Claudia Bareggi

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.

Outcomes of small-cell lung cancer patients treated with second-line chemotherapy: A multi-institutional retrospective analysis

BACKGROUND Patients with small-cell lung cancer (SCLC) that progress after first-line chemotherapy have a poor prognosis and the evidence of a benefit from second-line (SL) chemotherapy is limited. Patients relapsing or progressing more than 90 days after completion of first-line treatment are considered platinum sensitive and may be rechallenged with platinum-based chemotherapy. Topotecan is approved as SL treatment independent of time to progression. This retrospective analysis evaluates the clinical outcomes of SCLC patients who received SL chemotherapy after platinum-etoposide chemotherapy. PATIENTS AND METHODS We retrospectively reviewed 161 patients who received SL chemotherapy for SCLC. Patients were divided into four subgroups by type of SL treatment: (1) platinum-based rechallenge; (2) anthracycline-based regimens; (3) topotecan; (4) other single agents. The endpoints were overall survival (OS), progression-free survival (PFS) and response rate (RR). Survival curves were plotted using the Kaplan-Meier method. The Cox proportional hazard model was used for multivariate analysis to investigate factors influencing survival. RESULTS The median age was 63. There were 125 males and 36 females. Eastern Cooperative Oncology Group performance status (ECOG-PS) was 0, 1 and 2 in 12.5%, 62.5% and 25% of patients, respectively. Platinum sensitive/platinum resistant/platinum refractory/unknown=121/29/3/8 patients. Median time to SL chemotherapy was 6.9 months. The median PFS from starting second-line treatment was 4.3 months and median OS was 5.8 months. The overall RR was 22.9%. There was a trend toward higher RR (34.5% vs 17.5%, p for trend: 0.06) and OS (9.2 months vs 5.8 months, p=0.08) for patients with sensitive disease who were rechallenged with platinum-based chemotherapy. A multivariate analysis that adjusted for the time to SL treatment showed that a platinum-containing regimen achieves better RR, PFS and OS independently of the time to SL chemotherapy and that response to first-line treatment and PS at SL are the only independent prognostic factors. CONCLUSIONS The outcome for second-line therapy for SCLC was poor and benefit appeared to be limited to those patients with good PS and rechallenged with platinum-based chemotherapy. Platinum-based rechallenge should be considered as a standard comparator in future randomized controlled trials of SL chemotherapy.

Osteonecrosis of the jaw (ONJ) in cancer patients treated with Bisphosphonates: how the knowledge of a phenomenon can change its evolution

Goals of the workOsteonecrosis of the jaw (ONJ) is a severe complication of bisphosphonates treatment. Bisphosphonates reduce skeletal adverse events and give a clinical benefit to cancer patients. Therefore, it is necessary to identify appropriate procedures to reduce ONJ injures by using a successful monitoring program. In a retrospective study we analyzed the impact of a prevention program based on clinical oral cavity examination, dentists, and patients’ education. The aim of the study was to evaluate if this approach might improve ONJ outcome in patients receiving pamidronate or zoledronate.Materials and methodsWe analyzed retrospectively two different groups of patients treated at our Institution: patients treated from October 2003 to June 2005 (group A) and patients treated from June 2005 to April 2007 (group B). In June 2005 the prevention program started for all our patients.Main resultsOne hundred and eighty-six cancer patients with bone involvement, treated with bisphosphonates, were considered. Sixteen of them developed ONJ: eight before and eight after June 2005. We observed a consistent difference in the evolution of the two groups. In the first group, four patients underwent a major surgery (one partial maxillectomy, complicated by septic shock and oronasal communication; two partial mandibulectomies; and one segmental mandibular resection), with an important impairment of their quality of life; while the eight new ONJ cases, diagnosed after June 2005, were successfully treated without aggressive dental interventions, and achieved a good control of symptoms.ConclusionsBisphosphonates-related ONJ is a frequent adverse event (8.6%). The monitoring program proved very efficient to improve the clinical outcome of ONJ, avoiding an aggressive treatment and using a conservative approach and medical therapy.

Role of KRAS-LCS6 polymorphism in advanced NSCLC patients treated with erlotinib or docetaxel in second line treatment (TAILOR).

MicroRNAs were described to target mRNA and regulate the transcription of genes involved in processes de-regulated in tumorigenesis, such as proliferation, differentiation and survival. In particular, the miRNA let-7 has been suggested to regulate the expression of the KRAS gene, a common mutated gene in non-small cell lung cancer (NSCLC), through a let-7 complementary site (LCS) in 3′UTR of KRAS mRNA. We have reported the analysis performed on the role of the polymorphism located in the KRAS-LCS (rs61764370) which is involved in the disruption of the let-7 complementary site in NSCLC patients enrolled within the TAILOR trial, a randomised trial comparing erlotinib versus docetaxel in second line treatment. In our cohort of patients, KRAS-LCS6 polymorphism did not have any impact on both overall survival (OS) and progression free survival (PFS) and was not associated with any patient’s baseline characteristics included in the study. Overall, patients had a better prognosis when treated with docetaxel instead of erlotinib for both OS and PFS. Considering KRAS-LCS6 status, the TG/GG patients had a benefit from docetaxel treatment (HR(docetaxel vs erlotinib) = 0.35, 95% CI 0.15–0.79, p = 0.011) compared with the TT patients (HR(docetaxel vs erlotinib) = 0.72, 95% CI 0.52–1.01, p = 0.056) in terms of PFS.

Level of HER2/neu amplification in primary tumours and metastases in HER2-positive breast cancer and survival after trastuzumab therapy

BACKGROUND The level of HER2/neu amplification may vary widely in breast cancers with HER2/neu alteration. The clinical significance of this phenomenon is still unclear. This study was aimed to explore the level of HER2/neu amplification in primary tumours and metastases in HER2-positive metastatic breast cancer (MBC) and its potential impact on survival after a trastuzumab-containing therapy. METHODS We retrospectively identified MBC patients treated with a trastuzumab-containing therapy and performed dual-colour FISH on tumour samples from either primary tumour and/or metastasis in a central laboratory. RESULTS We retrieved 110 tumour samples from 91 patients and included 79 tumour samples (primary = 56; metastasis = 23) from 63 patients in the final analysis. We found higher level of HER2/neu amplification in the metastases than in the primary tumours (median HER2/CEP17 ratio: 10.5 vs. 7.0, respectively). In 69% of patients (n = 16) with two tumour samples, the level of HER2/neu amplification was higher in the metastasis than in the paired primary tumour (median HER2/CEP17 ratio: 10.9 vs. 8.3, respectively, p = 0.004). The incremental gain in level of HER2/neu amplification was associated with significantly shorter OS after trastuzumab-containing therapy (p = 0.023, HR 1.014, CI95%: 1.002-1.025). CONCLUSIONS The level of HER2/neu amplification tends to increase from the primary tumour to the paired metastases in a significant proportion of patients with HER2-positive MBC. This phenomenon, although still not completely understood, could lead to a shorter OS after trastuzumab therapy.

Secondary breast angiosarcoma and paclitaxel-dependent prolonged disease control: report of two cases and review of the literature.

Secondary breast angiosarcomas are a well-known entity generally characterized by a poor outcome, especially in patients with advanced disease. Among the drugs with demonstrated activity, taxane derivatives are one of the most effective histology-driven treatments against angiosarcomas. We report two cases of secondary breast angiosarcoma, both characterized by a very peculiar behavior towards paclitaxel. Both patients showed local recurrence of angiosarcoma after primary surgery, and they achieved complete remission following treatment with weekly paclitaxel. When a locoregional recurrence was observed as a result of a brief treatment interruption or a treatment delay, a new complete remission was rapidly achieved with the resumption of the drug, without evidence of any significant adverse effects.

A case of pseudoachalasia hiding a malignant pleural mesothelioma.

Purpose Malignant pleural mesothelioma (MPM) is a rare cancer with a poor prognosis. We describe a case of MPM with an uncommon onset, characterized by pseudoachalasia as demonstrated with high-resolution manometry (HRM). Methods A 56-year-old man was referred to our hospital reporting worsening dysphagia. On the hypothesis of an esophageal motor disorder, the patient was referred for an HRM examination, which revealed features consistent with a diagnosis of type II achalasia. Results At the time of the first pneumatic dilation the endoscopist stopped the procedure in order to prevent perforation when he noticed only partial expansion of the pneumatic balloon. A CT scan and subsequent CT-guided excisional biopsy revealed an epithelioid pleural mesothelioma infiltrating the muscle wall. Given his good clinical condition, the patient was eligible for chemotherapy with cisplatin 75 mg/m2 and pemetrexed 500 mg/m2, resulting in a good response with partial remission of the disease and resolution of the dysphagia symptoms. Conclusions Pseudoachalasia as the first or only manifestation of mesothelioma is a rare occurrence that may expose patients to the risk of diagnostic delay. Close attention should be paid whenever a patient with symptoms and signs consistent with achalasia shows unusual features.

1769d Combination of mirnas, mesothelin and fibulin-3 as potential biomarkers in malignant pleural mesothelioma and asbestos-exposed subjects

Introduction Malignant Pleural Mesothelioma (MPM) is an aggressive cancer mainly caused by asbestos exposure. Due to its long latency and insidious onset, MPM is often diagnosed in advanced stages with poor prognosis. In addition, asbestos is still used in many non-European countries and the incidence of MPM is expected to increase. In this context, the need of reliable diagnostic markers for early MPM diagnosis is of paramount importance. Along with the more frequently studied biological markers (mesothelin, fibulin-3), new emerging biomarkers include miRNA expression in peripheral blood. Methods We previously investigated 23 MPM patients and 19 subjects with past asbestos exposure (PAE) to examine if a specific miRNA signature in plasmatic extracellular vesicles (EV) might help to discriminate between MPM and PAE (PLoS One, 2017). Criteria for enrollment, blood collection, miRNA extraction, screening and validation have been previously described. We found a two miRNA (miR-103a-3p and mir-30-3ep) diagnostic signature that discriminates the two groups with high accuracy (AUC 0.942), high sensitivity (95.5%) and good specificity (80.0%). We are currently expanding our study population to additionally include 25 MPM cases, 50 subjects with PAE, and 20 subjects with other respiratory diseases. Alongside miRNA expression, plasma mesothelin and fibulin-3 will be also measured. Results The diagnostic performance (AUC, Sensitivity and Specificity) of the best five miRNAs previously detected in our study will be examined in combination with plasma mesothelin and fibulin-3, taking into account major confounders (e.g. age, gender, BMI and smoking habit). Conclusions The combination of biological markers belonging to different molecular pathways might help in identifying a panel of biomarkers able to improve the overall diagnostic performance as suggested by Weber et al. (PLoS One, 2014), who recently showed an improved AUC of 0.93 when combining mesothelin and miR-103a-3p.

1233 Estimating the prevalence of occupational exposure in lung cancer. results from an hospital-based case-series in italy

Introduction Lung cancer (LC) is the leading oncologic cause of death among males. The role of occupational history with exposure to well-established carcinogens is very important, but usually deeply underestimated. To undervalue the occupational origin of cancer can affect the efficacy of preventive measures and preclude patients to receive insurance benefits. We performed a systematic occupational medicine evaluation of a cases-series of lung cancer cases to properly quantify the proportion of LC cases with previous occupational exposure to carcinogens. Methods We systematically evaluated all consecutive LC cases hospitalised in a large university hospital, in Milan. An active systematic search was carried out for 24 months, by trained occupational physicians, using a standardised questionnaire. Results We collected 123 consecutive LC cases (66% males). Former and current smoking habit was found in 61% and 22%, respectively. A clear exposure to occupational carcinogens (in details: asbestos, polycyclic aromatic hydrocarbons, paintings, diesel exhaust) was recognised in 10% of males cases. Discussion Previous occupational exposure to carcinogens was frequent among males cases in Northern Italy. The observed prevalence was even lower than the one reported in a previous systematic search in Lombardy (Porru S, et al. Int Arch Occ Env Health 89:981–9). If we applied our observed proportion of occupational cases to the entire incident LC cases in Lombardy population, we should observe about 460 male occupational LC cases per year (AIRTUM-AIOM report 2016), actually more than the entire number of cancer (all sites, both gender) annually notified to National Institute for Insurance (INAIL Rapporto regionale 2015).

1769 Occupational disease and morbidity modelling

Aim of special session To highlight examples and best practice in the area of occupational disease and modelling morbidity.