Understanding delays to parathyroidectomy: A mixed-methods approach.

BACKGROUND: Patients from ethnic and racial minority groups with primary hyperparathyroidism may have greater time delays to curative parathyroidectomy. Contributing factors are unclear. METHODS: This was a sequential mixed-methods study. The quantitative phase was a retrospective chart review of adults with primary hyperparathyroidism who underwent parathyroidectomy between 2015 and 2020, collecting demographic and clinical data. Social vulnerability of the patients' residential area, measured with the Social Vulnerability Index, and relevant clinical time intervals were calculated. A multivariable analysis of factors associated with greater time intervals was performed. The qualitative phase involved semistructured interviews with endocrinologists, analyzed inductively for themes. RESULTS: On chart review of 1,083 patients, the median age was determined to be 61 years and 856 (79%) were female. Six hundred twenty-eight (57.9%) were non-Hispanic White and 456 (42.1%) were Hispanic ethnicity or Asian, Pacific Islander, Black, Native American, Other or Unknown race. Patients of Hispanic ethnicity, or Asian or Pacific Islander, Black, Native American, Other or Unknown race were more likely than non-Hispanic White patients to live in the most socially vulnerable areas (19.3% vs 5.9%, P < .01) and had greater time intervals than non-Hispanic White patients between index hypercalcemia and first parathyroid hormone level, surgical referral, or parathyroidectomy (all P < .05). On multivariable analysis, age (coefficient 7.9, 95% CI 2.8-13.0) and living in the most socially vulnerable areas (coefficient 297.9, 95% CI 87-508.7) were associated with greater days between index hypercalcemia and parathyroidectomy. In the study's qualitative phase, identified themes for reasons for care delays included socioeconomic, nonsocioeconomic patient, and nonsocioeconomic nonpatient factors. CONCLUSION: Care delays are driven by a combination of socioeconomic and nonsocioeconomic factors.

Social Determinants of Health and Quality of Life in Endocrine Surgery Patients.

INTRODUCTION: Quality of life (QoL) of endocrine surgery patients is an important patient outcome but the role of social determinants of health (SDH) on preoperative QoL is understudied. METHODS: This study used preoperative data of 233 endocrine surgery patients participating in a longitudinal QoL study to examine the influence of SDH (patient-level and environmental) on preoperative QoL. Patient-level SDH was assessed with structured survey questions and environmental SDH with the Social Vulnerability Index. Multiple domains of QoL were assessed with the Patient-Reported Outcomes Measurement Information System-29 (PROMIS-29). RESULTS: The average age of the sample was 52.9 y and 76.8% were female, 10% were Hispanic, 55.8% were White, 32.6% were Black, 6.9% were Other, and 4.7% were Asian. Patients with patient-level SDH were more likely to have worse preoperative QoL in multiple PROMIS domains. Patients who lived in the most socially vulnerable areas had the same or better QoL scores in the PROMIS-29 domains than those living in less vulnerable areas. Minority race patients were more likely to have patient-level SDH and to live in the most vulnerable areas. CONCLUSIONS: This study is the first to our knowledge to examine the role of patient-level and environmental SDH on preoperative QoL among endocrine surgery patients. The results identified specific patient-level factors that could be used as the basis for interventions aimed to improve patients' QoL. Future studies that evaluate the role of preoperative SDH on long-term QoL and clinical outcomes would further enhance our understanding of the impact of SDH on patient wellbeing.

Endocrine Patients' Views on Transoral Endoscopic Thyroidectomy via Vestibular Approach (TOETVA).

TOETVA's adoption has been slow in the Western hemisphere. Our study aimed to evaluate how endocrine patients in the United States perceive the risks and benefits of TOETVA. This was a cross-sectional study where a de novo survey was sent via email to patients seen from 2018 to 2020. The survey asked how each of TOETVA's risks and benefits affect their choice between traditional thyroidectomy (TT) and TOETVA on a scale from 1 (favors TT) to 10 (favors TOETVA). Statistical significance was determined at p < 0.05. Of 422 patients (3.2% response rate), 76.0% were female, 28.9% were non-Whites, 58.3% possessing graduate/professional degrees, and 34.1% were diagnosed with thyroid cancer. Significant differences were found between groups of age, race, educational attainment, thyroid cancer diagnosis, and history of thyroid or parathyroid surgery with respect to their preference for thyroidectomy between TT and TOETVA. In multivariate analysis, attitudes towards longer operative time (estimate 0.130, 95% CI 0.026-0.235, p = 0.002), limited outcome data (estimate 0.142, 95% CI 0.029-0.254, p = 0.024), having less pain (estimate 0.108, 95% CI 0.004-0.212, p = 0.042), travel to seek care (estimate 0.166, 95% CI 0.042-0.290, p = 0.009), as well as African American race (estimate 0.714, 95% CI 0.093-1.334, p = 0.024), and history of surgery (estimate - 0.843, 95% CI - 1.364- - 0.323, p = 0.002) were independently predictive of overall preferences. TOETVA's risks and benefits may carry varying degrees of significance in patients' decision-making process, which helps tailor the discussion to choose the right procedure for patients.

Comparing the rate and extent of malignancy in surgically excised thyroid nodules across race and ethnicity.

BACKGROUND: Few studies have compared the features of thyroid cancer among races and ethnicities. We hypothesized that race and ethnicity may influence the frequency and features of thyroid malignancy in thyroid nodules. METHOD: This was a retrospective chart review of patients between 2013 and 2020 who underwent thyroidectomy. RESULTS: In the analysis of 2737 patients, thyroid cancer was less prevalent among Blacks (24.0% vs Whites 52.1%, Hispanics 58.7%, Asians 71.7%, and Others 57.9%, p < 0.001). Thyroid cancer in Blacks was less likely to have extrathyroidal extension (9.7% vs Whites 18.6%, Hispanics 25.8%, Asians 18.2%, and Others 17.8%, p = 0.01), overall nodal involvement (12.4% vs Whites 31.1%, Hispanics 37.5%, Asians 36.3%, and Others 30.1%, p < 0.01), and lateral neck metastasis (4.4% vs Whites 10.8%, Hispanics 6.3%, Asians 13.2%, and Others 9.6%, p = 0.02). CONCLUSIONS: Race and ethnicity may play important roles in the risk of malignancy as well as in the extent of thyroid cancer.

Safety of Thyroid Surgery in the Elderly: A Propensity Score Matched Cohort Study.

BACKGROUND: Thyroid surgery is becoming more common in the elderly as elderly population continues to grow. We aim to evaluate the relative risk of morbidity from thyroidectomy in patients greater than 75 y of age. METHODS: A retrospective analysis was performed for patients who were undergoing thyroidectomy between 2001 and 2018 in a multihospital network. A matched control group was selected with use of a propensity score, which was based on gender, ethnicity, type of surgery, insurance status, and comorbidities. The Charlson Comorbidity Index was used to quantify comorbidities. Total complications included both thyroid-specific and systemic complications. RESULTS: We identified 313 patients over the age of 75 y with a propensity score matched group of 313 patients. There was no difference between the percent female (73% versus 73%, P = 0.92), race composition (P = 0.91), insurance status (P = 0.99), percent undergoing total thyroidectomy (84% versus 84%, P = 0.91), and Charlson Index (2.6 versus 2.69, P = 0.70) of the two groups. Overall complications (4.8% versus 1.9%, P = 0.05) and thrombotic events (1.2 versus 0%, P = 0.04) were significantly higher but there was no statistically significant difference between postoperative emergency room visits (7% versus 6%, P = 0.61), readmissions (11.5% versus 8.6%, P = 0.18), cardiovascular (1.3 versus 0.6%, P = 0.61), pulmonary (3.2 versus 0.9%, P = 0.07), or neurologic complications (1.0 versus 0.3%, P = 0.34). No reoperations were noted in either group. Elder patients did have a longer length of stay (2.64 versus 1.29 d, P < 0.01). CONCLUSIONS: Elderly patients did have a longer length of stay when compared to a matched younger population. Although there was a trend with higher complication rates in the elderly, those differences did not reach statistical significance.

Spinal metastases due to thyroid carcinoma: an analysis of 202 patients.

BACKGROUND: Spinal metastases (SMs) due to thyroid cancer (TC) are associated with significantly reduced quality of life. The goal of this study is to analyze the clinical manifestations, presentation, and treatments of TC SMs, and to describe specific features of SMs associated with different TC types. PATIENTS AND METHODS: A retrospective analysis of 202 TC SM patients treated at Medstar Washington Hospital Center (37) and collected from the literature (165) was performed. RESULTS: The mean age of patients with SMs was 56.9±14.7 years, and the female-to-male ratio was 2.1:1. Of all patients, 29% (28% of follicular thyroid cancer [FTC] and 37% of papillary thyroid cancer [PTC]) had SMs only. Twenty-nine percent of all patients and 54% of patients with single-site SMs had neither bone non-SMs nor solid organ metastases at the time of presentation. Thirty-five percent of patients had SMs as an initial presentation of TC. TC patients presenting with SMs had a lower rate of other bone and visceral involvement compared with patients whose SMs were diagnosed at the time of thyroid surgery or during follow-up (p<0.05). SMs were more often the initial manifestation of FTC (41% vs. 24%), while PTC SMs were more commonly diagnosed after TC diagnosis (76% vs. 59%; p<0.05). PTC SMs were more frequently diagnosed as synchronous (63% vs. 36% in FTC) versus FTC SMs that developed as metachronous metastases (64% vs. 37% in PTC; p<0.01). All FTC SMs developed within 82 (0-372) months and all PTC SMs within 35 (0-144) months (p<0.01). In FTC SMs as TC manifestation, solid organ metastases involvement was less common than in FTC SMs that were found after TC diagnosis (34% vs. 67%; p<0.01); multisite FTC SMs compared to solitary FTC SMs were associated with the development of other bone nonspinal metastases (82% vs. 30%; p<0.01) and solitary organ metastases (65% vs. 41%; p<0.01). These correlations were not observed in PTC SMs. FTC patients often had neural structure compression (myelopathy/radiculopathy; 72% vs. 36% in PTC), while PTC patients frequently were asymptomatic (38% vs. 5% in FTC; p<0.01). FTC SMs more commonly were (131)I-avid (p<0.01). FTC patients required surgery more frequently (72% vs. 55% in PTC; p<0.05). CONCLUSIONS: Our study reveals that a significant part of TC SMs patients have solitary spinal involvement at the time of presentation and may be considered for aggressive treatment with the intention to improve quality of life and survival. FTC SMs and PTC SMs appear to have distinct presentations, behavior, and treatment modalities, and should be categorized separately for treatment and follow-up planning.

Current treatment modalities for spinal metastases secondary to thyroid carcinoma.

BACKGROUND: The spine is the most common site of bone metastases due to thyroid cancer, which develop in more than 3% of patients with well-differentiated thyroid cancer. Nearly half of patients with bone metastases from thyroid cancer develop vertebral metastases. Spinal metastases are associated with significantly reduced quality of life due to pain, neurological deficit, and increased mortality. SUMMARY: Treatment options for patients with thyroid spinal metastases include radioiodine therapy, pharmacologic therapy, and surgical treatments, with recent advances in radiosurgery and minimally invasive spinal surgery as well. Therapeutic interventions require a multidisciplinary approach and aim to control pain, preserve or improve neurologic function, optimize local tumor control, and improve quality of life. We have proposed a three-tiered approach to the management and practical algorithms for patients with spinal metastases from thyroid carcinoma. CONCLUSIONS: The introduction of novel and improved techniques for the treatment of spinal metastases has created the opportunity to significantly improve control of metastatic tumor growth and the quality of life for the patients with spinal metastases from thyroid cancer. In order for these options to be effectively used, a multidisciplinary approach must be applied in the management of the patients with thyroid spinal metastases.

Graves' disease and thymic hyperplasia: the relationship of thymic volume to thyroid function.

BACKGROUND: Thymic hyperplasia is associated with Graves' disease, particularly in young patients. The degree of thymic transformation is minimal in most but not all patients. In the latter group radiological measurements of thyroid size and their change with treatment have rarely been reported. We present two patients with Graves' disease and relatively rapid resolution of thymic enlargement after successful treatment of their hyperthyroidism. SUMMARY: Three patients with thyrotoxicosis secondary to Graves' disease and marked thymic enlargement were seen at our institution during a 2-year period. On computed tomography (CT) studies their volumes were 67, 81, and 54 cm(3). Thymic hyperplasia in the setting of Graves' disease was the diagnosis of exclusion. Two of the patients returned for follow-up after successful treatment of thyrotoxicosis as requested. On repeat CT their thymic volumes had decreased by 72% and 78%, respectively. Two types of histological modifications of the thymus have been described in association with Graves' disease, namely, thymic parenchyma hyperplasia and medullary lymphoid hyperplasia. The mechanisms underlying thymic transformation in patients with Graves' hyperthyroidism are not completely elucidated, but autoimmune processes underlying Graves' disease are presumed to play a role. The clinical course of our patients is consistent with earlier literature, indicating that thymic enlargement may occur in conjunction with Graves' hyperthyroidism, and that it usually resolves as hyperthyroidism is treated, but there is little quantitative pre- and posttreatment of hyperthyroidism data. CONCLUSION: Although every patient must be individually considered, it appears that thymic hyperplasia can be diagnosed in most Graves' hyperthyroid patients by considering the clinical context and appropriate radiologic studies such as CT. Raising awareness of the association of thymic hyperplasia in patients with Graves' hyperthyroidism and its resolution with the reversibility of the hyperthyroid state should prevent unnecessary thymic evaluation and surgery with its attendant risks.

Promising molecular techniques for discriminating among follicular thyroid neoplasms.

To guide the extent of thyroidectomy for indeterminate follicular neoplasm (FN), clinicians have long sought ways to differentiate follicular adenoma from carcinoma pre- or intraoperatively. Several promising molecular techniques have recently appeared including loss of heterozygosity analysis and molecular profiling microarray analysis. These new tools may also prove useful in determining prognosis, thus and allow a paradigm change in current management of the thyroid nodule.

The role of interleukin 1 in growth and metastasis of human cancer xenografts.

BACKGROUND: Interleukin 1 (IL-1) is a pluripotent cytokine that promotes angiogenesis, tumor growth, and metastasis in experimental models; its presence in some human cancers is associated with aggressive tumor biology. The purpose of these studies was to characterize the role of IL-1 in human cancers and determine if inhibition of IL-1 via its receptor antagonist, IL-1Ra, alters tumor growth and metastatic potential. METHODS: IL-1 mRNA or protein levels were determined in clinical tumor samples, cancer cell lines, and xenografts using quantitative reverse transcription-PCR or ELISA. Biological activity of tumor-derived IL-1 protein was shown via induction of permeability across endothelial cell monolayers. The effects of recombinant IL-1Ra on tumor lines in culture (cell proliferation and IL-8 secretion) and in xenograft models (tumor growth, metastatic potential, and intratumoral levels of IL-8 and VEGF) were characterized. The effects of IL-1Ra-mediated regression of xenograft growth on angiogenic proteins (IL-8 and VEGF) were evaluated in an IL-1-producing melanoma (SMEL) xenograft model. RESULTS: IL-1 mRNA was highly expressed in more than half of all tested metastatic human tumor specimens including non-small-cell lung carcinoma, colorectal adenocarcinoma, and melanoma tumor samples. Constitutive IL-1 mRNA expression was identified in several cancer cell lines; tumor supernatant from these cell lines produced a significant increase in endothelial cell monolayer permeability, a hallmark event in early angiogenesis, in an IL-1-dependent manner. Moreover, systemic recombinant IL-1Ra resulted in significant inhibition of xenograft growth and neovessel density of IL-1-producing, but not non-IL-1-producing, tumor cell lines. Subsequent analysis of SMEL, a melanoma cell line with constitutive IL-1 production, showed that neither exogenous IL-1 nor IL-1Ra altered tumor cell proliferation rates in vitro. Gene expression analyses of IL-1Ra-treated SMEL xenografts showed a >3-fold down-regulation of 100 genes compared with control including a marked down-regulation of IL-8 and VEGF. CONCLUSIONS: These data show that the IL-1 gene is frequently expressed in metastases from patients with several types of human cancers. IL-1Ra inhibits xenograft growth in IL-1-producing tumors but has no direct antiproliferative effects in vitro; decreased tumor levels of IL-8 and VEGF may be an early surrogate of IL-1Ra-mediated antitumor activity. IL-1Ra may have a role alone or with other agents in the treatment of human cancers.

Interferon gamma-inducible protein 10 selectively inhibits proliferation and induces apoptosis in endothelial cells.

BACKGROUND: Interferon gamma-inducible protein 10 (IP-10) has antitumor effects in various murine models. The IP-10 receptor has two distinct splice variants, CXCR3A and CXCR3B, that have paradoxical effects after ligand-receptor interaction. METHODS: To characterize the putative antiangiogenic effects of IP-10, we measured proliferation rates and apoptosis in human umbilical vein endothelial cells (HUVECs), fibroblasts, and A375 melanoma or WIDR adenocarcinoma cell lines after exposure to the recombinant protein. CXCR3A (activating) and CXCR3B (inhibitory/proapoptotic) messenger RNA (mRNA) expression levels in fibroblasts, 2 human tumor cell lines, T lymphocytes, and HUVECs of varying cell densities were characterized. RESULTS: IP-10 resulted in dose-dependent and selective inhibition of proliferation and countered the proliferative effects of vascular endothelial growth factor in HUVECs but did not affect fibroblasts or 2 human tumor cell lines. In addition, IP-10 resulted in potent and selective induction of apoptosis in HUVECS but had no effect on fibroblasts or A375 melanoma. Confluent HUVECs had a predominance of mRNA for the CXCR3B splice variant by reverse transcriptase-polymerase chain reaction, and the ratio of CXCR3B to CXCR3A mRNA was >40 in HUVECs, compared with

Interleukin-1beta induced vascular permeability is dependent on induction of endothelial tissue factor (TF) activity.

IL-1beta is a pleotropic cytokine that may mediate increased procoagulant activity and permeability in endothelial tissue during inflammatory conditions. The procoagulant effects of IL-1beta are mediated through induction of tissue factor (TF) but its alterations on vascular permeability are not well characterized. We found that IL-1beta induced a rapid and dose-dependent increase in TF activity in human umbilical vein endothelial cells (ECs) under routine culture conditions. However, IL-1beta caused a rapid and marked increase in permeability across confluent EC monolayers using a two-compartment in vitro model only in the presence of factor VIII-deficient plasma that was completely abrogated by neutralizing anti-TF antibody pre-treatment. In vitro permeability was associated with loss of EC surface expression of VE-cadherin and contraction of F-actin cytoskeletal elements that resulted in EC intercellular gap formation. These data demonstrate that IL-1beta induces marked changes in permeability across activated endothelium via a TF dependent mechanism and suggest that modulation of TF activity may represent a strategy to treat various acute and chronic inflammatory conditions mediated by this cytokine.

Alterations in tumor necrosis factor-induced endothelial cell procoagulant activity by hyperthermia.

TNF is a cytokine with potent antitumor activity in murine models and when administered clinically via regional perfusion. There is substantial evidence that this antitumor activity depends in large part on TNF's procoagulant effect on tumor neovasculature, which is mediated by induction of endothelial cell tissue factor (TF), a component of the extrinsic clotting cascade. In regional perfusion of a cancer-bearing limb or organ, TNF is always administered under hyperthermic temperatures; however, little is known about the effect of hyperthermia on TNF-mediated procoagulant activity in endothelium. We examined the effects of hyperthermia on TNF-mediated procoagulant activity in human umbilical vein endothelial cells (HUVECs). HUVECs were exposed to TNF at normothermic (37 degrees C) and hyperthermic (41 degrees C) temperatures for 90 min, then assayed for clotting activity, TF protein production and mRNA production of TF and tissue factor pathway inhibitor-2 (TFPI-2), an endogenous inducible inhibitor of TF activity in HUVECs. TNF treatment at 41 degrees C significantly reduced clotting activity, TF protein and mRNA as well as TFPI-2 mRNA compared to treatment at 37 degrees C. These data show that hyperthermia significantly reduces the procoagulant effects of TNF on endothelial tissue compared to normothermia, which may have important clinical implications for the use of TNF in regional perfusion.

Effect of interleukin 1 receptor antagonist gene transduction on human melanoma xenografts in nude mice.

Interleukin (IL)-1 is a pleiotropic inflammatory cytokine that promotes angiogenesis and enhances tumor growth and metastases. We evaluated the effects of IL-1 receptor antagonist (IL-1ra) on tumor growth and metastases in human melanoma xenografts. We selected two human melanoma lines (SMEL and PMEL) with differential (high versus low, respectively) constitutive production of IL-1 by ELISA. The IL-1ra gene was isolated from monocyte RNA by PCR and retrovirally transduced into SMEL and PMEL. In vitro cell proliferation was evaluated using a WST-1 assay. Athymic nude mice received s.c. or i.v. injection with parental, vector-transduced, or IL-1ra-transduced melanoma cells, and tumor growth, lung metastases, and histology were characterized. IL-1 was produced by SMEL in vitro and ex vivo (117 and 67 pg/ml/10(6) cells/24 h, respectively), but not by PMEL (15 and 0 pg/ml/10(6) cells/24 h, respectively). Neither made IL-1ra natively. Gene-transduced cell lines secreted >1000 pg/ml/10(6) cells/24 h of IL-1ra by ELISA. In vitro proliferation of each parental cell line was comparable to the proliferation rate of each transduced cell line. IL-1ra-transduced SMEL (SMEL/IL-1ra) showed significantly slower tumor growth compared with null-transduced and parental cell lines (P < 0.001, ANOVA-Bonferroni/Dunn). There was no difference in growth rates between PMEL and IL-1ra-transduced PMEL (PMEL/IL-1ra). A mixing study of SMEL and SMEL/IL-1ra showed significant inhibition of tumor growth at various ratios (P < 0.001, ANOVA-Bonferroni/Dunn). There were significantly fewer lung metastases with SMEL/IL-1ra versus SMEL (P < 0.002). IL-1ra decreases in vivo growth and metastatic potential of a human melanoma xenograft that constitutively secretes IL-1. This effect may be exploitable using clinically available IL-1ra for the treatment of human cancers.

Regulation of herpes simplex virus 1 replication using tumor-associated promoters.

OBJECTIVE: To investigate use of transcriptional regulatory elements (promoters) for tumor-associated antigens to achieve HSV-1 replication preferentially in cells that overexpress the tumor-associated antigens. SUMMARY BACKGROUND DATA: An important advantage of replicating viruses for cancer therapy is their ability to simultaneously destroy tumor cells by replication and release progeny virion to infect and destroy adjacent cancer cells. This strategy requires regulation of the viral life cycle to obtain robust replication in neoplastic cells and minimize replication in nonneoplastic cells. METHODS: Promoters for the human carcinoembryonic antigen (CEA) and MUC1/DF3 tumor-associated antigens were characterized and cloned into HSV-1 mutants as heterologous promoters regulating expression of two different HSV-1 genes. Viral replication in tumor cells and cytotoxicity was quantified with in vitro assays. Antineoplastic efficacy was characterized in a flank tumor xenograft model. RESULTS: Several CEA promoters were cloned and characterized using luciferase reporter assays. The most specific promoter was used to construct and isolate two different HSV-1 mutants in which critical genes are regulated by this promoter (ICP4 and gamma(1) 34.5). Similarly, the promoter for the DF3/MUC1 tumor-associated antigen was cloned into a third HSV-1 mutant such that it regulates expression of gamma(1) 34.5. Regulation of ICP4 expression by the CEA promoter during HSV-1 infection overly attenuates viral replication. Regulation of gamma(1) 34.5 expression by either the CEA promoter or the MUC1/DF3 promoter during HSV-1 infection modulates viral replication, with preferential replication in cells that overexpress the corresponding tumor-associated antigen. A single intratumoral inoculation of an HSV-1 mutant with the MUC1/DF3 promoter regulating gamma(1) 34.5 expression results in significant antineoplastic activity in MUC1-positive pancreatic carcinoma xenografts as compared to mock inoculation. CONCLUSIONS: Promoters for tumor-associated antigens may be incorporated into the HSV-1 genome to regulate HSV-1 replication. The choices of HSV-1 gene and tumor-associated promoter are important determinants of success of this strategy. Because of its preferential replication in MUC1-positive tumors, an HSV-1 mutant with the MUC1/DF3 promoter regulating gamma(1) 34.5 expression will undergo further examination as a novel cancer therapy agent.

Isolation perfusion of the liver.

Thousands of patients die annually from unresectable metastatic or primary hepatic cancers confined to liver. Isolated hepatic perfusion (IHP) is a regional treatment strategy in which the vascular supply to the liver is isolated and perfused with a therapeutic regimen using an extracorporeal circuit consisting of a reservoir, heat exchanger, and oxygenator. Drug doses that would cause severe toxicities if delivered systemically can be confined to the liver by isolated hepatic perfusion, resulting in the ability to intensify treatment to the cancer-burdened region of the body. Agents and mechanisms commonly used in IHP include melphaIan, hyperthermia, and tumor necrosis factor. IHP appears to be efficacious for patients with advanced disease, as reflected by large tumor size, high number of lesions, or significant overall tumor burden in the liver. In addition, responses are observed for patients whose cancer is refractory to systemic and hepatic arterial infusion chemotherapy. Recent clinical trials have demonstrated that IHP has anti-tumor efficacy against primary hepatic neoplasms and metastases from various primary tumors, such as colorectal carcinoma, ocular melanoma, and neuroendocrine tumors. Current studies demonstrate that combining hepatic arterial infusion with floxuridine after IHP for patients with colorectal cancer metastases is associated with significant and durable response rates. Continued clinical evaluation is warranted for the use of IHP in the treatment of unresectable liver metastases.