Efficacy and tolerability of medical ozone gas insufflations in patients with osteonecrosis of the jaw treated with bisphosphonates-Preliminary data: Medical ozone gas insufflation in treating ONJ lesions.

Osteonecrosis of the Jaw (ONJ) is an adverse event reported especially in patients receiving cancer treatments regimen, bisphosphonates (BPs), and denosumab. We performed an open-label, prospective study in patients treated with zoledronic acid who developed ONJ lesions >2.5 cm, and had no benefit after the treatment with the standard therapy, to evaluate the efficacy and tolerability of medical ozone (O3) treatment delivered as gas insufflations on each ONJ lesions. Twenty-four patients (mean age 62.5, range 41-80; 12 female) with bone metastases due to breast (11), prostate (4)and lung (4)cancers, myeloma (2), or osteoporosis (3), previously treated with zoledronic acid and not underwent dental preventive measures and with ONJ lesions >2.5 cm, were observed and treated with topical O3 gas insufflation every third day for a minimum of 10 for each pathological area or till necrotic bone sequestrum or surgery. We used a special insufflation bell-shaped device adjusted to the specific characteristics of the patient, capable of eliminating any residue of O3 diffusion by degrading it and releasing O2 into the air. Azithromicin 500 mg/day was administered for 10 days in all patients before the first three gas insufflation although they had previously received various cycles of antibiotics. Ten patients required more than 10 O3 gas insufflations due to multiple lesions and/or purulent sovrainfections; one patient received two further O3 insufflations while waiting the day of surgery. Six of 24 patients interrupted the O3 gas therapy for oncological disease progression (five patients) and for fear of an experimental therapy (one patient). Six patients had the sequestrum and complete or partial (one patient) spontaneous expulsion of the necrotic bone followed by oral mucosa re-epithelization after a range of 4-27 of O3 gas insufflations. No patient reported adverse events. In 12 patients with the largest and deeper ONJ lesions, O3 gas therapy produced the sequestrum of the necrotic bone after 10 to 38 insufflations; surgery was necessary to remove it (11 patients). Of interest, removal was possible without the resection of healthy mandible edge because of the presence of bone sequestrum. All together the response rate was 75.0% (95% CI, 53.3-90.2%) in ITT analysis and 100% (95% CI, 81.5-100%) in the PP analysis. In all patients treated with O3 gas ± surgery, no ONJ relapse appeared (follow-up mean 18 months, range 1-3 years). Medical O3 gas insufflations is an effective and safe treatment for patients treated with BPs who developed ONJ lesions >2.5 cm. Short abstract: ONJ is an adverse event reported in patients receiving cancer treatments regimen, bisphosphonates and denosumab. We performed an open-label, prospective study in 24 patients with solid tumours, myeloma or osteoporosis due to hormonal therapy, treated with zoledronic acid without previuos preventive dental screening, who developed ONJ lesions >2.5 cm, and had no benefit after standard therapy, to evaluate the efficacy and tolerability of medical ozone (O3) treatment delivered as gas insufflations on each ONJ lesions. The patients were treated with O3 every third day for a minimum of 10 for each pathological area or till necrotic bone sequestrum or surgery. Eleven patients required more than ten O3 gas insufflations. Six of 24 patients interrupted the therapy for oncological disease progression. Six patients had the sequestrum and complete or partial (one patient) spontaneous expulsion of the necrotic bone followed by oral mucosa re-epithelization after a range of 4 to 27 of O3 gas insufflations. No patient reported adverse events. In 12 patients with the largest and deeper ONJ lesions, O3 gas therapy produced the sequestrum of the necrotic bone after 10 to 38 insufflations; surgery was necessary to remove it (11 patients). Of interest, removal was possible without the resection of healthy mandible edge because of the presence of bone sequestrum. All together the response rate was 75.0% (95% CI, 53.3-90.2%) in ITT analysis and 100% (95% CI, 81.5-100%) in the PP analysis. In all patients treated with O3 gas ± surgery, no ONJ relapse appeared (follow-up mean 18 months, range 1-3 years).

Decreased occurrence of osteonecrosis of the jaw after implementation of dental preventive measures in solid tumour patients with bone metastases treated with bisphosphonates. The experience of the National Cancer Institute of Milan.

BACKGROUND: Screening of the oral cavity and dental care was suggested as mandatory preventive measures of osteonecrosis of the jaw (ONJ) in patients receiving bisphosphonates (BPs). We investigated the occurrence of ONJ before and after implementation of dental preventive measures when starting BP therapy. PATIENTS AND METHODS: Since April 2005, 154 consecutive patients treated with BPs (POST-Group) have undergone a baseline mouth assessment (dental visit +/- orthopantomography of the jaws) to detect potential dental conditions and dental care if required. A retrospective review was also conducted of all consecutive cancer patients with bone metastases (PRE-Group) and treated for the first time with BPs from January 1999 to April 2005 in our clinic without receiving any preventive measure. Incidence proportion and incidence rate (IR) were used to estimate the incidence of ONJ. RESULTS: Among the study population (966 patients; male/female=179/787), 73% had breast cancer. 25% of patients were given zoledronic acid (ZOL), 62% pamidronate (PAM), 8% PAM followed by ZOL and 5% clodronate. ONJ was observed in 28 patients (2.9%); we observed a reduction in the incidence of ONJ from 3.2% to 1.3%, when comparing-pre and post-implementation of preventive measures programme. Considering the patients exposed to ZOL, the performance of a dental examination and the application of preventive measures led to a sustained reduction in ONJ IR (7.8% in the PRE-Group versus 1.7% in the POST-Group; P=0.016), with an IR ratio of 0.30 (95% confidence interval 0.03-1.26). CONCLUSIONS: ONJ is a manageable and preventable condition. Our data confirm that the application of preventive measures can significantly reduce the incidence of ONJ in cancer patients receiving BPs therapy. Dental exams combined to the identification of patients at risk in cooperation with the Dental Team can improve outcomes and increase the number of ONJ-free patients.

In vivo spectrophotometric evaluation of neoplastic and non-neoplastic skin pigmented lesions--I. Reflectance measurements.

Reflectance spectrophotometry from 400 to 800 nm on different cutaneous pigmented lesions, including primary and metastatic malignant melanoma, pigmented nevi, lentigo and seborrhoeic keratosis, has been performed by using an external integrating sphere coupled to a spectrophotometer. Measurements show that reflectance spectra of the different lesions manifest dissimilar patterns, particularly in the near IR region. Comparison of reflectance of nevi with that of malignant melanomas results in a highly significant difference (P less than 10(-6)) between the two samples. Though interpretation of the spectra remains difficult as a result of the complexity of the optical processes of scattering and absorption, our results suggest that a detailed analysis of the reflectance spectrum may give clinically useful information, and could be utilized as an aid in clinical diagnosis of cutaneous pigmented lesions, especially where malignant melanoma is concerned.

Changes in fibrinolysis in patients with localized tumors.

An array of fibrinolysis tests was applied to the plasmas of 125 untreated patients with breast carcinoma and malignant melanoma, localized or spread to regional lymph nodes with no detectable distant metastases, to see whether or not there may be changes related to the type or to the stage of malignancy. Breast carcinoma (a mucin secreting tumor) and melanoma (a neuroectodermal tumor) were chosen as examples of tumors that can be accurately staged for localization or spread. Forty healthy subjects matched for age served as controls. The most marked differences between malignant tumors and controls were elevated plasma levels of tissue plasminogen activator antigen (P less than 0.005), plasminogen activator inhibitor (P less than 0.01), cross-linked fibrin degradation products (P less than 0.001), fragment B beta 15-42 (P less than 0.001) and histidine-rich glycoprotein (P less than 0.005). For no fibrinolysis test were results significantly different between patients with localized and spread tumors. Our data indicate that in these tumors fibrinolytic alterations are an early phenomenon unrelated to spreading.

Early presence of activated ('exhausted') platelets in malignant tumors (breast adenocarcinoma and malignant melanoma).

To evaluate whether or not the finding of platelet activation in patients with tumors is related to the stage of malignancy, a study of biochemical markers indicative of the presence of circulating activated ('exhausted') platelets was carried out in 95 untreated patients with breast adenocarcinoma or malignant melanoma, localized or spread to regional lymph nodes with no detectable distant metastasis. These tumors were chosen as examples of tumors which can be accurately staged for localization or spread, and as examples of mucin-secreting tumors (breast adenocarcinoma) or neuroectodermic tumors (malignant melanoma). Results were compared with those for 26 patients with benign breast disease, 23 blood donors and 50 hospital workers. The most frequent abnormalities were low levels of intraplatelet ADP and 5-hydroxytryptamine and high ATP/ADP ratios. Although these abnormalities occurred with both types of tumor, they were more frequent and marked for melanomas and breast carcinomas spread to regional lymph nodes. Our data indicate that the presence of exhausted platelets is an early finding in patients with malignant tumors.

Hemostatic alterations are unrelated to the stage of tumor in untreated malignant melanoma and breast carcinoma.

A study of hemostatic variables was carried out in 80 untreated patients with breast adenocarcinoma or malignant melanoma, chosen as examples of tumors that can be accurately staged for localization or spread. The most marked abnormalities were high levels of clotting factors V and VIII, plasminogen, von Willebrand factor and fibrogen-fibrin degradation products. These abnormalities occurred in both types of tumors, albeit slightly more markedly in melanomas, and were also present in localized tumors. Our data indicate that in tumors, abnormalities of the hemostatic system are an early phenomenon unrelated to the presence of widespread malignancy.