Jan Mattsson

Breast conservation surgery, with and without radiotherapy, in women with lymph node-negative breast cancer: a randomised clinical trial in a population with access to public mammography screening

The effect of postoperative radiotherapy after sector resection for stage I-II lymph node-negative breast cancer was evaluated in a patient population with access to public mammographical screening. 1187 women were randomised to no further treatment or postoperative radiotherapy following a standardised sector resection and axillary dissection. Radiation was administered to a dose of 48-54 Gy. Median age was 60 years, and median size of the detected tumours was 12 mm. Of the women 65% had their tumours detected by mammographical screening. The relative risk (RR) of ipsilateral breast recurrence was significantly higher in the non-irradiated patients compared with the irradiated patients, RR=3.33 (95% Confidence Interval (CI) 2.13-5.19, P<0.001). The corresponding cumulative incidence at 5 years was 14% versus 4%, respectively. Overall survival (OS) was similar, RR=1.16 (95% CI 0.81-1.65, P=0.41), with 5 year probabilities of 93 and 94%, respectively. Recurrence-free survival (RFS) at 5 years was significantly lower in the non-irradiated women, 77% versus 88% (P<0.001). Although women above 49 years of age, whose tumours were detected with mammographical screening, had the lowest rate of ipsilateral breast recurrence in this study, the cumulative incidence of such event amounted to 10% at 5 years if radiotherapy was not given. Such a recurrence rate has been considered as unacceptably high, but is, however, in the same range as that reported after lumpectomy and postoperative radiotherapy in published series.

MicroRNA in exosomes isolated directly from the liver circulation in patients with metastatic uveal melanoma.

BackgroundUveal melanoma is a tumour arising from melanocytes of the eye, and 30 per cent of these patients develop liver metastases. Exosomes are small RNA containing nano-vesicles released by most cells, including malignant melanoma cells. This clinical translational study included patients undergoing isolated hepatic perfusion (IHP) for metastatic uveal melanoma, from whom exosomes were isolated directly from liver perfusates. The objective was to determine whether exosomes are present in the liver circulation, and to ascertain whether these may originate from melanoma cells.MethodsExosomes were isolated from the liver perfusate of twelve patients with liver metastases from uveal melanoma undergoing IHP. Exosomes were visualised by electron microscopy, and characterised by flow cytometry, Western blot and real-time PCR. Furthermore, the concentration of peripheral blood exosomes were measured and compared to healthy controls.ResultsThe liver perfusate contained Melan-A positive and RNA containing exosomes, with similar miRNA profiles among patients, but dissimilar miRNA compared to exosomes isolated from tumor cell cultures. Patients with metastatic uveal melanoma had a higher concentration of exosomes in their peripheral venous blood compared to healthy controls.ConclusionsMelanoma exosomes are released into the liver circulation in metastatic uveal melanoma, and is associated with higher concentrations of exosomes in the systemic circulation. The exosomes isolated directly from liver circulation contain miRNA clusters that are different from exosomes from other cellular sources.

Isolated Hepatic Perfusion for Ocular Melanoma Metastasis: Registry Data Suggests a Survival Benefit

AbstractBackgroundUveal melanoma is the most common primary intraocular malignancy in adults. Despite successful control of the primary tumor, metastatic disease will ultimately develop in approximately 35xa0% of the patients, with the liver being the most common site for metastases. These metastases are generally refractory to systemic chemotherapy, and the median survival for patients with liver metastases is about 6xa0months. This phase II trial reports the experience of isolated hepatic perfusion (IHP) as a treatment option.nMethodA total of 34 patients with isolated liver metastasis from ocular melanoma underwent IHP. An overall survival comparison was made using data retrieved from the National Patient Register managed by the Swedish National Board of Health and Welfare.ResultsAn overall radiological response was seen in 68xa0% of the patients, with 12xa0% having a complete response. Time to local progression was 7xa0months; 68xa0% of the patients developed extrahepatic metastases after a median of 13xa0months, and the median overall survival was 24 months. There was a significant survival advantage of 14 months (pxa0=xa00.029) when comparing these patients with a control group consisting of the longest surviving patients in Sweden with uveal melanoma liver metastases not treated with IHP.ConclusionsIHP is a treatment option with a high response rate and a potential survival benefit of more than 1xa0year. IHP should be considered an option in the treatment of uveal melanoma metastases. A randomized trial comparing IHP and best alternative care will start during 2013 (the SCANDIUM trial, ClinicalTrials.gov identifier NCT01785316).

Sentinel node biopsy in malignant melanoma : Swedish experiences 1997-2005

The sentinel node biopsy (SNB) procedure is a multidisciplinary technique, invented to gain prognostic information in different malignant tumors. The aim of the present study was to study the cohort of patients with malignant melanoma, operated with SNB, from the introduction of the technique in Sweden, concerning the prognostic information retrieved and the outcome of the procedures. In Sweden all patients with malignant melanoma are registered at regional Oncological Centers. From these databases ten centers were identified, treating malignant melanoma and performing sentinel node biopsy. Consecutive data concerning tumor characteristics, outcome of the procedure and disease related events during the follow-up time were collected from these ten centers. All cases from the very first in each centre were included. The SNB procedure was performed in 422 patients with a sentinel node (SN) detection rate of 97%, the mean Breslow thickness of the primary tumors was 3.2 mm (median 2.4 mm) and the proportion of ulcerated melanomas 38%. Metastasis in the SN was found in 19% of the patients but there was a wide range in the proportion of SN metastases between the different centers (5–52%). After a follow-up of median 12 months of 361 patients, SN negative patients had better disease-free survival than SN positive (p<0.0001). A false negative rate of 14% was found during the follow-up time. In this study the surgical technique seemed acceptable, but the non-centralized pathology work-up sub-optimal. However, SNB was still found to be a significant prognostic indicator, concerning disease free survival.

Influence of noradrenaline on local tumour blood flow

Abstract The local blood flow in a transplantable rat sarcoma and in normal rat muscle and subcutaneous tissue was studied by local 133 Xe clearance technique. Noradrenaline, mixed and injected with the isotope, reduced significantly the local blood flow in both tumour and normal tissues. This suggests that the tumour vascular bed, opposite to what has earlier mostly been stated on the basis of lack of adrenergic innervation, might be directly influenced by vasoactive drugs.

No germline mutations in supposed tumour suppressor genes SAFB1 and SAFB2 in familial breast cancer with linkage to 19p

BackgroundThe scaffold attachment factor B1 and B2 genes, SAFB1/SAFB2 (both located on chromosome 19p13.3) have recently been suggested as tumour suppressor genes involved in breast cancer development. The assumption was based on functional properties of the two genes and loss of heterozygosity of intragenic markers in breast tumours further strengthened the postulated hypothesis. In addition, linkage studies in Swedish breast cancer families also indicate the presence of a susceptibility gene for breast cancer at the 19p locus. Somatic mutations in SAFB1/SAFB2 have been detected in breast tumours, but to our knowledge no studies on germline mutations have been reported. In this study we investigated the possible involvement of SAFB1/SAFB2 on familiar breast cancer by inherited mutations in either of the two genes.ResultsMutation analysis in families showing linkage to the SAFB1/2 locus was performed by DNA sequencing. The complete coding sequence of the two genes SAFB1 and SAFB2 was analyzed in germline DNA from 31 affected women. No missense or frameshift mutations were detected. One polymorphism was found in SAFB1 and eight polymorphisms were detected in SAFB2. MLPA-anlysis showed that both alleles of the two genes were preserved which excludes gene inactivation by large deletions.ConclusionSAFB1 and SAFB2 are not likely to be causative of the hereditary breast cancer syndrome in west Swedish breast cancer families.

Long-term follow-up of 163 consecutive patients treated with isolated limb perfusion for in-transit metastases of malignant melanoma

Abstract Purpose: The aim of the present study is to describe our experience with isolated limb perfusion (ILP) in the treatment of in-transit metastases of malignant melanoma and to determine prognostic factors for response, local progression, survival and toxicity. Materials and methods: A retrospective follow-up of all patients (nu2009=u2009163) treated between January 1984 and December 2008 using data collected from individual patient records and the Swedish National Patient Register. Results: Clinical response was evaluable in 155 patients, 65% had a complete response (CR) and 20% had a partial response (PR). Local progression occurred in 63% of the patients after a median time of 16 months. Negative prognostic factors in univariate analyses were proximal location of the primary tumour, >10 in-transit metastases and if there was no CR after ILP. In multivariate analysis, proximal location of the primary tumour and no CR after ILP were significant prognostic factors. Median cancer-specific survival was 30 months, and negative prognostic factors in univariate analyses were male gender, positive lymph node status, systemic metastases, bulky tumour, >10 in-transit metastases and if there was no CR after ILP. In multivariate analysis, positive lymph node status, bulky tumour and no CR after ILP were significant prognostic factors. A majority (97%) of the patients had a Wieberdink grade II–III local toxicity. Four patients underwent limb amputation after a median of 19 months, none because of toxicity. Conclusion: We found that ILP is a safe method with a high response rate for the treatment of patients with in-transit metastases of malignant melanoma.

No breast cancer subgroup can be spared postoperative radiotherapy after breast-conserving surgery. Fifteen-year results from the Swedish Breast Cancer Group randomised trial, SweBCG 91 RT.

BACKGROUNDnBreast-conserving surgery (BCS) followed by radiotherapy (RT) is an established treatment for women with T1-2N0 breast cancers. Since subgroups of patients have low ipsilateral breast tumour recurrence (IBTR) rates, it is important to study whether RT is necessary for all patients.nnnPATIENTS AND METHODSnA total of 1187 women with primary T1-2N0M0 breast cancer were randomised, after standardised sector resection, to postoperative whole breast RT or no local treatment. Adjuvant systemic therapy was offered to patients with stage II cancers. Patients were followed with clinical examinations and annual mammography for 10 yearsxa0and thereafter referred to the Swedish mammography screening program.nnnRESULTSnAfter 15 years of follow-up, a higher cumulative incidence of IBTR was observed in control patients, 23.9%, versus irradiated patients, 11.5%, P<0.001. Recurrence-free survival was inferior, 51.7% versus 60.4%, P=0.0013. The main effect of RT was seen during the first 5 years. However, overall survival was not significantly lower 68.4% versus 71.1%, P=0.68, nor was breast cancer-specific mortality significantly higher.nnnCONCLUSIONSnRT after BCS significantly reduced the incidence of IBTR at 15 years of follow-up. We were unable to identify subgroups which could be spared RT. Breast cancer mortality was not significantly reduced after RT. Good predictive markers for radiation sensitivity and improved adjuvant systemic therapy are needed to omit RT after BCS.

Long-Term Outcome of Isolated Limb Perfusion in Advanced Soft Tissue Sarcoma of the Extremity

BackgroundIsolated limb perfusion with tumor necrosis factor alpha and melphalan (TM-ILP) has proven to be a successful option in treating advanced soft tissue sarcomas (STS), where amputation otherwise is needed to achieve safe surgical margins.MethodsFrom 2000 to 2009, 54 patients with locally advanced STS, who all were candidates for amputation, were treated with totally 57 TM-ILP procedures and then followed prospectively. The median follow-up time was 30xa0months. Median tumor size was 10xa0cm, and 94% of the patients had high-grade tumors.ResultsThe clinical overall response after TM-ILP was 71% (including 21% CR), and 60% of the patients underwent resection of the tumor remnant after a median of 2xa0months. The histopathologic response rate in the resected specimens was 76%. Local recurrence/progress occurred in 37% of the patients after a median of 7xa0months. Thirteen patients finally underwent amputation after a median of 11xa0months, giving a long-term limb salvage of 76%.ConclusionsTM-ILP of advanced soft tissue sarcoma of the extremities makes limb-sparing surgery possible in a high proportion of patients.

Regional hyperthermic perfusion with melphalan after surgery for recurrent malignant melanoma of the extremities – Long-term follow-up of a randomised trial

Abstract Introduction: Isolated limb perfusion (ILP) is a treatment option most commonly used in the treatment of melanoma in-transit metastases of the extremities. The principle idea is to surgically isolate a region of the body and then deliver a high concentration of a chemotherapeutic agent together with hyperthermia. There have been three randomised trials exploring whether adjuvant ILP to patients with recurrent or high-risk primary melanomas increases survival; one of these trials has now been updated with a 25-year follow-up. Methods: The original study randomised 69 patients (between 1981 and 1989) with their first satellite or in-transit recurrence to either wide excision (WE group, nu2009=u200936 patients) or to WE and adjuvant ILP (WEu2009+u2009ILP group, nu2009=u200933 patients). Follow-up data 25 years later concerning survival and cause of death was retrieved from the Swedish National Cause of Death Register. Results: In the WEu2009+u2009ILP group there were 20 deaths (61%) due to melanoma compared with 26 deaths (72%) in the WE group (pu2009=u20090.31). Median melanoma-specific survival was 95 months for WEu2009+u2009ILP compared to 38 months for the WE group, an almost 5 year benefit without statistical significance (pu2009=u20090.24). Discussion: There is no evidence that adjuvant ILP prolongs survival in patients with high-risk or recurrent melanoma; however, the existing randomised trials are largely underpowered to detect such a difference. New studies are exploring systemic immunological effects of ILP, and a combination of regional therapy and immunotherapy may serve as a rationale for new trials using ILP in the future.