Low levels of endostatin in the urine from patients with malignant disease.

Endostatin, a C-terminal subfragment of collagen XVIII, and angiostatin, a family of fragments originating from the NH(2)-terminal portion of plasminogen, have been described as potent inhibitors of angiogenesis and malignant growth. We have earlier reported the presence of angiostatin fragments in urine from cancer patients. In this study, we investigated the occurrence of endostatin and the correlation between the amounts of endostatin and angiostatin in urine collected from 104 patients with different types of malignancies and in 16 controls. The amounts of endostatin were measured with a commercial immunoassay. Angiostatin fragments were quantitated by Western blot analysis. Only small amounts of endostatin were observed, both in patients and controls, and there was no significant difference in the amount of endostatin between the patients and the controls. Both endostatin and angiostatin concentrations in the urine showed a strong dependence on impaired kidney function, especially tubulus function, measured as the amount of urine alpha(1)-microglobulin. Interestingly, there was no significant correlation between endostatin and angiostatin concentrations in the patients with impaired kidney function (elevated urine albumin or urine alpha(1)-microglobulin), suggesting a possible difference in circulating concentrations of these inhibitors.

A Swedish study of chemoradiation in squamous cell carcinoma of the esophagus.

This multicenter study describes the development of a chemoradiation protocol for the treatment of non-metastatic squamous cell carcinoma of the esophagus. Eighty patients were treated with three courses of chemotherapy (cisplatinum and 5-fluorouracil) with concomitant radiotherapy (40 Gy) during the last two courses of chemotherapy. Esophagectomy was performed, when feasible. If no operation was performed, patients were planned to receive a target dose of 64 Gy. Toxicity was mainly attributable to hematological impairment and led to two adjustments of the treatment protocol (addition of filgrastim and lowering of the 5-fluorouracil dose). These changes made it possible to administer the planned treatment in a gradually higher proportion of patients (13/23 [57%] before changes of treatment compared with 30/36 [83%] after changes). Treatment-related mortality was 3.75% (3 patients, associated with leucopenic septicemia after chemotherapy). Fifty-four patients were resected. No per- or postoperative mortality was encountered. The complete response (pathological CR) rate in operated patients was 46% (27/59 patients) after chemoradiation. In the whole series the CR rate (including clinical CR for non-resected patients) was 44%. With a minimum follow-up of 37 months, the 3-year survival for the whole group was 31% compared with 57% for the CR patients. Total 5-year survival thus far (July 1999) is 26%.

Apoptosis and cell growth inhibition as antitumor effector functions of interferons.

Since their introduction to the clinic some 30 yr ago, interferons (IFNs) have become standard therapy for a range of disorders, including malignant and benign tumors as well as various viral diseases. Although IFNs will induce remissions in some patients with cancer, they are of no benefit or, at best, lead only to minor improvements in the great majority of patients with malignant disease. One of the great challenges of IFN research is to understand the multiple ways by which IFNs influence the behavior of tumor cells and to identify the factors that underlie the resistance of some tumors to IFNs. This review is written with a focus on two anticellular effects of IFN, inhibition of proliferation and induction of apoptosis, possible mechanisms underlying the antitumor action of IFN. In addition, possible reasons for IFN tumor cell resistance are also discussed.

Shrinkage of desmoid tumor with interferon alfa treatment: a case report.

We report on a case with desmoid tumor sucessfully treated with low-dose interferon alfa. A desmoid tumor was diagnosed in August 1998 in the right shoulder area of a 23-year-old woman. Surgery would probably have permanently impaired muscle function in her shoulder and arm. Therefore, interferon alfa treatment (0.9 million units twice daily subcutaneously) was started in November 1998 (time = 0). The tumor volume based on magnetic resonance imaging (MRI) was initially 16 cm3. The size of the tumor decreased gradually during 12 months of treatment, and in November 1999 (time = 12 months) MRI showed no clear tumor demarcation. This treatment modality may be considered as an alternative to mutilating surgery in patients with desmoid tumor.

Perceived symptoms and quality of life in women with breast cancer receiving radiation therapy.

The purpose of this study was to describe symptoms, side-effects and quality of life (QoL) of women with breast cancer during and following treatment with radiation therapy. The sample consisted of 134 women with breast cancer. Symptoms were measured using a modified version of the Oncology Treatment Toxicity Tool (OTTAT) and QoL was measured using the Cancer Rehabilitation Evaluation System-short form (CARES-sf). The results showed an increase in experienced symptoms and their severity as the treatment progressed. QoL was perceived as poorest at baseline before treatment had started. During the treatment, QoL scores leveled out and an improvement could be seen after completion of treatment. The study findings provide directions and suggestions for assessment and management of perceived symptoms for women receiving radiation therapy for breast cancer from the second week and up to 2 weeks after completion of therapy is the critical time-period for targeting interventions for experienced symptoms and side-effects from radiation therapy.

Prognostic impact of complete remission after preoperative irradiation of tonsillar carcinoma: a retrospective analysis of the radiumhemmet data, 1980-1995.

PURPOSE: This retrospective study was done to determine the outcome of patients with tonsillar carcinoma treated at Radiumhemmet, Karolinska Hospital, between January 1980 and December 1995 with radiotherapy alone or in combination with surgery. In addition the importance of tumor remission for patient survival was analyzed. METHODS AND MATERIALS: The analysis is based on 167 previously untreated patients with biopsy-proven, invasive tonsillar squamous cell carcinoma of the tonsillar region. All patients were consecutively admitted to the Department of General Oncology, Radiumhemmet, and treated with curative intent. The median follow-up time was 20 months. The median target dose was 64 Gy, delivered in fractions of 2 Gy 5 times weekly. Twenty-eight percent of the patients underwent surgery of the primary site and/or neck dissection after radiotherapy (RT). RESULTS: The overall local control rate for the whole patient group after radiotherapy was 79%. Probability of survival after 5 years for patients responding with complete remission (CR) was 43% and for patients with incomplete response (non-CR) 9%, (p<0.0001). The survival in the non-CR group treated with combination therapy was 20 months longer than in patients receiving radiotherapy alone (p<0.0001). There was no statistically significant difference in prediction of long-term survival when the patient population was stratified according to tumor differentiation grade, age, sex, nodal status, or treatment time. CONCLUSION: The strongest clinical predictor of survival was the degree of tumor remission after RT. For the non-CR group receiving combination treatment including surgery there was a survival benefit as compared to patients treated with RT alone (p<0.0001) although there were few long-term survivors in this patient group.

Effects of a nursing intervention on subjective distress, side effects and quality of life of breast cancer patients receiving curative radiation therapy--a randomized study.

The purpose of this randomized study was to investigate whether a nursing intervention using Orem's self-care theory as a framework would affect subjective distress, side effects and quality of life as perceived by breast cancer patients receiving curative radiation therapy. The intervention consisted of five 30-min sessions once a week during the treatment period and two follow-up sessions after completion of treatment. The experimental group consisted of 67 patients, as did the control group. Measurements were collected five times: at baseline before commencement of treatment, at weeks 3 and 5 (completion of treatment) and follow-up periods of 2 weeks and 3 months. No measurable effect of the nursing intervention was found for side effects or quality of life but nursing intervention proved to have a positive effect in minimizing stress reactions (p = < 0.05). It is suggested that a nursing intervention should be implemented for breast cancer patients receiving curative radiation therapy.

Chemotherapy in soft tissue sarcoma. The Scandinavian Sarcoma Group experience.

The first chemotherapy study of soft tissue sarcoma (STS) by the Scandinavian Sarcoma Group was started in 1981 (SSG I). It evaluated the single agent adjuvant doxorubicin in a randomized setting in patients with high-grade STS. No improvement was noted in the overall survival or disease-free survival rate. More intense chemotherapy was thereafter (1991-1994) evaluated in a phase 2 study, introducing ifosfamide and a continuous infusion of etoposide with growth factor (SSG X). The response rate of previously untreated patients was high (42%), but complete remissions were few. Analysis of patients undergoing surgery after preoperative chemotherapy suggested an increased survival. A recent meta-analysis of adjuvant chemotherapy for localized resectable STS in adults, including the SSG I trial, indicated a better disease-free survival and possibly improved overall survival (Thierny et al. 1997). At present, we are studying whether such a benefit can be shown in patients with high-risk prognostic criteria by giving adjuvant ifosfamide and doxorubicin treatment after primary surgery (SSG XIII). In the latter SSG study, started on July 1, 1998, the adjuvant therapy is evaluated in a phase 2 study in selected patients with high-grade STS and other unfavorable prognostic factors.

Angiostatin fragments in urine from patients with malignant disease.

Angiostatin, a family of fragments originating from the NH2-terminal portion of plasminogen, has been described as a potent inhibitor of angiogenesis. In order to examine to what extent angiostatin can be detected in cancer patients, urine was collected from 117 patients with different types of malignancies and subjected to Western blot analysis, utilizing antibodies raised against "kringles" 1-3 in plasminogen. A heterogeneous mixture of fragments was observed, with patterns that also varied between patients. Angiostatin fragments were quantified by densitometric scanning. The concentrations were 27 +/- 75 (SD) micrograms L-1 (range, 1-565 micrograms L-1) in urine from cancer patients, as compared to 3 +/- 2 (SD) micrograms L-1 (range, 1-10 micrograms L-1) in urine from healthy individuals. Thirty-three patients (28%) had elevated levels using a cut off level at 15 micrograms L-1 (clearly above the highest level obtained among control subjects). NH2-terminal amino acid sequence analysis of purified angiostatin fragments from one patient showed a heterogeneous pattern, but were consistent with the region between the preactivation peptide in plasminogen and "kringle" 1, as expected. Several of the patients with urinary angiostatin showed signs of poor kidney function. We conclude that angiostatin can be detected in urine from cancer patients, but at present, the clinical significance of this finding is unclear.

Independent expression of serum vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in patients with carcinoma and sarcoma.

Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) were quantified in the sera of 100 patients with sarcoma, head and neck carcinoma, oesophageal carcinoma, mesothelioma and lung carcinoma. VEGF and bFGF levels were generally higher in the sera of the tumor patients compared to the sera of healthy control subjects. Interestingly, VEGF and bFGF levels were generally not elevated in the same sera (p < 0.01), and covariation of the VEGF and the bFGF levels was only rarely observed during progressive disease, arguing for actual independence of factors. Very high levels of VEGF (668 pg/ml, n = 12) were observed in patients with mesothelioma, whereas bFGF levels were not increased in these patients. Our data suggest that VEGF levels increase with tumor progression and may be a useful marker for clinical monitoring of sarcoma and carcinoma patients.

Correlation between basic fibroblast growth factor immunostaining of stromal cells and stromelysin-3 mRNA expression in human breast carcinoma.

We examined the localization of basic fibroblast growth factor (bFGF) in a series of human breast carcinomas using immunohistochemistry. Staining was observed in tumour cells in 15 out of 54 (28%) tumours and in the adjacent stroma in 34 out of 54 (63%) tumours examined. No correlation was observed between positive staining of these two compartments. The relationship between bFGF staining and expression of the metalloprotease stromelysin-3, and between bFGF and microvessel density, was examined. A statistically significant correlation (P < 0.003) was observed between bFGF staining of the stromal compartment and high expression of stromelysin-3 (ST-3; MMP-11) metalloprotease mRNA by stromal cells. In contrast, no correlation was observed between bFGF and intratumour microvessel density (IMD). These results raise the possibility that bFGF may be involved in the induction of stromelysin-3 mRNA expression in breast cancer stroma.

Evaluation of tissue and serum VEGF in patients with head and neck carcinoma.

Serum vascular endothelial growth factor (VEGF) was measured in 54 cancer patients with head and neck carcinoma. In addition, tumor VEGF was examined by immunohistochemistry in sections of biopsies obtained within 4 weeks to serum sampling in 37 of these patients. Serum VEGF levels were higher in the sera of the tumor patients than in the sera of healthy control subjects (P < 0.005). Patients with stage II-IV tumors showed increased levels of serum VEGF, whereas patients with stage I tumors did not. The receiver operating characteristics (ROC) of serum VEGF were similar to those observed with TPS (tissue protein specific antigen). Immunohistochemistry of tissue sections showed that 24/37 tumors were VEGF positive. No connection was observed between strong VEGF staining of tumor tissue sections and high levels of serum VEGF. We conclude that serum VEGF could be a useful marker for monitoring head and neck carcinoma patients, but that serum and tissue VEGF levels do not appear to correlate with each other.

Ifosfamide and continuous infusion etoposide in advanced adult soft tissue sarcoma. A Scandinavian Sarcoma Group Phase II Study.

The purpose of this study was to evaluate tumour response and toxicity to ifosfamide and continuous infusion etoposide in metastatic or locally advanced soft tissue sarcoma, with dose escalations under G-CSF (granulocyte colony-stimulating factor) support. Of 92 eligible patients (median age 51 years), 85% had tumours of high-grade malignancy and 82% had metastatic disease. Chemotherapy, the baseline dose, consisted of etoposide 600 mg/m2 as a 72 h infusion and ifosfamide 1500 mg/ m2/day for 3 days, followed by G-CSF support (VIG regimen). Stepwise 10% dose escalations were performed depending on haematological toxicity. For patients considered operable after induction chemotherapy, surgical resection of all identifiable residual tumour was attempted. Complete and partial response rates were 11% and 31%, for an overall response rate of 42% (95% CI 31-52%). Forty-eight per cent of courses were dose escalated by a median of 20%. Complete responders had significantly higher, and patients with progressive disease had significantly lower, dose levels than other patients. None of 20 patients with liver metastases responded despite high dose levels. Compared to a preceding pilot study, the addition of G-CSF led to significantly higher dose levels, improved schedule adherence and less haematological toxicity, but no apparent increase in response rate. In view of the modest dose of ifosfamide applied in this study, it is possible that the prolonged infusion of etoposide made a significant contribution to the regimen's antitumour activity, although this can only be determined definitively in a randomised study.

The outcome of advanced soft tissue sarcoma patients with complete tumour regression after either chemotherapy alone or chemotherapy plus surgery. The Scandinavian Sarcoma Group experience.

The intensified induction regimens used and the potential use of high-dose consolidation chemotherapy (CT) in advanced soft tissue sarcomas (STS) has focused interest on the outcome of those patients who can achieve complete remission (CR) by current therapy. The files from four institutions with a special interest in STS were studied. 38 adult patients with advanced STS who were converted disease-free by either CT alone (n = 14) or CT followed by surgery (n = 24) were found. The median follow-up time was 29 months. The median disease-free survival (DFS) was 18 months and the estimated 2-year DFS 34%. The median disease-specific survival (DSS) was 40 months and the estimated 2-year DSS 78%. For patients who achieved CR by CT alone, and for patients who were converted to CR by surgery, the corresponding DFS figures were 23 months (estimated 2 year DFS 48%) and 10 months (26%) (P = 0.07), respectively. The histological response to CT significantly predicted outcome in patients subjected to surgery (DFS P value 0.004, DSS P value 0.02). Patients who achieved CR by surgery shortly after having achieved a clinical partial response (PR with early surgery) did better than those who where converted to CR by surgery after protracted CT following a clinical PR (PR with late surgery) (DFS P value 0.02, DSS P value 0.1). Our results confirm that CT alone can induce prolonged DFS in rare patients with advanced STS. In patients subjected to surgery, a good histological response indicates improved outcome.

Use of interferon-alpha in laryngeal papillomatosis: eight years of the Cuban national programme.

Laryngeal papillomatosis is one of the first diseases where interferon (IFN) was found to be effective. In 1983, a programme for the treatment of all such cases started in Cuba. Up to December 1991, 125 patients (92 children, 33 adults) have been treated: 102 with leucocyte IFN-alpha, 12 with recombinant IFN-alpha-2b, and 11 have received both preparations. Case management consisted of surgical removal of the lesions followed by an IFN schedule starting with 10(5) IU/kg of weight in children or 6 x 10(6) IU in adults, i.m. daily. The dose was progressively reduced, as long as no relapses occurred. At the end of the one-year schedule the doses were reduced to 5 x 10(4) IU/kg in children or 3 x 10(6) IU in adults, weekly. If there was a relapse, it was removed surgically and the patient returned to a higher dose level. Most cases (89; 71 per cent) have not relapsed after the treatment; 60 of them have been followed for more than three years. In those with relapses, the frequency of recurrence decreased in all but four patients. The treatment seemed to be more effective if initiated less than three months after the disease onset. The tracheostomy could be removed in five out of seven patients who needed it before the IFN treatment and was necessary in only three new cases during IFN treatment. In two of these, decannulation was possible later on. In a total of 14 patients relapses persisted after several cycles of IFN treatment. They were considered resistant to such treatment. No severe side effects were reported. The most frequent ones were fever, drowsiness, increased bronchial secretion, chills and headache. The establishment of this programme has maintained the disease under control in Cuba.

Distribution of stromelysin-3 mRNA transcripts and microvessels in human breast carcinomas.

Several proteinases, implicated in tumor invasion, are expressed in fibroblastic cells surrounding neoplastic cells, and are believed to be induced by paracrine stimulation. Such stimulation, by the local release of angiogenic factors, is also responsible for the induction of new capillary blood vessels, a crucial aspect of tumor growth and metastasis. We have here compared the expression of a matrix metalloproteinase, stromelysin-3 (ST3), with the distribution of tumor microvessels in invasive breast carcinomas. The highest level of ST3 mRNA in each tumor was recorded and compared to the highest microvessel density. No correlation between these two parameters was observed by analysis of 63 tumors. Detailed examination of 19 individual tumors did not reveal any correlation between the distribution of ST3 mRNA and microvessels. In the material studied here, ST3 expression was observed to correlate with long-term survival of the patients, whereas microvessel density did not correlate.

Interferons and the tumor cell.

Optimal use of interferons (IFNs) for the treatment of tumor disease requires experimental work in order to precisely define IFN actions. We have pointed out three modes of such actions relevant for the antitumor efficacy exerted by IFNs: effects on apoptosis, effects on genes involved in malignant transformation and effects on angiogenesis. These are but three selected areas forming a basis for the development of optimal IFN therapy. Further experimental work, undertaken in these and additional IFN areas, is mandatory for the most effective clinical use of IFNs for the treatment of tumor disease.