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PurposeTo evaluate the results of 15 years of experience with proton beam radiotherapy in the treatment of intraocular melanoma, and to determine univariate and multivariate risk factors for local failure, eye retention, and survival.MethodsA total of 368 cases of intraocular melanoma were treated with proton beam radiotherapy at Centre Lacassagne Cyclotron Biomedical of Nice, France, between 1991 and 2006. Actuarial methods were used to evaluate rate of local tumor control, eye retention, and survival after proton beam radiotherapy. Cox regression models were extracted to evaluate univariate risk factors, while regularized least squares algorithm was used to have a multivariate classification model to better discriminate risk factors.ResultsTumor relapse occurred in 8.4% of the eyes, with a median recurrence time of 46 months. Enucleation was performed on 11.7% of the eyes after a median time of 49 months following proton beam; out of these, 29 eyes were enucleated due to relapse and 16 due to other causes. The univariate regression analysis identified tumor height and diameter as primary risk factors for enucleation. Regularized least squares analysis demonstrated the higher effectiveness of a multivariate model of five risk factors (macula distance, optic disc distance, tumor height, maximum diameter, and age) in discriminating relapsed vs nonrelapsed patients.ConclusionsThis data set, which is the largest in Italy with relatively long-term follow-up, demonstrates that a high rate of tumor control, survival, and eye retention were achieved after proton beam irradiation, as in other series.

Bei grosflachiger, diffuser oder multilokularer Ausdehnung des Bindehautmelanoms kann die Protonenbestrahlung bei bestimmten Indikationen eine mogliche Alternative zur Exenteratio darstellen. Bei ausgedehnten Tumoren kann es in der Folge zu Problemen der Augenoberflache und der Tranenproduktion kommen. In dieser Studie untersuchten wir die Beschaffenheit der Augenoberflache von 10 Patienten, die zwischen 1996 und 2002 mit Protonen behandelt worden waren. Die Patienten wurden im Rahmen der Nachbeobachtung untersucht. Dabei waren 8 der 10 durch Protonenbestrahlung behandelten Falle Melanomrezidive, die zuvor bereits adjuvant vorbehandelt worden waren. Neben der ophthalmologischen Grunduntersuchung wurde eine ausfuhrliche Tranenfilmdiagnostik und Analyse der okularen Oberflache durchgefuhrt. Der Nachbeobachtungszeitraum betrug 17 bis 87 Monate (Mittel 40,9±20,1). Bei 6 Patienten wurden mehr als 50% des Ober- und Unterlids in das Strahlenfeld eingeschlossen. Bei diesen lag in allen Fallen eine mittlere bis schwere Sicca-Symptomatik vor. Die Impressionszytologie der Bindehaut zeigte eine squamose Metaplasie in 9 von 10 Fallen. Die squamose Metaplasie der konjunktivalen Epithelien deutet auf eine radiogene, dauerhafte Differenzierungsstorung der konjunktivalen Zellverbande hin. Die Tranenfilminstabilitat korreliert mit dem Verlust von muzinbildenden Becherzellen und der Atrophie von Meibom’schen Drusen.

Unresectable carcinomas of the oropharynx and hypopharynx still have a poor long-term prognosis. Following a previous phase II study, this phase III multicenter trial was conducted between November 1997 and March 2002.Nontreated, strictly unresectable cases were eligible. Twice-daily radiation: two fractions of 1.2 Gy/day, 5 days per week, with no split (D1--D46). Total tumor doses: 80.4 Gy/46 day (oropharynx), 75.6 Gy/44 day (hypopharynx). Chemotherapy (arm B): Cisplatin 100 mg/m2 (D1, D22, D43); 5FU, continuous infusion (D1--D5), 750 mg/m2/day cycle 1; 430 mg/m2/day cycles 2 and 3.A total of 163 evaluable patients. Grade 3-4 acute mucositis 82.6% arm B/69.5% arm A (NS); Grade 3-4 neutropenia 33.3% arm B/2.4% arm A (p0.05). Enteral nutrition through gastrostomy tube was more frequent in arm B before treatment and at 6 months (p0.01). At 24 months, overall survival (OS), disease-free survival (DFS), and specific survival (SS) were significantly better in arm B. OS: 37.8% arm B vs. 20.1% arm A (p = 0.038); DFS: 48.2% vs. 25.2% (p = 0.002); SS: 44.5% vs. 30.2% (p = 0.021). No significant difference between the two arms in the amount of side effects at 1 and 2 years.For these unresectable cases, chemoradiation provides better outcome than radiation alone, even with an "aggressive" dose-intensity radiotherapy schedule.

Purpose: A total of 69 families affected by uveal melanoma have been reported in the literature. This report describes two additional families. In addition to presenting these cases, which constitute exceptions, the paper reviews the literature. Material and Methods: Two families, each with two affected members, were analysed in this retrospective study. The pedigree of each family has been pieced together. Results: Considering the low incidence of familial uveal melanoma in the general population, it seems unlikely that inherited genetic factors are responsible for the condition; this question remains difficult to resolve. Discussion: The characteristics of each family history are described and compared with the literature data. The mode of possible inheritance is discussed. Both the histopathology and anatomical location are studied, after which we discuss the body of evidence to establish whether there is an inherited cancer predisposition syndrome in patients with familial uveal melanoma. Conclusion: The statistical likelihood of such an uncommon tumour occurring independently in two or more family members leads us to believe that some cases of familial uveal melanoma may go unrecognized, and that reports on too few families have been published worldwide to prove the existence of a single mendelien gene. However, appropriate tissue samples, such as blood and tumour samples, should be obtained and conserved for present or future cytogenetic and molecular genetic studies.

The aim of the present study was to check whether platinum (Pt) concentrations achieved in tumors with a daily low-dose schedule were close to those promoting radiosensitization. Fifteen previously untreated patients with histologically proven advanced uterine cervix tumors were studied. They received a daily irradiation 30 min after a short infusion of 5 mg cisplatin for 5 consecutive days every week. A biopsy was taken from the accessible tumor mass, 4 to 6 hr after the daily injection. Blood samples were obtained once a week, just before the daily injection (H0) and 30 min after (H30). Quantificative analysis of Pt concentrations was performed by atomic absorption spectrophotometry. Plasma and tumoral Pt concentrations exhibited a marked intersubject variability. The median tumoral Pt concentration was 1,710 mg/g. Median total and ultrafiltrable Pt concentrations in plasma taken at H0 and H30 were 231 and 360 ng/ml, and 7 and 90 ng/ml respectively. Tumoral and total plasma Pt concentrations significantly increased during the course of treatment. Present data show that tumoral Pt concentrations achieved with this CDDP schedule are in the range of tumoral Pt concentrations previously shown to promote radiosensitization (2,000 ng/g). These results suggest that this CDDP radiosensitization regimen might be started with higher CDDP doses in order to reach earlier radiosensitizing Pt tumoral concentrations.

In an effort to clarify the relationship between sensitivity of human tumour cells to low-LET and to fast neutron irradiation, 10 human tumour cell lines were exposed to cobalt gamma-rays and to 60 MeV (p -Be+) neutron beam. The data were pooled with results of 31 human tumour cell lines previously published. The analysis of date using the linear-quadratic model indicated that not only alpha values increased after neutron irradiation, but so did beta values too, although to a lesser extent. The mean inactivation dose (MID) was derived for each cell line from the linear-quadratic parameters after low-LET and high-LET exposure. MID values following neutron irradiation were closely correlated to those after gamma-ray irradiation. In these 41 cell lines, the extreme values of RBE derived by the ratio of MID varied by a factor of 3 among the cell lines. RBE was positively correlated to photon MID, meaning that intrinsically radiation resistant tumour cells have a higher neutron RBE, on average. Similar findings were observed if alpha ratios were used instead of MID ratios. In addition, the RBE/dose variations were more marked in cells with the higher RBE. Taken together, these data suggest that, although considerable variations exist among human tumour cell lines, intrinsically radioresistant cells are relatively more sensitized when exposed to high LET beams than radioresponsive tumours. An 'intrinsic gain factor' may thus be expected in irradiating radiation resistant tumours with fast neutrons, in addition to the hypoxic or kinetic gain factors. Because the quadratic component is still present after neutron irradiation, we suggest using MID ratio as a reference RBE when comparing survival curves of cells exposed to radiations of different qualities.

Little is known about the action of charged particles of very high linear energy transfer (LET) on human cells and, in particular, the relationship between DNA damage and reproductive death. The aim of this study was to measure the biological efficiency of a low-energy argon beam (E = 7.1 MeV/nucleon, LET = 1590 keV/micron) produced at GSI, Darmstadt, on a human melanoma cell line (CAL4) established in our Institute. Two different methods were used: the micronucleus (MN) test and the colony-forming assay. The MN test, using the cytochalasin-block method, is a measure of genotoxic damage. MN are scored in binucleate cells (BNC) and are formed from acentric fragments or whole chromosomes that have not been incorporated into daughter nuclei at mitosis. The colony-forming assay quantifies reproductive death. Parallel experiments were run with cobalt gamma-rays for comparison. After Co irradiation, the MN-free BNC dose-response curve coincided with that of the loss of colony-forming ability, suggesting the potential of the former as a predictive test of cell killing. After Ar irradiation, there was a dissociation between the two effects, especially at high doses: cell death was greater than the frequency of BNC with MN. The inactivation cross-section was 74 microns2; it was 39 microns2 for MN yield. Therefore, the relative biological effectiveness (RBE) was higher for cell killing than for MN yield (0.8 and 0.5, respectively at a Co dose of 3 Gy). The total MN count in BNC followed the same pattern of response as the fraction of BNC with MN.(ABSTRACT TRUNCATED AT 250 WORDS)

From September 1983 to September 1987, 238 patients with squamous cell carcinoma of the upper aerodigestive tract were given 3 cycles of chemotherapy [cisplatinum (cis-DDP), 100 mg/m2 on day 1; 5-fluorouracil (5-FU), 1,000 mg/m2 on days 2-6] before any local treatment. Eighty-one of these patients had pharyngolaryngeal cancer. Of the 45 of 50 laryngeal cancers and 26 of 31 hypopharyngeal cancers suitable for evaluation, complete responses (CR) were obtained in 51.1% and 53.8%, respectively. These response rates led to changes in the postchemotherapy protocols. For CRs, mutilating surgical protocols were replaced by definitive radiotherapy: one local recurrence has been observed among the 9 laryngeal cancers, and 3 of 10 hypopharyngeal cancer patients, who had an initial indication of total laryngectomy or total pharyngolaryngectomy replaced by radiotherapy. In the group of CR, survival rates at 2 years were 93% and 69%, respectively, for the larynx and hypopharynx vs 65.6% and 40% for non-CR patients. The possibility of conservative treatment sparing vocal function with a high degree of reliability would in itself appear to be justification for induction chemotherapy in pharyngolaryngeal cancers, even though its long-term effects remain controversial.

A total of 69 families affected by uveal melanoma have been reported in the literature. This report describes two additional families. In addition to presenting these cases, which constitute exceptions, the paper reviews the literature.Two families, each with two affected members, were analysed in this retrospective study. The pedigree of each family has been pieced together.Considering the low incidence of familial uveal melanoma in the general population, it seems unlikely that inherited genetic factors are responsible for the condition; this question remains difficult to resolve.The characteristics of each family history are described and compared with the literature data. The mode of possible inheritance is discussed. Both the histopathology and anatomical location are studied, after which we discuss the body of evidence to establish whether there is an inherited cancer predisposition syndrome in patients with familial uveal melanoma.The statistical likelihood of such an uncommon tumour occurring independently in two or more family members leads us to believe that some cases of familial uveal melanoma may go unrecognized, and that reports on too few families have been published worldwide to prove the existence of a single mendelien gene. However, appropriate tissue samples, such as blood and tumour samples, should be obtained and conserved for present or future cytogenetic and molecular genetic studies.

Use of the low-energy helium-neon laser (LEL) appears to be a simple atraumatic technique for the prevention and treatment of mucositis of various origins. Preliminary findings, and significant results obtained for chemotherapy-induced mucositis in a previous phase III study, prompted a randomized multicenter double-blind trial to evaluate LEL in the prevention of acute radiation-induced stomatitis. Irradiation by LEL corresponds to local application of a high-photon-density monochromatic light source. Activation of epithelial healing for LEL-treated surfaces, the most commonly recognized effect, has been confirmed by numerous in vitro studies. The mechanism of action at a molecular and enzymatic level is presently being studied. From September 1994 to March 1998, 30 patients were randomized. Technical specification: 60 mW (25 mW at Reims, 1 patient), He-Ne, wavelength 632.8 nm. The trial was open to patients with carcinoma of the oropharynx, hypopharynx and oral cavity, treated by radiotherapy alone (65 Gy at a rate of 2 Gy/fraction, 5 fractions per week) without prior surgery or concomitant chemotherapy. The malignant tumor had to be located outside the tested laser application areas (9 points): posterior third of the internal surfaces of the cheeks, soft palate and anterior tonsillar pillars. Patients were randomized to LEL or placebo light treatment, starting on the first day of radiotherapy and before each session. The treatment time (t) for each application point was given by the equation : t (s)=energy (J/cm2)×surface (cm2)/Power (W). Objective assessment of the degree of mucositis was recorded weekly by a physician blinded to the type of treatment, using the WHO scale for grading of mucositis and a segmented visual analogue scale for pain evaluation. Protocol feasibility and compliance were excellent. Grade 3 mucositis occured with a frequency of 35.2% without LEL and of 7.6% with LEL (P