacovigilance experts. After every 6 trial sets, drug and AE dictionaries were updated, and rules were modified to improve the system. Excellent performance was achieved for drug and AE entity recognition with over 92% precision and recall. On the final 6 sets of discharge summaries (600 records), our algorithm achieved 75% precision and 59% recall for identification of valid drug-AE relations. PRINCIPAL CONCLUSIONS: Adverse drug reactions are a significant contributor to health care costs and utilization. Our algorithm is not restricted to particular drugs, drug classes or specific medical specialties, which is an important attribute for a national regulatory authority to carry out comprehensive safety monitoring of drug products. Drug and AE dictionaries may be updated periodically to ensure that the tool remains relevant for performing surveillance activities. The development of the algorithm, and the ease of reviewing and correcting the results of the algorithm as part of an iterative machine learning process, is an important step towards use of hospital discharge summaries for an active pharmacovigilance program.

Tailoring of recommendations to reduce serious cutaneous adverse drug reactions: a pharmacogenomics approach.

The Health Sciences Authority launched a pharmacogenetics initiative in 2008 to facilitate evaluation of pharmacogenetics associations pertinent for Chinese, Malays and Indians in Singapore. The aim was to reduce the incidence and unpredictability of serious adverse drug reactions, with a focus on serious skin adverse drug reactions. This paper describes the gathering of evidence and weighing of factors that led to different genotyping recommendations for HLA-B*15:02 with carbamazepine and HLA-B*58:01 with allopurinol, despite both having strong genetic associations. Translation of pharmacogenomics at a national level requires careful deliberation of the prevalence of at-risk allele, strength of genetic associations, positive predictive value, cost-effectiveness and availability of alternative therapies. Our experience provides a perspective on translating genomic discoveries in advancing drug safety.

Cost-effectiveness analysis of genotyping for HLA-B*5801 and an enhanced safety program in gout patients starting allopurinol in Singapore.

AIMS: Allopurinol is an efficacious urate-lowering therapy (ULT), but is associated with rare serious adverse drug reactions of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), with higher risk among HLA-B*5801 carriers. We assessed the cost-effectiveness of HLA-B*5801 testing, an enhanced safety program or strategies with both components. METHODS: The analysis adopted a health systems perspective and considered Singaporean patients with chronic gout, over a lifetime horizon, using allopurinol or probenecid. The model incorporated SJS/TEN and gout treatment outcomes, allele frequencies, drug prices and other medical costs. RESULTS: Based on cost-effectiveness threshold of US$50,000 per quality-adjusted life year, HLA-B*5801-guided ULT selection or enhanced safety program was not cost effective. Avoidance of ULTs was the least preferred strategy as uncontrolled gout leads to lower quality-adjusted life years and higher costs. CONCLUSION: The analysis underscores the need for biomarkers with higher positive predictive value for SJS/TEN, less expensive genetic tests or safety programs, or more effective gout drugs. .

Pharmacogenetic risk for adverse reactions to irinotecan in the major ethnic populations of Singapore: regulatory evaluation by the health sciences authority.

BACKGROUND: For genetic polymorphisms known to alter drug effect or safety, regulatory authorities can tap into population genomic databases and other sources of allele and genotype distribution data to make a more informed decision about the anticipated impact of such variants on the main ethnic groups in a country's population. OBJECTIVE: The aim of this short communication is to describe how the Singapore Health Sciences Authority (HSA) made use of allele and genotype distributions in the main ethnic groups in Singapore (Chinese, Malay, Indian) and population genetic tools to compare with North American Caucasians and Japanese. METHODS: Published papers and publicly accessible genomic databases were searched up to August 2009 to obtain allele and genotype frequencies for UGT1A1*6 and *28, two common variants of UGT1A1, a gene that encodes for a key enzyme in the pathway of irinotecan metabolism. These variants are associated with greater risk of serious toxicity. RESULTS: In Singapore, the combined prevalence of three high-risk genotypes, UGT1A1*6/*6, *6/*28 and *28/*28, is 9.7% in Chinese, 5.0% in Malays and 18.7% in Indians, compared with 11.5% in North American Caucasians and 8.1% in Japanese. Indians are at an elevated risk of irinotecan-induced neutropenia associated with UGT1A1*28 compared with Chinese and Japanese, and at an even higher risk compared with North American Caucasians. On the other hand, Chinese and Japanese are at an elevated risk of irinotecan-induced neutropenia associated with UGT1A1*6 relative to Indians in Singapore or North American Caucasians. Population genotype data were the basis for the HSA to request revision of the package insert from manufacturers of irinotecan products. Moreover, the data provided the impetus for the HSA to publicize the availability of UGT1A1 genetic testing at the National Cancer Centre. CONCLUSION: With the growing volume of genomic data and pharmacogenomic associations, a regulatory authority is now able to more readily utilize population genetic information and tools to supplement evaluations of drug products pertinent to the country's ethnic demography.

Population PK and IgE pharmacodynamic analysis of a fully human monoclonal antibody against IL4 receptor.

PURPOSE: For AMG 317, a fully human monoclonal antibody to interleukin receptor IL-4Rα, we developed a population pharmacokinetic (PK) model by fitting data from four early phase clinical trials of intravenous and subcutaneous (SC) routes simultaneously, investigated important PK covariates, and explored the relationship between exposure and IgE response. METHODS: Data for 294 subjects and 2183 AMG 317 plasma concentrations from three Phase 1 and 1 Phase 2 studies were analyzed by nonlinear mixed effects modeling using first-order conditional estimation with interaction. The relationship of IgE response with post hoc estimates of exposure generated from the final PK model was explored based on data from asthmatic patients. RESULTS: The best structural model was a two-compartment quasi-steady-state target-mediated drug disposition model with linear and non-linear clearances. For a typical 80-kg, 40-year subject, linear clearance was 35.0 mL/hr, central and peripheral volumes of distribution were 1.78 and 5.03 L, respectively, and SC bioavailability was 24.3%. Body weight was an important covariate on linear clearance and central volume; age influenced absorption rate. A significant treatment effect was observable between the cumulative AUC and IgE response measured. CONCLUSION: The population PK model adequately described AMG 317 PK from IV and SC routes over a 60-fold range of doses with two dosing strengths across multiple studies covering healthy volunteers and patients with mild to severe asthma. IgE response across a range of doses and over the sampling time points was found to be related to cumulative AMG 317 exposure.

Effect of albumin fusion on the biodistribution of interleukin-2.

PURPOSE: We investigated and compared the biodistribution of Albuleukin, a human serum albumin (HSA)-interleukin-2 (IL-2) fusion protein, with those of IL-2 and HSA. The objective was to determine whether Albuleukin distributes differently to normal organs and lymphoid tissues than IL-2 by virtue of its genetic fusion with HSA. METHODS: The chelating agent 2-( p-isothiocyanato-benzyl)-cyclohexyl-diethylenetriaminepentaacetic acid (CHX-A(II) was selected for radiolabeling with (111)In, and conjugation with CHX-A(II) did not alter bioactivities of IL-2 and Albuleukin on proliferation of CTLL-2 cells. The radiolabeled proteins were injected intravenously into mice, uptake in organs was measured, and whole-body autoradiography was performed. RESULTS: Striking differences in the biodistribution of IL-2 and Albuleukin were noted. (111)In-IL-2 cleared from blood rapidly, with less than 1% ID/g (percentage of injected dose per gram of tissue) at 20 min after injection. At this time, the kidneys showed more than 120% ID/g uptake, and these high levels persisted through 6 h. (111)In-Albuleukin, by contrast, showed significantly longer circulation (14% ID/g at 6 h), lower kidney uptake (<6% ID/g), and higher localization in liver, spleen, and lymph nodes (maximal uptake approximately 22% ID/g for all three organs). Uptake in liver, spleen, and lymph nodes appears to be mediated in part by the IL-2 component of Albuleukin because (111)In-HSA showed significantly lower accumulation in those tissues despite more prolonged circulation in blood. CONCLUSION: These data support the hypothesis that Albuleukin targets tissues where lymphocytes reside to a much greater extent than does IL-2, and suggest that Albuleukin may exhibit improved efficacy and reduced toxicity in the treatment of solid tumors. Clinical trials underway will determine whether the improved targeting in the mice translates into a better therapeutic index in humans.

Convective distribution of macromolecules in the primate brain demonstrated using computerized tomography and magnetic resonance imaging.

OBJECT: Convection-enhanced delivery (CED), the delivery and distribution of drugs by the slow bulk movement of fluid in the extracellular space, allows delivery of therapeutic agents to large volumes of the brain at relatively uniform concentrations. This mode of drug delivery offers great potential for the treatment of many neurological disorders, including brain tumors, neurodegenerative diseases, and seizure disorders. An analysis of the treatment efficacy and toxicity of this approach requires confirmation that the infusion is distributed to the targeted region and that the drug concentrations are in the therapeutic range. METHODS: To confirm accurate delivery of therapeutic agents during CED and to monitor the extent of infusion in real time, albumin-linked surrogate tracers that are visible on images obtained using noninvasive techniques (iopanoic acid [IPA] for computerized tomography [CT] and Gd-diethylenetriamine pentaacetic acid for magnetic resonance [MR] imaging) were developed and investigated for their usefulness as surrogate tracers during convective distribution of a macromolecule. The authors infused albumin-linked tracers into the cerebral hemispheres of monkeys and measured the volumes of distribution by using CT and MR imaging. The distribution volumes measured by imaging were compared with tissue volumes measured using quantitative autoradiography with [14C]bovine serum albumin coinfused with the surrogate tracer. For in vivo determination of tracer concentration, the authors examined the correlation between the concentration of the tracer in brain homogenate standards and CT Hounsfield units. They also investigated the long-term effects of the surrogate tracer for CT scanning, IPA-albumin, on animal behavior, the histological characteristics of the tissue, and parenchymal toxicity after cerebral infusion. CONCLUSIONS: Distribution of a macromolecule to clinically significant volumes in the brain is possible using convection. The spatial dimensions of the tissue distribution can be accurately defined in vivo during infusion by using surrogate tracers and conventional imaging techniques, and it is expected that it will be possible to determine local concentrations of surrogate tracers in voxels of tissue in vivo by using CT scanning. Use of imaging surrogate tracers is a practical, safe, and essential tool for establishing treatment volumes during high-flow interstitial microinfusion of the central nervous system.

Rapid and specific targeting of 125I-labeled B lymphocyte stimulator to lymphoid tissues and B cell tumors in mice.

UNLABELLED: B lymphocyte stimulator (BLyS) protein is a member of the tumor necrosis factor (TNF) superfamily of cytokines that binds to B lineage cells, but not T cells, monocytes, natural killer cells, or granulocytes. BLyS protein binding to B cells is restricted to immunoglobulin-positive cells and is not evident on pro- or pre-B cell populations. This unique binding profile suggests that a radiolabeled form of BLyS protein may be a useful treatment for B cell neoplasias such as B cell lymphoma and multiple myeloma. Here, we report the biodistribution of radiolabeled recombinant human BLyS after intravenous injection into normal mice and mice bearing BCL1 tumor in the spleen or J558 tumor in the subcutaneous space. We also report the use of these data to estimate human dosimetry. METHODS: (125)I-Labeled BLyS protein (50 micro g/kg, 0.185-0.37 MBq per mouse) was injected intravenously into BALB/c mice, and biodistribution was measured by direct counting of radioactivity in dissected tissues and by quantitative whole-body autoradiography (QWBA). RESULTS: The half-life of radiolabeled BLyS protein in blood was approximately 2.7 h in both normal and tumor-bearing mice. The spleen showed the highest uptake of BLyS protein in both normal and tumor-bearing mice, with a maximum concentration (C(max)) of 35-45 percentage injected dose per gram (%ID/g) occurring between 1 and 3 h after injection. In lymph nodes, C(max) was approximately 20 %ID/g in normal and J558 tumor-bearing mice and 8-15 %ID/g in BCL1 tumor-bearing mice. Limited biodistribution data from the J558 tumors showed a C(max) of approximately 15 %ID/g. By contrast, C(max) was only approximately 5 %ID/g for both kidney and liver. QWBA confirmed high radioactivity in spleen, lymph nodes, and stomach contents and low radioactivity in kidney and liver. After 24 h, spleen and lymph nodes were still positive in QWBA images, whereas liver and kidney no longer had observable levels. CONCLUSION: Radiolabeled BLyS showed specific and rapid targeting to lymphoid tissues and B cell tumors in mice. Unlike monoclonal antibodies, which have long plasma half-lives and considerable liver uptake, BLyS has distinct pharmacokinetic and biodistribution properties that may offer advantages compared with antibody-based radioimmunotherapy.

Pharmacokinetic and pharmacodynamic studies of a human serum albumin-interferon-alpha fusion protein in cynomolgus monkeys.

Interferon-alpha (IFN-alpha) is indicated for the treatment of certain viral infections including hepatitis B and C, and cancers such as melanoma. The short circulating half-life of unmodified IFN-alpha makes frequent dosing (daily or three times weekly) over an extended period (6-12 months or more) necessary. To improve the pharmacokinetics of IFN-alpha and decrease dosing frequency, IFN-alpha was fused to human serum albumin producing a new protein, Albuferon. In vitro comparisons of Albuferon and IFN-alpha showed similar antiviral and antiproliferative activities, although Albuferon was less potent on a molar basis than IFN-alpha. Pharmacokinetic and pharmacodynamic properties of the fusion protein were enhanced in monkeys. After a single intravenous injection (30 microg/kg,) clearance was 0.9 ml/h/kg, and the terminal half-life was 68 h. After 30 microg/kg subcutaneous injection, apparent clearance (clearance divided by bioavailability) was 1.4 ml/h/kg, the terminal half-life was 93 h, and bioavailability was 64%. The rate of clearance of Albuferon was approximately 140-fold slower, and the half-life 18-fold longer, than for IFN-alpha given by the subcutaneous route in other monkey studies. Sera from Albuferon-treated monkeys demonstrated dose-related antiviral activity for > or =8 days based on an in vitro bioassay, whereas antiviral activity from IFN-alpha-treated animals was only slightly elevated relative to vehicle on day 0. Significant increases in 2',5'-oligoadenylate synthetase mRNA relative to IFN-alpha- or vehicle-treated animals were maintained for > or =10 days after subcutaneous dosing. The improved pharmacokinetics of Albuferon are accompanied by an improved pharmacodynamic response suggesting that Albuferon may offer the benefits of less frequent dosing and a potentially improved efficacy profile compared with IFN-alpha.

Antibody penetration into a spherical prevascular tumor nodule embedded in normal tissue.

A finite-element (FE) method is used to numerically solve a pharmacokinetic model that describes the uptake of systemically administered antibody (mAb) in a prevascular spherical tumor nodule embedded in normal tissue. The model incorporates plasma kinetics, transcapillary transport, lymphatic clearance, interstitial diffusion in both the normal tissue and tumor, and binding reactions. We use results from the FE analysis to assess previous predictions that employed either a Dirichlet boundary condition (b.c.), or an approximate, composite (Dirichlet and Neumann) b.c. at the tumor surface. We find that the Dirichlet b.c. significantly overpredicted the mean total tumor mAb concentration. In contrast, the composite b.c. yielded good agreement with FE predictions, except at early times. We also used the FE model to investigate the influence of the approximately 30-fold difference in the values of mAb diffusion coefficient measured by Clauss and Jain (Cancer Res. 50:3487-3492, 1990) and Berk et al. (Proc. Natl. Acad. Sci. U.S.A. 94:1785-1790, 1997). For low diffusivity, diffusional resistance slows both mAb uptake by and efflux from the tumor. For high diffusivity at the same mAb dose, more rapid uptake produces earlier and higher peak mAb levels in the tumor, while the efflux rate is limited by the dissociation of the mAb-tumor antigen complex. The differences in spatial and temporal variation in mAb concentration between low and high diffusivities are of sufficient magnitude to be experimentally observable, particularly at short times after antibody administration.