Mauri Kouri

Oncolytic Adenovirus Coding for Granulocyte Macrophage Colony-Stimulating Factor Induces Antitumoral Immunity in Cancer Patients

Granulocyte macrophage colony-stimulating factor (GMCSF) can mediate antitumor effects by recruiting natural killer cells and by induction of tumor-specific cytotoxic T-cells through antigen-presenting cells. Oncolytic tumor cell-killing can produce a potent costimulatory danger signal and release of tumor epitopes for antigen-presenting cell sampling. Therefore, an oncolytic adenovirus coding for GMCSF was engineered and shown to induce tumor-specific immunity in an immunocompetent syngeneic hamster model. Subsequently, 20 patients with advanced solid tumors refractory to standard therapies were treated with Ad5-D24-GMCSF. Of the 16 radiologically evaluable patients, 2 had complete responses, 1 had a minor response, and 5 had disease stabilization. Responses were frequently seen in injected and noninjected tumors. Treatment was well tolerated and resulted in the induction of both tumor-specific and virus-specific immunity as measured by ELISPOT and pentamer analysis. This is the first time that oncolytic virus-mediated antitumor immunity has been shown in humans. Ad5-D24-GMCSF is promising for further clinical testing.

Boron Neutron Capture Therapy in the Treatment of Locally Recurred Head-and-Neck Cancer: Final Analysis of a Phase I/II Trial

PURPOSE To investigate the efficacy and safety of boron neutron capture therapy (BNCT) in the treatment of inoperable head-and-neck cancers that recur locally after conventional photon radiation therapy. METHODS AND MATERIALS In this prospective, single-center Phase I/II study, 30 patients with inoperable, locally recurred head-and-neck cancer (29 carcinomas and 1 sarcoma) were treated with BNCT. Prior treatments consisted of surgery and conventionally fractionated photon irradiation to a cumulative dose of 50 to 98 Gy administered with or without concomitant chemotherapy. Tumor responses were assessed by use of the RECIST (Response Evaluation Criteria in Solid Tumors) and adverse effects by use of the National Cancer Institute common terminology criteria version 3.0. Intravenously administered L-boronophenylalanine-fructose (400 mg/kg) was administered as the boron carrier. Each patient was scheduled to be treated twice with BNCT. RESULTS Twenty-six patients received BNCT twice; four were treated once. Of the 29 evaluable patients, 22 (76%) responded to BNCT, 6 (21%) had tumor growth stabilization for 5.1 and 20.3 months, and 1 (3%) progressed. The median progression-free survival time was 7.5 months (95% confidence interval, 5.4-9.6 months). Two-year progression-free survival and overall survival were 20% and 30%, respectively, and 27% of the patients survived for 2 years without locoregional recurrence. The most common acute Grade 3 adverse effects were mucositis (54% of patients), oral pain (54%), and fatigue (32%). Three patients were diagnosed with osteoradionecrosis (each Grade 3) and one patient with soft-tissue necrosis (Grade 4). Late Grade 3 xerostomia was present in 3 of the 15 evaluable patients (20%). CONCLUSIONS Most patients who have inoperable, locally advanced head-and-neck carcinoma that has recurred at a previously irradiated site respond to boronophenylalanine-mediated BNCT, but cancer recurrence after BNCT remains frequent. Toxicity was acceptable. Further research on novel modifications of the method is warranted.

Diploid predominance in hereditary nonpolyposis colorectal carcinoma evaluated by flow cytometry

Fifty‐nine colorectal carcinomas of patients with verified cancer family syndrome (CFS) were analyzed for DNA ploidy using flow cytometry. Sixty‐eight percent of the tumors were diploid, and 32% were aneuploid. The aneuploid tumors had a median DNA index of 1.24 (range, 1.12–1.97). In 90% of all tumors the DNA index was less than 1.27. This predominance of diploid/near‐diploid tumors was seen both in primary and in metachronous carcinomas. In 21 cases a cell cycle analysis was possible. Tumors with the S‐phase fraction (SPF) ± 9.8% had a worse prognosis than tumors with the SPF of <9.8%. These findings suggest that the predominance of diploid/near diploid DNA values is one of the characteristics of colorectal carcinomas in CFS. This might signify the existence of two or more pathogenetically different subgroups of colorectal carcinoma and explain the proposed better prognosis of colorectal carcinoma in CFS compared with other colorectal carcinomas.

Comparison of granulocyte-macrophage colony-stimulating factor and sucralfate mouthwashes in the prevention of radiation-induced mucositis: a double-blind prospective randomized phase III study

PURPOSE To compare granulocyte-macrophage colony-stimulating factor (GM-CSF) mouthwashes with sucralfate mouthwashes in the prevention of radiation-induced mucositis. METHODS AND MATERIALS Forty patients with radically operated head-and-neck cancer were randomly allocated to use either GM-CSF (n = 21) or sucralfate (n = 19) mouthwashes during postoperative radiotherapy (RT). All patients received conventionally fractionated RT to a total dose of 50-60 Gy in 2-Gy daily fractions during 5-6 weeks to the primary site and regional lymphatics. A minimum of 50% of the oral cavity and oropharyngeal mucosa was included in the clinical target volume. GM-CSF mouthwashes consisted of 37.5 microg GM-CSF and sucralfate mouthwashes of 1.0 g of sucralfate distilled in water. Both washes were used 4 times daily, beginning after the first week of RT and continued to the end of the RT course. Symptoms related to radiation mucositis and body weight, serum prealbumin level, and blood cell counts were monitored weekly. RESULTS Oral mucositis tended to be less severe in the GM-CSF group (p = 0.072). Complete (n = 1) or partial (n = 4) healing of mucositis occurred during the RT course in 5 patients (24%) in the GM-CSF group and in none of the patients in the sucralfate group (p = 0.049). Patients who received GM-CSF had less mucosal pain (p = 0.058) and were less often prescribed opioids for pain (p = 0.042). Three patients in the sucralfate group needed hospitalization for mucositis during RT compared with none in the GM-CSF group. Four patients (21%) in the sucralfate group and none in the GM-CSF group required an interruption in the RT course (p = 0.042). No significant differences in weight, prealbumin level, or blood cell count were found between the groups, and both mouthwashes were well tolerated. CONCLUSION GM-CSF mouthwashes may be moderately more effective than sucralfate mouthwashes in preventing radiation-induced mucositis and mucositis-related pain, and their use may lead to less frequent RT course interruptions from mucositis. The present findings need to be confirmed before adopting GM-CSF mouthwashes in routine clinical use.

The prognostic value of DNA-ploidy in colorectal carcinoma: a prospective study

One hundred and fifty-seven patients with usual colorectal cancer were analysed prospectively for DNA-ploidy, DNA-index and S-phase fraction (SPF) using flow cytometry. An abnormal DNA-stemline was observed in 68% of tumours. The patients have been followed for a median of 36 months. In univariate analysis, tumour stage was the most significant prognostic factor. After excluding patients with stage D disease, DNA-aneuploidy was significantly associated with a shorter survival and a shorter disease free survival. SPF, however, did not correlate with prognosis. In multiple samples from the same tumour there was on average a 29% difference between the highest and the lowest SPF indicating considerable heterogeneity in proliferative activity within the tumours. In diploid tumours the variation was even higher. Patients with proximal tumours as well as female patients had DNA-diploid tumours more often than the others. This may indicate that there are different, so far unknown, aetiological factors leading to different types of ploidy pattern.

Scintigraphy in prediction of the salivary gland function after gland-sparing intensity modulated radiation therapy for head and neck cancer

BACKGROUND AND PURPOSE To evaluate salivary gland scintigraphy in prediction of salivary flow following radiation therapy. PATIENTS AND METHODS Twenty patients diagnosed with head and neck cancer were treated with intensity modulated radiation therapy with an intention to spare the salivary gland function. The total quantitative saliva secretion was measured prior to and 6 and 12 months after therapy, and the function of the major salivary glands was monitored using Tc-99m-pertechnetate scintigraphy. Two models were designed for prediction of the post-treatment salivary flow: an average model, based on the average proportions of saliva produced by each of the four major glands in healthy subjects, and an individual model, based on saliva produced by each gland as measured by scintigraphy prior to therapy. These models were compared with volume-based (Lyman) normal tissue complication probability models using two published sets of model parameters. RESULTS The D(50) for the parotid and the submandibular gland function assessed at 6 and 12 months after radiotherapy was approximately 39Gy. The scintigraphy-based individual model predicted well the measured post-treatment saliva flow rates. The correlation coefficient between the predicted stimulated and the measured saliva flow rate was 0.77 (p<0.0001) at 6 months and 0.55 (p=0.034) at 12 months after completion of radiotherapy. The relative changes in unstimulated and stimulated salivary flow rates showed similar dependency on the cumulative radiation dose. CONCLUSIONS Salivary gland function assessed by scintigraphy prior to radiotherapy is useful in prediction of the residual salivary flow after radiotherapy.

Outcome of fractionated stereotactic radiotherapy in patients with pituitary adenomas resistant to conventional treatments: a 5·25‐year follow‐up study

Objective  To investigate the long‐term outcome of fractionated stereotactic radiotherapy (FSRT) [45 Gy (range 45–54) in 25 fractions] in patients with pituitary adenomas characterized by tumour progression or hormonally active disease despite surgery and/or medical therapy.

Stereotactic radiotherapy of symptomatic circumscribed choroidal hemangiomas

PURPOSE To determine feasibility of low-dose stereotactic radiotherapy in the treatment of symptomatic circumscribed choroidal hemangioma. DESIGN Prospective, noncomparative, interventional case series. PARTICIPANTS Five consecutive patients with perifoveolar and peripapillary circumscribed choroidal hemangioma and visual symptoms from exudative retinal detachment. METHODS A dose of 20 Gy was delivered stereotactically with linear accelerator. Tumor dimensions were determined by B-scan ultrasonography. MAIN OUTCOME MEASURES Resolution of subretinal fluid, best-corrected visual acuity, and reduction in tumor height. RESULTS Median tumor height at baseline was 2.8 mm (range, 2.0-4.2 mm). Two tumors were subfoveolar, two were juxtafoveolar, and one was extrafoveolar. Cystic macular edema and subretinal fibrosis were present in both eyes with subfoveolar tumor. Exudative retinal detachment resolved within a median of 5 months (response rate, 100%; 95% CI, 48%-100%). Median best-corrected visual acuity was 20/50 (range, 20/22-20/100) at diagnosis and 20/25 (range, 20/20-20/60) 20 months after treatment. Tumor height had decreased a median of 24% (range, 0%-31%) by 6 months and 29% (range, 9%-59%) by 20 months. Secondary retinal pigment epithelial mottling associated with tumor regression occurred in two patients. One eye developed a paracentral scotoma. CONCLUSIONS Stereotactic radiotherapy can be targeted precisely enough to induce regression of subretinal fluid from circumscribed choroidal hemangiomas.

A Phase I/II Trial of Gefitinib Given Concurrently With Radiotherapy in Patients With Nonmetastatic Prostate Cancer

PURPOSE To estimate the safety and tolerability of daily administration of 250 mg of gefitinib given concurrently with three-dimensional conformal radiotherapy for patients with nonmetastatic prostate cancer. METHODS AND MATERIALS A total of 42 patients with T2-T3N0M0 tumors were treated in a nonrandomized single-center study. A prostate-specific antigen (PSA) level of <20 and a good performance status (WHO, 0-1) were required. Adjuvant or neoadjuvant hormone treatments were not allowed. A daily regimen of 250 mg of gefitinib was started 1 week before radiation therapy began and lasted for the duration of radiation therapy. A dose of 50.4 Gy (1.8 Gy/day) was administered to the tumor, prostate, and seminal vesicles, followed by a 22-Gy booster (2 Gy/day) for a total dose of 72.4 Gy. Correlative studies included analysis of epidermal growth factor receptor (EGFR), EGFRvIII, and phosphorylated EGFR in tumors and tumor necrosis factor, interleukin-1alpha (IL-1alpha), and IL-6 in serum. RESULTS Maximum tolerated dose was not reached in phase I (12 patients), and 30 additional patients were treated in phase II. Thirty (71.4%) patients completed trial medication. Dose-limiting toxicities were recorded for 16 (38.1%) patients, the most common of which was a grade 3 to 4 increase in transaminase (6 patients). After a median follow-up of 38 months, there were no deaths due to prostate cancer. The estimated PSA relapse-free survival rate at 4 years (Kaplan-Meier) was 97%, the salvage therapy-free survival rate was 91%, and the overall survival rate was 87%. These figures compared favorably with those of matched patients treated with radiation only at higher doses. CONCLUSIONS The combination of gefitinib and radiation is reasonably well tolerated and has promising activity against nonmetastatic prostate cancer.

Boron detection from blood samples by ICP-AES and ICP-MS during boron neutron capture therapy.

Objective. The concept of boron neutron capture therapy (BNCT) involves infusion of a 10B containing tracer into the patients bloodstream followed by local neutron irradiation(s). Accurate estimation of the blood boron level for the treatment field before irradiation is required. Boron concentration can be quantified by inductively coupled plasma atomic emission spectrometry (ICP‐AES), mass spectrometry (ICP‐MS), spectrofluorometric and direct current atomic emission spectrometry (DCP‐AES) or by prompt gamma photon detection methods. Material and methods. The blood boron concentrations were analysed and compared using ICP‐AES and ICP‐MS to ensure congruency of the results if the analysis had to be changed during the treatment, e.g. for technical reasons. The effect of wet‐ashing on the results was studied in addition. Results. The mean of all samples analysed with ICP‐MS was 5.8 % lower than with ICP‐AES coupled to wet‐ashing (R2 = 0.88). Without wet‐ashing, the mean of all samples analysed with ICP‐MS was 9.1 % higher than with ICP‐AES (R2 = 0.99). Conclusions. Boron concentration analysed from whole blood samples with ICP‐AES correlated well with the values of ICP‐MS with wet‐ashing of the sample matrix, which is generally considered the reference method. When using these methods in parallel at certain intervals during the treatments, reliability of the blood boron concentration values remains satisfactory, taking into account the required accuracy of dose determination in the irradiation of cancer patients.