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B B Kroon

Publications and source records attributed to B B Kroon.

At least 73 records · Page 4Linked to original sources
PubMed1997

Isolation limb perfusion with tumor necrosis factor alpha and chemotherapy for advanced extremity soft tissue sarcomas.

The unique property of high dose recombinant tumor necrosis factor alpha (rTNF alpha) is to activate and selectively destroy the tumor-associated microvasculature. For the systemic application of rTNF alpha it has been shown that the maximum tolerated dose (MTD) is 10 times less than the effective dose in animals. The main toxicity corresponds to systemic inflammatory response syndrome with a decrease in vascular resistance and hypotension. We found that it is possible to administer rTNF alpha at 10 times the MTD in an isolated limb perfusion (ILP) system with heart-lung machine, for locally advanced extremity soft tissue sarcomas. One hundred forty patients received an ILP with high-dose TNF alpha. In 55 patients treated with the combination of high-dose rTNF alpha + interferon-gamma + melphalan an overall objective response rate of 87% with 36% complete responses was observed; it was 81% and 28%, respectively, in a group treated with TNF alpha and melphalan (n = 85). Angiographic and immunohistological studies showed the selective and early damage of the sarcoma-associated microvasculature preceded by the upregulation of adhesion molecules and intratumoral leak of von Willebrand factor. Tumor invasion by platelets and, in some cases, by polymorphonuclear cells, appeared within hours after the application of rTNFa long before the lysis of the tumor. Thus, ILP with high-dose TNF alpha and chemotherapy seems to act through a dual targeting: TNF hits the tumor associated vasculature, and chemotherapy attacks the tumor cells. Therefore, ILP with TNF is a new option in the management of locally advanced soft tissue sarcoma of the extremities.

Adolescent↗
PubMed1996

[Identification of the sentinel node in patients with breast carcinoma].

OBJECTIVE: To investigate the hypothesis that lymphatic metastasis of breast cancer progresses in a sequential fashion, and whether the first lymph node on a direct drainage pathway (first-echelon node, sentinel node) can be identified in a mastectomy specimen. DESIGN: Descriptive analysis. SETTING: The Netherlands Cancer Institute (Antoni van Leeuwenhoek Hospital), Amsterdam, the Netherlands. METHODS: In 22 patients with clinically localized breast cancer and five with breast cancer and axillary lymphadenopathy, patent blue dye was administered preoperatively into the primary tumor. After mastectomy and axillary lymph node dissection, blue stained lymphatic channels were dissected down to the first draining lymph nodes. These sentinel nodes were removed from the specimen and examined separately for presence of metastatic disease. RESULTS: In 2/5 patients with palpable axillary metastases and in one patient with a tumour in the medial upper quadrant, no sentinel node was found. A total of 35 first-echelon nodes was identified in the 22 patients without palpable lymphadenopathy, on average 1.6 nodes per patient (range: 1-4). In 10 of these patients, metastatic tumour was found in the sentinel nodes. In 6 of these 10 patients, no metastatic disease was detected in the remaining axillary nodes. Metastasis was never found in the other axillary nodes if the sentinel node was disease-free. CONCLUSIONS: Dissemination of breast cancer to the axillary nodes appears to occur in a sequential fashion. Patent blue dye drains from the tumour in the breast to the axillary lymph nodes in mammary cancer patients. These blue nodes can be identified in the surgical specimen.

Adult↗
PubMed1996

Thirty-five years of isolated limb perfusion for melanoma: indications and results.

Isolated limb perfusion (ILP) for limb melanoma remains controversial despite its frequent use for over 35 years. To determine whether it has proven benefits, reported results have been reviewed. The value of adjuvant ILP cannot be determined from the multitude of retrospective studies on this subject. Preliminary results of the large European Organization for Research and Treatment of Cancer-World Health Organization-North American Perfusion Group trial suggest that patients with melanomas of 1.5-3.0 mm in thickness who do not undergo elective lymph node dissection may have a locoregional control benefit from ILP. However, as long as a definite survival advantage for ILP has not been demonstrated, such treatment does not seem justified for these patients. The value of prophylactic ILP after resection of recurrent limb melanoma is also scientifically unproven. The potential prevention of further limb recurrence for only a limited period of time, as demonstrated in a rather small Swedish trial, probably does not justify routine use of ILP in these patients; a large international trial will be needed to assess whether ILP provides a survival advantage. For those with locally inoperable limb melanoma, ILP appears to be the treatment of choice since it results in complete disappearance of all macroscopic disease in a substantial proportion of patients, removing the need for amputation and providing palliation of symptoms. However, high limb recurrence rates and short duration of response need improvement. Results of alternative treatments should be compared prospectively with those of ILP in this clinical situation.

Antineoplastic Agents↗
PubMed1996

Systemic toxicity after isolated limb perfusion with melphalan for melanoma.

Systemic exposure to melphalan is minimized during isolated limb perfusion (ILP) by isolating a limb from the rest of the body. Consequently, there should be no toxicity to vital organs. At present systemic toxicity after ILP has not been studied in detail. Therefore, the incidence, nature and risk factors of systemic toxicity was retrospectively studied in 368 patients who underwent a single ILP with melphalan between 1978-1990. Some form of systemic toxicity occurred in 98 patients (27%). Nausea and vomiting after the 1st post-ILP day was seen in 73 patients (20%), and in seven (2%) treatment was required. Bone marrow depression was encountered in seven patients (2%): WHO grade II in five, and grade III in two. Miscellaneous systemic side-effects, including fever and minimal scalp hair loss, occurred in 19 patients (5%). Leakage from the isolated circuit to the systemic circulation was measured with radioactive tracers. Mean cumulative leakage during ILP was 0.9%. Systemic toxicity was not increased in patients with leakage greater than 1% or 5%. Female sex was associated with an increased incidence of systemic toxicity (P<0.05). Age over 60 years (P<0.05) and more severe acute regional toxicity (P<0.05) were correlated with nausea and vomiting. The miscellaneous systemic side-effects were more frequently encountered in women than in men (P<0.05). In conclusion, systemic toxicity was rarely severe, with nausea and vomiting being the most frequently encountered side-effects. Age over 60 years, female sex and more severe acute regional toxic reactions were correlated with an increased incidence of systemic side-effects. Systemic leakage during ILP was not associated with toxicity, probably due to the low incidence of significant leakage.

Adolescent↗
PubMed1996

Isolated limb perfusion with tumor necrosis factor and melphalan for limb salvage in 186 patients with locally advanced soft tissue extremity sarcomas. The cumulative multicenter European experience.

OBJECTIVE: The objective of the study was to achieve limb salvage in patients with locally advanced soft tissue sarcomas that can only be treated by amputation or functionally mutilating surgery by performing an isolated limb perfusion (ILP) with tumor necrosis factor (TNF) + melphalan (M) as induction biochemotherapy to obtain local control and make limb-sparing surgery possible. SUMMARY BACKGROUND DATA: To increase the number of limb-sparing resections in the treatment of locally advanced extremity soft tissue sarcoma, preoperative radiation therapy or chemotherapy or a combination of the two often are applied. The ILP with cytostatic agents alone is another option but rarely is used because of rather poor results. The efficacy of the application of TNF in ILP markedly has changed this situation. METHODS: In 8 cancer centers, 186 patients were treated over a period of almost 4.5 years. There were 107 (57%) primary and 79 (43%) recurrent sarcomas, mostly high grade (110 grade III; 51 grade II; and 25 very large, recurrent, or multiple grade I sarcomas). The composition of this series of patients is unusual: 42 patients (23%) had multifocal primary or multiple recurrent tumors; median tumor size was very large (16 cm); 25 patients (13%) had known systemic metastases at the time of the ILP. Patients underwent a 90-minute ILP at 39 to 40 C with TNF + melphalan. The first 55 patients also received interferon-tau. A delayed marginal resection of the tumor remnant was done 2 to 4 months after ILP. RESULTS: A major tumor response was seen in 82% of the patients rendering these large sarcomas resectable in most cases. Clinical response rates were: 33 complete response (CR) (18%), 106 partial response (PR) (57%), 42 no change (NC) (22%), and 5 progressive disease (PD) (3%). Final outcome was defined by clinical and pathologic response: 54 CR (29%), 99 PR (53%), 29 NC (16%), and 4 PD (2%). At a median follow-up of almost 2 years (22 months; range, 6-58 months), limb salvage was achieved in 82%. Regional toxicity was limited and systemic toxicity minimal to moderate, easily managed, with no toxic deaths. CONCLUSIONS: In the setting of isolated limb perfusion, TNF is an active anticancer drug in patients. The ILP with TNF + melphalan can be performed safely in many centers and is an effective induction treatment with a high response rate that can achieve limb salvage in patients with locally advanced extremity soft tissue sarcoma.

Adolescent↗
PubMed1996

Physiological implications of hyperbaric oxygen tensions in isolated limb perfusion using melphalan: a pilot study.

Controversy exists concerning the optimal pO2 of the perfusate during isolated limb perfusion (ILP) with melphalan. Therefore we studied the implications of hyperbaric oxygen tensions in the perfusate. In 12 consecutive patients, subcutaneous pO2 (Continucath 1000), tissue and tumor pH, and blood gas values were monitored throughout the ILP procedure. ILP started with an oxygen flow through the bubble oxygenator which was set routinely at one half of the flow of the perfusate; 30 min before the end of ILP, the oxygen flow was tripled. Mean arterial pO2 before and during ILP (before and after increasing the oxygen supply) was 19.4, 25.5 and 49.4 kPa, respectively. Mean subcutaneous pO2 values before, during (before and after increasing the oxygen supply), and post-ILP, were 7.4, 10.1, 16.3, and 9.1 kPa, respectively. Tissue pH values in the subcutis and muscle decreased during routine oxygen supply (p = 0.001); muscle pH moved towards starting values after increase of the oxygen supply (p = 0.011). In 4 patients, tumor pH was recorded showing a rise after increasing the oxygen supply (from 7.10 to 7.22; p = 0.11). In conclusion, high pO2 in the perfusate improves muscle pH during ILP. However, a concomitant rise in tumor pH may unfavorably influence the therapeutic effect of ILP, as it has been shown that low pH increases the cytotoxicity of melphalan.

Adult↗
PubMed1996

Isolated limb perfusion with high-dose tumor necrosis factor-alpha in combination with interferon-gamma and melphalan for nonresectable extremity soft tissue sarcomas: a multicenter trial.

PURPOSE: To determine the efficacy of isolated limb perfusion (ILP) with tumor necrosis factor-alpha (TNF) in combination with interferon-gamma (IFN) and melphalan as induction therapy to render tumors resectable and avoid amputation in patients with nonresectable extremity soft tissue sarcomas (STS). PATIENTS AND METHODS: Among 55 patients with 30 primary and 25 recurrent sarcomas, there were 48 high-grade and seven grade 1 sarcomas (very large, recurrent, or multiple). The composition of this series of patients is unusual: 13 patients (24%) had multifocal primary sarcomas or multiple recurrent tumors; tumors were very large (median, 18 cm); and nine patients (16%) had known systemic metastases. IFN was administered subcutaneously on the 2 days before ILP with TNF, IFN, and melphalan. A delayed marginal resection of the tumor remnant was usually performed 2 to 3 months after ILP. RESULTS: A major tumor response was seen in 87% of patients and rendered the sarcomas resectable in most cases. Clinical response rates were as follows: 10 (18%) completes responses (CRs), 35 (64%) partial responses (PRs), and 10 (18%) no change (NC). Final outcome was defined as follows by clinical and pathologic response: 20 (36%) CRs, 28 (51%) PRs, and seven (13%) NC. Limb salvage was achieved in 84% (follow-up duration, 20+ to 50+ months). In 39 patients, resection of the tumor remnant (n = 31) or of two to eight tumors (n = 8) after ILP was performed; local recurrence developed in five (13%). When no resection was performed (multiple tumors or systemic metastases), local recurrences were frequent (five of 16), but limb salvage was often achieved as patients died of systemic disease. Regional toxicity was limited and systemic toxicity minimal to moderate with no toxic deaths. Histology showed hemorrhagic necrosis; angiographies showed selective destruction of tumor-associated vessels. CONCLUSION: ILP with TNF, IFN, and melphalan is a safe and highly effective induction biochemotherapy procedure that can achieve limb salvage in patients with nonresectable extremity STS. TNF is an active anticancer drug in humans in the setting of ILP.

Adolescent↗
PubMed1996

Repeat isolated limb perfusion with melphalan for recurrent melanoma of the limbs.

BACKGROUND: Melanoma recurring locoregionally after isolated limb perfusion (ILP) constitutes a therapeutic dilemma. Major amputation is a deterrent option for local control and palliation in these patients who have a rather poor prognosis. Little is known about the feasibility and efficacy of repeat ILP in these situations. STUDY DESIGN: From 1978 to 1993, 28 patients with recurrent melanoma after ILP were retreated with various ILP procedures using melphalan. Eighteen patients underwent reperfusion by a single and four by a multiple normothermic schedule. Hyperthermia was applied in six repeat ILP procedures. RESULTS: A complete remission was achieved in 14 (74 percent) of 19 patients with measurable disease, with a median limb recurrence-free interval of 11 months. A partial remission was obtained in one patient (5 percent). Two patients had no change of disease and two patients had progressive disease. In the remaining nine patients, all macroscopic tumor tissue was excised before or during the repeat ILP procedure. The median limb recurrence-free interval of these nine patients was 15 months. After a median follow-up period of 30 months after repeat ILP, seven (25 percent) of the 28 total patients were alive without disease. Acute regional tissue toxicity was more severe after repeat ILP than after the first procedure (p < 0.05). Long-term regional morbidity occurred in 11 percent of the patients. CONCLUSIONS: A high complete remission rate can be obtained with repeat ILP using melphalan. However, the high limb recurrence rate and relatively short limb recurrence-free interval need improvement. Increased acute regional toxicity after repeat ILP can be explained by the use of more intensive schedules.

Adult↗
PubMed1996

Reproducibility of lymphoscintigraphy for lymphatic mapping in cutaneous melanoma.

UNLABELLED: One of the indications for lymphoscintigraphy in patients with melanoma is to determine the lymphatic drainage pattern and position of the first draining lymph node--the sentinel node. Metastasis in the sentinel node indicates the need for therapeutic lymph node dissection. The purpose of the present study was to examine the reproducibility of lymphoscintigraphy in assessing the location and number of sentinel nodes. METHODS: Twenty-five patients with clinically localized melanoma were investigated. The same investigator performed two scintigraphic studies with a 2-4 wk interval in each patient, in an identical manner. A 60-MBq dose of 99mTc-nanocolloid was injected intradermally at the primary tumor site. The lymph flow was studied dynamically, complemented by lateral/oblique views. The images were evaluated by a panel of three observers. RESULTS: The sentinel node was visualized within 20 min in all patients. A difference in number of sentinel nodes depicted on the first and second study was noted in three patients (12%). The melanoma was situated on the head (two patients) and arm (one patient) in these patients. Otherwise, the images were identical for number and location of nodes. CONCLUSIONS: Reproducibility of lymphoscintigraphy with 99mTc-nanocolloid was high in this study. However, some sentinel nodes may be missed in lymphoscintigraphy for melanoma.

Adult↗
PubMed1995

Long-term morbidity after regional isolated perfusion with melphalan for melanoma of the limbs. The influence of acute regional toxic reactions.

OBJECTIVE: To determine the influence of acute regional toxic reactions on the incidence and characteristics of long-term morbidity after regional isolated perfusion with melphalan. DESIGN: Retrospective study. SETTING: The Amsterdam and Rotterdam perfusion centers, the Netherlands. PATIENTS: All patients with melanoma who were treated between 1978 and 1990 and had a minimum follow-up of 1 year after perfusion (n = 367). INTERVENTION: Fifty-four patients (15%) had perfusion of the upper limb, 313 (85%) had perfusion of the lower limb, and 164 patients (45%) underwent regional lymph node dissection at the time of perfusion. MAIN OUTCOME MEASURE: Incidence and characteristics of morbidity 1 year after perfusion and the influence of acute regional toxic reactions on long-term morbidity. RESULTS: One hundred sixty patients (44%) showed some degree of objective or subjective morbidity; most (104 [28%]) had lymphedema. Other long-term morbidity consisted of muscle atrophy or fibrosis (42 [11%]), limb malfunction (55 [15%]), neuropathy (13 [4%]), pain (28 [8%]), and recurrent infection (11 [3%]). Miscellaneous complications were seen in 14 patients (4%). Seventy-one patients (19%) had more than one complication. Acute regional toxic reactions had a statistically significant effect on the incidence of long-term morbidity (P < .01). Moderate to severe acute regional toxic reactions were strongly linked to the occurrence of muscle atrophy or fibrosis (P < .001) and limb malfunction (P < .001). Regional lymph node dissection was statistically significantly related to lymphedema (P = .05). CONCLUSION: Improvement of the perfusion technique should be pursued in an effort to reduce acute regional toxic reactions, and thereby long-term morbidity, without compromising the therapeutic effect.

Adult↗
PubMed1995

VWF release and platelet aggregation in human melanoma after perfusion with TNF alpha.

Twenty-nine stage IIIA/B melanoma patients treated by isolated limb perfusion (ILP) with a high dose of recombinant human tumour necrosis factor alpha (rHuTNF alpha), interferon gamma (IFN gamma), and melphalan were histologically documented with emphasis on therapy-induced changes of the tumour vasculature. Sequential biopsies were taken at various intervals before and after the treatment to compare the morphological change. In order to visualize microvascular changes, immunostaining was performed for von Willebrand factor (VWF), type IV collagen, alpha-smooth muscle actin, endothelial antigen PAL-E, tissue factor, CD41 (thrombocyte marker), and fibrin. In biopsies prior to perfusion, necrosis, haemorrhage, and fibrin thrombi were not found. Within 3 h following triple combination therapy, a change in the distribution of VWF staining occurred, from a discrete endothelial pattern in the untreated lesions to a fuzzy perivascular and subepidermal pattern in the treated lesions. Within 24 h, this was accompanied by intravascular thrombocyte aggregation and erythrostasis, in the absence of tissue factor and fibrin deposits. These findings indicate that the thrombocyte aggregation observed is not caused by local procoagulant activity, but is rather the result of the therapy-associated vascular damage or haemostasis. Although it is difficult to derive the dynamics of this process from static images, we assume that TNF alpha induced endothelial cell damage, leading to VWF release. Release VWF may play a role in the adhesion between thrombocytes and the damaged endothelium or the denuded subendothelium. As a consequence, the blood flow is impaired, leading to congestion and oedema, compatible with an early stage of haemorrhagic infarction.

Chemotherapy, Cancer, Regional Perfusion↗
PubMed1995

A retrospective comparative study evaluating the results of mild hyperthermic versus controlled normothermic perfusion for recurrent melanoma of the extremities.

The aim of this study was to investigate the role of mild hyperthermia (39-40 degrees C) in isolated cytostatic perfusion for patients with recurrent melanoma of the extremities. A total of 218 patients treated with mild hyperthermic perfusion was compared to 166 patients perfused under controlled normothermic conditions (37-38 degrees C). Only patients whose lesions had been excised before or at the moment of perfusion were eligible for this study. A variety of prognostic factors was controlled for in a Cox proportional hazards analysis. The application of mild hyperthermia did not influence limb recurrence-free interval nor survival (corrected P values 0.46 and 0.18, respectively). In this retrospective comparative study, no benefit for mild hyperthermia in regional isolated perfusion could be identified.

Adolescent↗
PubMed1995

Report of a symposium on diagnosis and treatment of adult soft tissue sarcomas in the head and neck.

A series of presentations and discussions was held during a symposium on the diagnosis and treatment of adult soft tissue sarcomas in the head and neck (HNSTS). The purpose of this meeting was to define guidelines on diagnosis and treatment of HNSTS. The results of this symposium are summarized and condensed in this report. Recommendations are made for diagnostic strategies and for treatment. Diagnostic efforts in PET scanning and dynamic MRI need to be expanded to detect early recurrences. Firm pathological diagnosis remains the basis for further treatment strategy. Wide surgical excision, if feasible, in combination with radiotherapy is the treatment of choice.

Adult↗
PubMed1995

Severe acute regional toxicity after normothermic or 'mild' hyperthermic isolated limb perfusion with melphalan for melanoma.

Incidence, nature and cause of severe acute regional toxicity were studied in 181 patients who underwent normothermic (37-38 degrees C) or 'mild' hyperthermic (38-40 degrees C) isolated limb perfusion (ILP) with melphalan. The known risk factors for toxicity (sex, tissue temperature, blood gas values, isolation level and melphalan peak concentration) were analysed. Severe acute regional toxicity occurred in 30 patients (16%). The limb was painful, swollen, red and warm in 19, often with a smooth and glistening aspect. Blistering scattered over the extremity was seen in 11 cases. In another 11 patients, late blistering limited to the footsole or handpalm developed. Twenty-six patients with severe toxicity had undergone ILP at the iliac isolation level (p < 0.05). Sex and tissue temperature did not predict toxicity. Venous perfusate blood gas values were severely deteriorated in four patients; high calculated melphalan peak concentrations occurred in nine patients. Irreversible long-term morbidity as a sequence of severe toxicity occurred in 10 of the 30 patients. Only one of the 11 patients with late blisters limited to sole or palm developed long-term morbidity (p < 0.05). Thus, the only risk factor for severe acute regional toxicity that could be identified was iliac isolation level. However, in 27 of the 30 patients two or more risk factors were found.

Adult↗
PubMed1994

[Characteristics of patients with recurrence of primary melanoma at least 10 years following surgical treatment].

OBJECTIVE: Assessment of incidence and risk factors of late recurrence (after a disease-free interval of at least 10 years) following treatment for primary melanoma. METHODS: Retrospective study taking into account a total of 2579 melanoma patients admitted to the Netherlands Cancer Institute/Antoni van Leeuwenhoek Huis in the period 1956 to 1991; patients with ocular melanoma were excluded. RESULTS: Twenty-three patients had a disease-free interval of at least 10 years (median 11 years; range: 10-21) after treatment for primary melanoma: 17 women and 6 men, with a median age of 43 years (20-62). This group predominantly consisted of women with a primary melanoma localised on the extremities. Most of them had melanomas of intermediate thickness (Breslow thickness: 1-2 mm). Patients with a first recurrence locoregionally (16) had a 5-year survival rate of over 50%; 6 of the 7 patients with a first relapse at distant sites died within a few months. CONCLUSION: Melanoma patients who are discharged from follow-up after a disease-free interval of 10 years are advised to continue loco-regional self-examination.

Adult↗
PubMed1994

Patient- and treatment-related factors associated with acute regional toxicity after isolated perfusion for melanoma of the extremities.

In order to gain some insight into the cause of acute regional toxicity after isolated perfusion using melphalan, 15 patient-related and perfusion-technique-related factors were tested in a logistic regression model. Acute toxicity was graded according to Wieberdink's grading system. In a group of 425 patients, 362 (85%) encountered no or slight toxicity with a grade I or II reaction, and 63 (15%) patients encountered more severe toxicity with a grade III, IV, or V reaction. Most patients were treated with a standard dose of 10 or 13 mg melphalan per liter of perfused tissue for leg and arm perfusions, respectively. Factors associated with a more severe toxicity reaction proved to be tissue temperatures of 40 degrees C or higher, female gender, a deterioration of the gas values of the venous perfusate during perfusion, and perfusion at a proximal level of isolation. Consideration of these prognostic factors may lead to a further decrease of acute regional toxicity in perfusion.

Adult↗