Local Destruction of Tumors and Systemic Immune Effects.

Current immune-based therapies signify a major advancement in cancer therapy; yet, they are not effective in the majority of patients. Physically based local destruction techniques have been shown to induce immunologic effects and are increasingly used in order to improve the outcome of immunotherapies. The various local destruction methods have different modes of action and there is considerable variation between the different techniques with respect to the ability and frequency to create a systemic anti-tumor immunologic effect. Since the abscopal effect is considered to be the best indicator of a relevant immunologic effect, the present review focused on the tissue changes associated with this effect in order to find determinants for a strong immunologic response, both when local destruction is used alone and combined with immunotherapy. In addition to the T cell-inflammation that was induced by all methods, the analysis indicated that it was important for an optimal outcome that the released antigens were not destroyed, tumor cell death was necrotic and tumor tissue perfusion was at least partially preserved allowing for antigen presentation, immune cell trafficking and reduction of hypoxia. Local treatment with controlled low level hyperthermia met these requisites and was especially prone to result in abscopal immune activity on its own.

Long-term Follow-up After Interstitial Laser Thermotherapy of Breast Cancer.

AIM: To review the effect of immunological changes induced by interstitial laser thermotherapy (ILT) on long-term outcome of patients with breast cancer. PATIENTS AND METHODS: Twenty-four patients with invasive breast cancer were treated with ILT followed by standard surgical excision. Immunohistological reactions on immunocompetent cells were performed on specimens obtained before and after ILT. Follow-up time was 116 (range=91-136) months. RESULTS: Significant prognostic factors were histologically-positive axillary lymph nodes and Ki67 positivity. ILT increased cytotoxic T (CD8(+)) lymphocytes within the tumor and mature dendritic cells (CD83(+)) and reduced the number of T-regulatory cells (Treg) CD25(+)/Forkhead box p3(+) (FOXP3(+)) lymphocytes in regional lymph nodes. These changes did not correlate with prognosis. The number of CD8(+) cells within the tumor, both before and after treatment, was significantly higher in patients with recurrence than in those without recurrence (p<0.01 and p<0.05, respectively). Patients with recurrent disease had a lower number of CD57(+) cells in tumor-free lymph nodes than did patients without recurrence (p<0.05). CONCLUSION: ILT did not have any long-term adverse effects. The clinical impact of the supposedly favourable immune changes after ILT should be examined in a larger patient population.

Interstitial laser thermotherapy of a rat liver tumour: effect of hepatic inflow occlusion.

BACKGROUND AND OBJECTIVE: Interstitial laser thermotherapy was used to treat rat liver tumours. The aim was to investigate the influence of temperature and temporary hepatic inflow occlusion on tumour growth and blood perfusion. STUDY DESIGN/MATERIALS AND METHODS: Liver tumours were treated at 44°C at the tumour border for 30 minutes, hepatic inflow occlusion only, or a combination of these methods. Interstitial laser Doppler flowmetry was used to measure hepatic perfusion at the tumour border during and after heat treatment, for a total time of 60 minutes. Tumour growth was evaluated 6 days after treatment. RESULTS: Tumours subjected to the combined treatment of hepatic inflow occlusion and interstitial laser thermotherapy displayed a blood perfusion reduction 30 minutes after treatment to 18 ± 5% of initial perfusion, which was significantly lower than achieved with thermotherapy alone (52 ± 10%, P = 0.02). The combined treatment and treatment with thermotherapy alone resulted in relative tumour growth of 0.3 ± 0.1 and 1.0 ± 0.2, respectively (P = 0.04). CONCLUSION: Inflow occlusion enhanced the effect of thermotherapy not by augmenting treatment temperatures but by increasing the thermal sensitivity of the tumour, reflected by an immediate effect on tumour blood perfusion.

Intraoperative radiotherapy for patients with carcinoma of the pancreas.

BACKGROUND/AIMS: Local recurrence is one of the most common sites of failure after resection of exocrine pancreatic adenocarcinoma. Intraoperative radiotherapy (IORT) involves delivery of high doses of irradiation to the pancreas in patients with locally advanced disease, and to the surgical bed following pancreatic resection while uninvolved and dose-limiting tissues are displaced. Here we report our current experience with IORT in patients with pancreatic cancer. METHODS: IORT was given as adjuvant treatment in 18 and palliatively in 37 patients. External beam radiotherapy (EBRT) was in addition delivered to 10 patients in the resection group and 29 in the palliation group. The cancer diagnosis was verified histologically and/or cytologically in all patients. RESULTS: There was no hospital mortality. Among the resected patients the postoperative complication rate was 44% (8/18). The corresponding figure after palliative operation was 14% (5/37). None of the postoperative complications were regarded as a consequence of IORT. Symptoms and complaints were observed after EBRT in 70 and 90%, respectively, in the two groups. However, no symptom was serious in nature. After resection the median survival time was 9 months (range 3-58) and local recurrence was diagnosed in 33% (6/18). In the palliatively treated patients the median survival was 7 months (range 2-30) and pain requiring opioids was present in 89% (24/27) of the patients within 6 months. CONCLUSION: In this nonrandomized study no apparent beneficial effects were seen after IORT in patients with pancreatic cancer, neither adjuvantly nor palliatively. However, radiotherapy did not lead to any major complications.

Heat shock protein 70 (HSP70) after laser thermotherapy of an adenocarcinoma transplanted into rat liver.

The heat shock proteins (HSPs) HSP70 and gp96 from necrotic tumour cells are considered to function as chaperones in presenting tumour antigens. We therefore studied HSP70 and immune cells in a transplantable carcinoma in the liver of rats after interstitial laser thermotherapy (ILT). Experiments were performed in Wistar FU rats using a dimethyl-hydrazine-induced adenocarcinoma implanted into the left lateral lobe of the liver. Rats were randomized to one of the following groups: a) ILT of tumour, b) sham ILT, or c) control. ILT was suboptimal and was performed at a steady-state temperature of 43 degrees C at the tumour margin for 30 minutes. Rats were killed 15 minutes, 5 hours, 10 hours, 15 hours or 12 days after treatment. Double immunohistochemistry was performed for HSP70 and ED1 macrophages or CD8 lymphocytes, and ELISA for serum concentrations of HSP70. After ILT, there was an increase of HSP70 immunoreactivity in tumours as compared to sham ILT. At the same time, tumour cells affected by ILT showed a shift of HSP70 from the cytoplasm to the nucleus with a peak at 10 hours. Few CD8-positive cells were found. There was an increase of tumour-infiltrating ED1 macrophages after ILT as compared to sham ILT at 10-15 hours after treatment. HSP70 was present in ED1 macrophages significantly more frequently after ILT than after sham ILT, and this was true both for HSP70 localized to the surface and the cytoplasm of the macrophage. There was a significant increase in serum HSP70 during the first 15 hours after ILT. In conclusion, laser thermotherapy resulted in increased HSP70 immunoreactivity within tumours and HSP70 shifts from cytoplasm to nucleus. Furthermore, it resulted in increased numbers of tumour-infiltrating macrophages and an increased presence of HSP70 in the membrane and cytoplasm of these macrophages.

Linomide improves the effect of interstitial laser thermotherapy in a rat liver tumour model.

AIM: The aim of this study was to investigate if Linomide affects growth and spread of a rat liver tumour when given alone and in combination with interstitial laser thermotherapy (ILT). MATERIALS AND METHODS: Experiments were performed in Wistar rats using a dimethyl-hydrazine-induced adenocarcinoma implanted into the left lateral lobe of the liver. The rats were randomised to one of the following groups: a) ILT and Linomide, b) ILT only, c) sham ILT, d) Linomide only, or e) control. ILT was intentionally suboptimal. Linomide (100 mg/kg/day) was given in the drinking water from the start of treatment for five days. ED1, ED2 macrophages and v Willebrand (factor VIII) were determined by an immunohistochemical technique. RESULTS: Linomide reduced viable liver tumour volume both when it was given alone (p < 0.01) and when combined with ILT (p < 0.05), whereas it lowered intraperitoneal spread in ILT-treated rats alone. Six days after ILT, there was a reduction in the number of newly-recruited macrophages and blood vessels in the viable tumour tissue in rats receiving Linomide. CONCLUSION: Linomide reduced the growth of an adenocarcinoma transplanted into rat liver, when given alone or combined with laser thermotherapy and reduced the spread of tumour in laser-treated rats. The effects of Linomide in laser-treated rats appeared, at least in part, to be due to a reduction in newly-formed vessels, which might have been secondary to a reduced number of tumour-associated macrophages.

Extended operation with or without intraoperative (IORT) and external (EBRT) radiotherapy for gallbladder carcinoma.

BACKGROUND/AIMS: Gallbladder carcinoma is a rare disease with dismal prognosis. However, lately improved survival has been reported after extended operation including liver resection and lymphadenectomy in addition to cholecystectomy. The aim of this study was to evaluate such a surgical strategy with and without adjuvant intra- and postoperative radiotherapy (IORT/EBRT). METHODOLOGY: 20 patients underwent extended operation and the last 10 of them IORT/EBRT in addition. Tumor staging was done using the TNM system, determination of histological tumor differentiation and immunohistochemical assessment of p53, Ki67, metallothionein, deleted in colorectal cancer and carcinoembryogenic antigen in tumor tissue. RESULTS: There was no hospital mortality. Postoperative complications occurred in 3 patients (15%). Actuarial 5-year survival was 47% in the radiotherapy group and 13% after operation only (NS). The corresponding figures for median survival are 28.8 and 20.2 months, respectively. Five patients are still alive in the radiotherapy group. There was no difference in tumour stages of the two groups irrespective of the way of evaluation. CONCLUSIONS: The results suggest that extended operation for gallbladder carcinoma +/- IORT/EBRT can be done safely. The tendency to longer survival after adjuvant radiotherapy was not statistically significant.

[Guidelines for management of patients with pancreatic cancer]. / Riktlinjer för handläggning av patienter med pankreascancer.

The incidence of pancreatic cancer has fallen during the last ten years in Sweden. Early signs and symptoms of the disease are still undiscovered and when diagnosis is made the disease is incurable in most patients. Transabdominal ultrasonography is the first-line imaging test followed by spiral computed tomography (CT) and magnetic resonance imaging (MRI) if required for definite diagnosis. Spiral CT is also the imaging test of choice for assessment of resectability of the tumor. Surgical removal of the tumor is the only chance of cure. Markedly improved hospital mortality after pancreaticoduodenectomy is reported and an association between hospital volume and outcome of the operation has been established. Longterm survival after attempted curative resection continues to be dismal, however. Adjuvant treatment should not be given outside clinical studies. Palliative treatment has improved thanks to progress in the field of endoscopy, interventional radiology and in management of pain and nutrition. Palliative chemotherapy should only be given selectively outside clinical studies. Radiotherapy has no proven effects on survival. Special pancreatic cancer treatment teams with catchment areas of 2-4 million inhabitants are recommended by international authorities.