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1.  Outcome of Microscopic Incomplete Resection (R1) of Colorectal Liver Metastases in the Era of Neoadjuvant Chemotherapy 
Annals of Surgical Oncology  2011;19(5):1618-1627.
Background
Data from patients with colorectal liver metastases (CRLM) who received neoadjuvant chemotherapy before resection were reviewed and evaluated to see whether neoadjuvant chemotherapy influences the predictive outcome of R1 resections (margin is 0 mm) in patients with CRLM.
Methods
Between January 2000 and December 2008, all consecutive patients undergoing liver resection for CRLM were analyzed. Patients were divided into those who did and did not receive neoadjuvant chemotherapy. The outcome after R0 (tumor-free margin >0 mm) and R1 (tumor-free margin 0 mm) resection was compared.
Results
A total of 264 were eligible for analysis. Median follow-up was 34 months. Patients without chemotherapy showed a significant difference in median disease-free survival (DFS) after R0 or R1 resection: 17 [95% confidence interval (CI) 10–24] months versus 8 (95% CI 4–12) months (P < 0.001), whereas in patients with neoadjuvant chemotherapy the difference in DFS between R0 and R1 resection was not significant: 18 (95% CI 10–26) months versus 9 (95% CI 0–20) months (P = 0.303). Patients without chemotherapy showed a significant difference in median overall survival (OS) after R0 or R1 resection: 53 (95% CI 40–66) months versus 30 (95% CI 13–47) months (P < 0.001). In patients with neoadjuvant chemotherapy, the median OS showed no significant difference: 65 (95% CI 39–92) months for the R0 group versus the R1 group, in whom the median OS was not reached (P = 0.645).
Conclusions
In patients treated with neoadjuvant chemotherapy, R1 resection was of no predictive value for DFS and OS.
doi:10.1245/s10434-011-2114-4
PMCID: PMC3332355  PMID: 22006375
Medicine & Public Health; Oncology; Surgical Oncology; Surgery
2.  20 Years Experience of TNF-Based Isolated Limb Perfusion for In-Transit Melanoma Metastases: TNF Dose Matters 
Annals of Surgical Oncology  2011;19(2):627-635.
Background
Approximately 5–8% of melanoma patients will develop in-transit metastases (IT-mets). Tumor necrosis factor-α (TNF) and melphalan-based isolated limb perfusion (TM-ILP) is an attractive treatment modality in melanoma patients with multiple IT-mets. This study reports on a 20 years experience and outlines the evolution and major changes since the introduction of TNF in ILP.
Methods
A total of 167 TM-ILPs were performed in 148 patients, between 1991 and 2009. TM-ILPs were performed at high doses of TNF (3–4 mg) from 1991 to 2004 (n = 99) and at low doses of TNF (1–2 mg) from 2004 to 2009 (n = 68) under mild hyperthermic conditions (38°C–39.5°C.). Melphalan doses were unchanged at 10–13 mg/l (leg and arm, respectively). Characteristics for the 167 ILPs were: 81 stage IIIB, 65 stage IIIC, and 21 stage IV disease.
Results
The overall response rate was 89% (n = 148). (Complete response [CR] = 61%; partial response [PR] = 28%). CR rates correlated with stage (P = .001) and with high-dose vs. low-dose TNF (70% vs. 49%; P < .006). High-dose TNF prolonged local control (median 16 months vs. 11 months; P = .076). Survival was not influenced by TNF dose. CR after ILP and number of lesions also correlated with local progression-free interval. Overall survival did correlate with stage of disease (P < .001), size of the lesions (P = .001), and a CR (P < .001).
Conclusions
This 2-decade single-center experience demonstrates that TM-ILP is a safe and effective treatment modality for melanoma patients with multiple IT-mets. Higher dose of TNF was associated with significantly higher CR rates and prolonged local control without an effect on overall survival.
doi:10.1245/s10434-011-2030-7
PMCID: PMC3264869  PMID: 21879272
3.  Is the Clinical Risk Score for Patients with Colorectal Liver Metastases Still Useable in the Era of Effective Neoadjuvant Chemotherapy? 
Annals of Surgical Oncology  2011;18(10):2757-2763.
Background
Several clinical risk scores (CRSs) for the outcome of patients with colorectal liver metastases have been validated, but not in patients undergoing neoadjuvant chemotherapy. Therefore, this study evaluates the predictive value of these CRSs in this specific group.
Methods
Between January 2000 and December 2008, all patients undergoing a metastasectomy were analyzed and divided into two groups: 193 patients did not receive neoadjuvant chemotherapy (group A), and 159 patients received neoadjuvant chemotherapy (group B). In group B, the CRSs were calculated before and after administration of neoadjuvant chemotherapy. Results were evaluated by using the CRSs proposed by Nordlinger et al., Fong et al., Nagashima et al., and Konopke et al.
Results
In groups A and B, the overall median survival was 43 and 47 months, respectively (P = 0.648). In group A, all CRSs used were of statistically significant predictive value. Before administration of neoadjuvant chemotherapy, only the Nordlinger score was of predictive value. After administration of neoadjuvant chemotherapy, all CRSs were of predictive value again, except for the Konopke score.
Conclusions
Traditional CRSs are not a reliable prognostic tool when used in patients before treatment with neoadjuvant chemotherapy. However, CRSs assessed after the administration of neoadjuvant chemotherapy are useful to predict prognosis.
doi:10.1245/s10434-011-1819-8
PMCID: PMC3171666  PMID: 21638093
4.  Outcome After Therapeutic Lymph Node Dissection in Patients with Unknown Primary Melanoma Site 
Annals of Surgical Oncology  2011;18(13):3586-3592.
Purpose
The aim of this study was to evaluate the incidence and outcome of melanoma of unknown primary site (MUP) after therapeutic lymph node dissection (TLND) of palpable nodal melanoma metastases. Disease-free (DFS) and overall survival (OS) time of MUP patients were analyzed and compared to patients undergoing a TLND for known primary melanomas (MKP).
Methods
This single institution retrospective study analyzed 342 consecutive patients who were treated with 415 TLNDs for palpable nodal disease from 1982 to 2009. Univariate and multivariate analyses included: MUP versus MKP, gender, Breslow thickness, ulceration of primary tumor, site of primary tumor, site of dissection, extracapsular extension, number of collected nodes, number of positive nodes and the node positive ratio.
Results
A total of 47 MUP were identified in 342 patients (13.7%). In univariate analysis, a trend was seen toward better survival for MUP patients compared to MKP patients having 5-year OS rates of 40% and 27%, respectively (P = 0.06). Multivariate analysis for OS showed two highly significant factors associated with worse prognosis: extracapsular extension and N3 status (both P < 0.001). Two factors were associated with a significant better prognosis: MUP (P = 0.03) and a neck dissection (P = 0.04).
Conclusions
Patients with MUP showed a statistically significant better OS compared to patients with melanoma metastases from known primary tumors. Presence of extracapsular extension and an increased number of positive nodes are statistically significantly negative prognostic factors for OS. The absence of a primary melanoma in stage III melanoma patients does not preclude surgery.
doi:10.1245/s10434-011-1801-5
PMCID: PMC3222814  PMID: 21611857
5.  Radiotherapy for Soft Tissue Sarcomas after Isolated Limb Perfusion and Surgical Resection: Essential for Local Control in All Patients? 
Annals of Surgical Oncology  2010;18(2):321-327.
Background
Standard treatment for localized soft tissue sarcoma (STS) is resection plus adjuvant radiotherapy (RTx). In approximately 10% of cases, resection would cause severe loss of function or even require amputation because of the extent of disease. Isolated limb perfusion (ILP) with tumor necrosis factor alpha (TNF-α) and melphalan can achieve regression of the tumor, facilitating limb-saving resection. RTx improves local control but may lead to increased morbidity.
Methods
In our database of over 500 ILPs, 122 patients with unifocal STS were treated by ILP followed by limb-sparing surgery. All included patients were candidates for amputation.
Results
Surgery resulted in 69 R0 resections (57%), and in 53 specimens (43%) resection margins contained microscopic evidence of tumor (R1). Histopathological examination revealed >50% ILP-induced tumor necrosis in 59 cases (48%). RTx was administered in 73 patients (60%). Local recurrence rate was 21% after median follow-up of 31 months (2–182 months). Recurrence was significantly less in patients with >50% ILP-induced necrosis versus ≤50% necrosis (7% vs. 33%, P = 0.001). A similar significant correlation was observed for R0 versus R1 resections (15% vs. 28%, P = 0.04). In 36 patients with R0 resection and >50% necrosis, of whom 21 were spared RTx, no recurrences were observed during follow-up.
Conclusions
In patients with locally advanced primary STS, treated with ILP followed by R0 resection, and with >50% ILP-induced necrosis in the resected specimen, RTx is of no further benefit.
doi:10.1245/s10434-010-1400-x
PMCID: PMC3032224  PMID: 21049306
6.  Improved Endpoints for Cancer Immunotherapy Trials 
Unlike chemotherapy, which acts directly on the tumor, cancer immunotherapies exert their effects on the immune system and demonstrate new kinetics that involve building a cellular immune response, followed by changes in tumor burden or patient survival. Thus, adequate design and evaluation of some immunotherapy clinical trials require a new development paradigm that includes reconsideration of established endpoints. Between 2004 and 2009, several initiatives facilitated by the Cancer Immunotherapy Consortium of the Cancer Research Institute and partner organizations systematically evaluated an immunotherapy-focused clinical development paradigm and created the principles for redefining trial endpoints. On this basis, a body of clinical and laboratory data was generated that supports three novel endpoint recommendations. First, cellular immune response assays generate highly variable results. Assay harmonization in multicenter trials may minimize variability and help to establish cellular immune response as a reproducible biomarker, thus allowing investigation of its relationship with clinical outcomes. Second, immunotherapy may induce novel patterns of antitumor response not captured by Response Evaluation Criteria in Solid Tumors or World Health Organization criteria. New immune-related response criteria were defined to more comprehensively capture all response patterns. Third, delayed separation of Kaplan–Meier curves in randomized immunotherapy trials can affect results. Altered statistical models describing hazard ratios as a function of time and recognizing differences before and after separation of curves may allow improved planning of phase III trials. These recommendations may improve our tools for cancer immunotherapy trials and may offer a more realistic and useful model for clinical investigation.
doi:10.1093/jnci/djq310
PMCID: PMC2943524  PMID: 20826737
7.  Multimarker Reverse Transcriptase-Polymerase Chain Reaction Assay in Lymphatic Drainage and Sentinel Node Tumor Burden 
Annals of Surgical Oncology  2010;17(12):3314-3323.
Purpose
We assessed molecular (presence of melanoma cells markers in lymph fluid [LY]) and pathological features (sentinel lymph node [SN] tumor burden according to Rotterdam criteria, metastases microanatomic location) and correlated them with survival and melanoma prognostic factors in a group of patients with positive SN biopsy.
Methods
We analyzed 368 consecutive SN-positive patients after completion lymph node dissection (CLND). In 321 patients we obtained data on SLN microanatomic location/tumor burden (only 7 cases had metastases <0.1 mm); in 137 we additionally analyzed 24-hour collected LY after CLND (multimarker reverse transcriptase-polymerase chain reaction [MM-RT-PCR] with primers for tyrosinase, MART1 (MelanA), and uMAGE mRNA (27.7% positive samples)]. Median follow-up time was 41 months.
Results
According to univariate analysis, the following factors had a negative impact on overall survival (OS): higher Breslow thickness (P = .0001), ulceration (P < .0001), higher Clark level (P = .008), male gender (P = .0001), metastatic lymph nodes >1 (P < .0001), nodal metastases extracapsular extension (P < .0001), metastases to additional non-SNs (P = .0004), micrometastases size ≥0.1 mm (P = .0006), and positive LY MM-RT-PCR (P = .0007). SN tumor burden showed linear correlation with increasing Breslow thickness (P = .01). The 5-year OS rates for SLN tumor burden <0.1 mm, 1–1.0 mm, and >1.0 mm were 84%/66%/44%, respectively, and for positive and negative LY MM-RT-PCR 47%/0%, respectively. The independent factors for shorter OS (multivariate analysis): male gender, primary tumor ulceration, number of involved nodes ≥4, micrometastases size >1.0 mm, and, in additional model including molecular analysis—positive MM-RT-PCR results (hazard ratio [HR] 3.2), micrometastases size >1.0 mm (HR 1.13), and primary tumor ulceration (HR 2.17). Similar results were demonstrated for disease-free survival (DFS) data.
Conclusions
SN tumor burden categories according to Rotterdam criteria and the positive result of LY MM-RT-PCR assay demonstrated additional, independent prognostic value in SN-positive melanoma patients, showing significant correlation with shorter DFS and OS.
doi:10.1245/s10434-010-1142-9
PMCID: PMC2995879  PMID: 20607422
8.  Hyperthermia and Thermosensitive Liposomes for Improved Delivery of Chemotherapeutic Drugs to Solid Tumors 
Pharmaceutical Research  2010;27(8):1750-1754.
ABSTRACT
Lipid-based nanocarriers or liposomes have been proven successful in the delivery of chemotherapeutic agents and are currently applied clinically in the treatment of various types of cancer. Liposomes offer the advantage of a high drug payload, decreased drug toxicity and enhanced drug accumulation at tumor sites. Increased accumulation is due to the relatively leaky tumor vasculature that allows liposome extravasation. Between different types of tumors and even within one tumor, vascular permeability and thus liposome extravasation may differ greatly. Furthermore, upon accumulation of liposomes in the tumor area, drug bioavailability is not guaranteed. At present, these are the major issues for clinically used liposomal drugs.
Mild hyperthermia (HT), the heating of tumor tissue to temperatures of up to 43°C, has been developed in the past decades as an established and efficacious treatment modality in combination with chemo- and radiotherapy. HT can be used to further improve liposomal chemotherapy in two ways: HT is known to increase vascular permeability in solid tumors and may therefore increase levels of liposome accumulation, and thermosensitive liposomes have been developed that can be triggered to release their contents upon hyperthermia. By applying these two strategies, drug delivery to tumors can be strongly enhanced.
doi:10.1007/s11095-010-0154-2
PMCID: PMC2896623  PMID: 20424894
cancer; chemotherapy; hyperthermia; nanomedicine; thermosensitive liposomes; triggered release
9.  Isolated Limb Perfusion with Melphalan and TNF-α in the Treatment of Extremity Sarcoma 
Opinion statement
Isolated limb perfusion (ILP) with chemotherapy alone has uniformly failed in the treatment of irresectable extremity soft tissue sarcomas. The addition of tumor necrosis factor-alpha (TNF-α) to this treatment approach contributed to a major step forward in the treatment of locally advanced extremity soft tissue sarcoma (STS). High response rates and limb salvage rates have been reported in multicenter trials, which combined ILP with TNF-α plus melphalan, which resulted in the approval of TNF-α for this indication in Europe in 1998. Subsequently a series of confirmatory single institution reports on the efficacy of the procedure have now been published. TNF-α has an early and a late effect; it enhances tumor-selective drug uptake during the perfusion and plays an essential role in the subsequent selective destruction of the tumor vasculature. These effects result in a high response rate in high-grade soft tissue sarcomas. This induction therapy thus allows for resection of tumor remnants some 3 months after ILP and thus avoidance of limb amputation. TNF-α-based ILP is a well-established treatment to avoid amputations. It represents an important example of tumor vasculatory-modulating combination therapy and should be offered in large volume tertiary referral centers.
doi:10.1007/s11864-007-0044-y
PMCID: PMC2781100  PMID: 18066703
11.  Polymorphisms in the CD28/CTLA4/ICOS genes: role in malignant melanoma susceptibility and prognosis? 
Cancer Immunology, Immunotherapy   2009;59(2):303-312.
The appearance of vitiligo and spontaneous regression of the primary lesion in melanoma patients illustrate a relationship between tumor immunity and autoimmunity. T lymphocytes play a major role both in tumor immunity and autoimmunity. CD28, Cytotoxic T lymphocyte antigen 4 (CTLA4) and inducible costimulator (ICOS) molecules are important secondary signal molecules in the T lymphocyte activation. Single nucleotide polymorphisms (SNPs) in the CD28/CTLA4/ICOS gene region were reported to be associated with several autoimmune diseases including, type-1 diabetes, SLE, autoimmune thyroid diseases and celiac disease. In this study, we investigated the association of SNPs in the CD28, CTLA4 and ICOS genes with the risk of melanoma. We also assessed the prognostic effect of the different polymorphisms in melanoma patients. Twenty-four tagging SNPs across the three genes and four additional SNPs were genotyped in a cohort of 763 German melanoma patients and 734 healthy German controls. Influence on prognosis was determined in 587 melanoma cases belonging to stage I or II of the disease. In general, no differences in genotype or allele frequencies were detected between melanoma patients and controls. However, the variant alleles for two polymorphisms in the CD28 gene were differentially distributed in cases and controls. Similarly no association of any polymorphism with prognosis, except for the rs3181098 polymorphism in the CD28 gene, was observed. In addition, individuals with AA genotype for rs11571323 polymorphism in the ICOS gene showed reduced overall survival. However, keeping in view the correction for multiple hypothesis testing our results suggest that the polymorphisms in the CD28, CTLA4 and ICOS genes at least do not modulate risk of melanoma and nor do those influence the disease prognosis in the investigated population.
Electronic supplementary material
The online version of this article (doi:10.1007/s00262-009-0751-2) contains supplementary material, which is available to authorized users.
doi:10.1007/s00262-009-0751-2
PMCID: PMC2776942  PMID: 19672595
Melanoma; Polymorphism; CD28/CTLA4/ICOS; Susceptibility; Prognosis
12.  Nitric oxide production and monoamine oxidase activity in cancer patients during interferon-α therapy 
Amino Acids  2008;37(4):703-708.
Both increased and decreased nitric oxide (NO) synthesis have been reported in patients treated with interferon-α (IFN-α). Animal studies showed that IFN-α administration results in increased levels of biogenic amines, subsequent activation of monoamine oxidases (MAOs), and finally in a change in NO production due to the H2O2 generated by MAOs. We examined the potential relationship between NO production in plasma and MAO-B activity in platelets of 43 cancer patients during 8 weeks of treatment with IFN-α. NO synthesis was quantitated by measuring both the ratio of citrulline and arginine (CIT/ARG-ratio) and total nitrite/nitrate (NOx) levels. Compared to baseline, MAO activity and NOx increased, while the CIT/ARG-ratio decreased. No associations were found between NOx, MAO and CIT/ARG-ratio. Only few associations were observed between changes in the biochemical parameters and changes in psychopathology induced by IFN-α, of which the association between changes in CIT and lassitude was the most consistent. The results suggest that peripheral NO production and MAO activity are unrelated to each other, and that peripheral changes in these biochemical parameters induced by IFN-α are unlikely to contribute to definite psychiatric disturbance.
doi:10.1007/s00726-008-0191-x
PMCID: PMC2753771  PMID: 18953681
Citrulline; Depression; Interferon-α; Nitric oxide; Monoamine oxidase; Cancer
13.  Factors Influencing Prognosis After Initial Inadequate Excision (IIE) for Soft Tissue Sarcoma 
Sarcoma  2003;7(3-4):159-165.
Purpose. The influence of initial inadequate excision (IIE) of soft tissue sarcoma (STS) on local control and overall survival is not well established. It is generally believed that an IIE may have a negative impact on both, despite subsequent treatment by radical surgery and radiotherapy. However, data on local recurrence-free survival/overall survival are conflicting and there are no data on the effect of IIE on overall survival.
Patients and methods. A retrospective analysis was made of 86 patients with soft tissue sarcoma of the extremities and trunk after an IIE had been performed due to inappropriate work-up. The minimal follow-up was 7 years. Specimens of the subsequent radical resection were evaluated for residual tumor, grade of tumor and complications of IIE. Endpoints were recurrence-free survival and overall survival.
Results. Specimens of the subsequent radical resection showed residual tumor in 66 patients (77%). The most common complication after IIE was hematoma. In both univariate and multivariate analyses, grade II/III tumors and complications after IIE are significant negative prognostic factors for local recurrence-free survival (P = 0.008 and P = 0.002, respectively, in the Cox model). For this survival, three prognostic groups could be formed based on grade, or presence or absence of complications. Adjuvant radiotherapy did not change the rate of local recurrence-free survival. For overall survival, only tumor grade is a significant factor (log-rank test).
Conclusion. This retrospective study shows that complications associated with an IIE have a significant negative effect on local control, but not on overall survival, because IIE is often the result of inappropriate work-up before surgery. For better diagnosis and therapy STS should be treated in specialized centers.
doi:10.1080/13577140310001650321
PMCID: PMC2395531  PMID: 18521381
14.  Identification of MAGE-3 Epitopes Presented by HLA-DR Molecules to CD4+ T Lymphocytes  
MAGE-type genes are expressed by many tumors of different histological types and not by normal cells, except for male germline cells, which do not express major histocompatibility complex (MHC) molecules. Therefore, the antigens encoded by MAGE-type genes are strictly tumor specific and common to many tumors. We describe here the identification of the first MAGE-encoded epitopes presented by histocompatibility leukocyte antigen (HLA) class II molecules to CD4+ T lymphocytes. Monocyte-derived dendritic cells were loaded with a MAGE-3 recombinant protein and used to stimulate autologous CD4+ T cells. We isolated CD4+ T cell clones that recognized two different MAGE-3 epitopes, MAGE-3114–127 and MAGE-3121–134, both presented by the HLA-DR13 molecule, which is expressed in 20% of Caucasians. The second epitope is also encoded by MAGE-1, -2, and -6. Our procedure should be applicable to other proteins for the identification of new tumor-specific antigens presented by HLA class II molecules. The knowledge of such antigens will be useful for evaluation of the immune response of cancer patients immunized with proteins or with recombinant viruses carrying entire genes coding for tumor antigens. The use of antigenic peptides presented by class II in addition to peptides presented by class I may also improve the efficacy of therapeutic antitumor vaccination.
PMCID: PMC2192951  PMID: 10049940
human; invariant chain; peptide; tumor; histocompatibility leukocyte antigen class II
15.  Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation 
The New England journal of medicine  2011;364(26):2507-2516.
Background
Phase 1 and 2 clinical trials of the BRAF kinase inhibitor vemurafenib (PLX4032) have shown response rates of more than 50% in patients with metastatic melanoma with the BRAF V600E mutation.
Methods
We conducted a phase 3 randomized clinical trial comparing vemurafenib with dacarbazine in 675 patients with previously untreated, metastatic melanoma with the BRAF V600E mutation. Patients were randomly assigned to receive either vemurafenib (960 mg orally twice daily) or dacarbazine (1000 mg per square meter of body-surface area intravenously every 3 weeks). Coprimary end points were rates of overall and progression-free survival. Secondary end points included the response rate, response duration, and safety. A final analysis was planned after 196 deaths and an interim analysis after 98 deaths.
Results
At 6 months, overall survival was 84% (95% confidence interval [CI], 78 to 89) in the vemurafenib group and 64% (95% CI, 56 to 73) in the dacarbazine group. In the interim analysis for overall survival and final analysis for progression-free survival, vemurafenib was associated with a relative reduction of 63% in the risk of death and of 74% in the risk of either death or disease progression, as compared with dacarbazine (P<0.001 for both comparisons). After review of the interim analysis by an independent data and safety monitoring board, crossover from dacarbazine to vemurafenib was recommended. Response rates were 48% for vemurafenib and 5% for dacarbazine. Common adverse events associated with vemurafenib were arthralgia, rash, fatigue, alopecia, keratoacanthoma or squamous-cell carcinoma, photosensitivity, nausea, and diarrhea; 38% of patients required dose modification because of toxic effects.
Conclusions
Vemurafenib produced improved rates of overall and progression-free survival in patients with previously untreated melanoma with the BRAF V600E mutation. (Funded by Hoffmann–La Roche; BRIM-3 ClinicalTrials.gov number, NCT01006980.)
doi:10.1056/NEJMoa1103782
PMCID: PMC3549296  PMID: 21639808
16.  Isolated Hypoxic Hepatic Perfusion with Retrograde Outflow in Patients with Irresectable Liver Metastases; A New Simplified Technique in Isolated Hepatic Perfusion 
Annals of Surgical Oncology  2008;15(5):1367-1374.
Background
Isolated hepatic perfusion with high-dose chemotherapy is a treatment option for patients with irresectable metastases confined to the liver. Prolonged local control and impact on survival have been claimed. Major drawbacks are magnitude and costs of the procedure. We developed an isolated hypoxic hepatic perfusion (IHHP) with retrograde outflow without the need for a heart-lung machine.
Patients and Methods
Twenty-four consecutive patients with irresectable metastases of various origins were treated. IHHP inflow was via the hepatic artery, outflow via the portal vein with occlusion of the retrohepatic caval vein. Radiolabeled albumine was used for leakage monitoring. Melphalan was used at 1–2 mg/kg. A 25-minute perfusion period was followed by a complete washout. Local and systemic melphalan concentrations were determined.
Results
Compared with oxygenated classical IHP, the IHPP procedure reduced operation time from >8 h to 4 hours, blood loss from >4000 to 900 cc and saved material and personnel costs. Leakage was 0% with negligible systemic toxicity and 0% perioperative mortality. Tumor response: complete response (CR) in 4%, partial response (PR) in 58%, and stable disease (SD) in 13%. Median time to progression was 9 months (2–24 months); pharmacokinetics demonstrated intrahepatic melphalan concentrations more than 9 fold higher than postperfusion systemic concentrations.
Conclusions
IHPP is a relatively simple procedure with reduced costs, reduced blood loss, no mortality, limited toxicity, and response rates comparable to classic IHP. The median duration of 9 months of tumor control should be improved. Hereto, vasoactive drugs, will be explored in further studies.
doi:10.1245/s10434-007-9714-z
PMCID: PMC2277449  PMID: 18239976
Isolated hepatic perfusion; Retrograde outflow; Hypoxic; Metastasis; Melphalan

Results 1-16 (16)