A multicenter observational study on Medication-Related Osteonecrosis of the Jaw (MRONJ) in advanced cancer and myeloma patients of a cancer network in North-Western Italy.

BACKGROUND: Incidence of Medication-Related Osteonecrosis of the Jaw (MRONJ) related to cancer and myeloma treatments is undetermined, with scarce data varying from 2 to 7.8/million/year in limited investigated populations. A 9-years [2009-2018] regional-wide survey was conducted, deploying the North-Western Italy Cancer Network ("Rete Oncologica Piemonte e Valle d'Aosta"), to assess number and main characteristics of MRONJ cases among myeloma/cancer patients, within a population of 4.5 million inhabitants. MATERIAL AND METHODS: MRONJ cases were collected retrospectively from January 2009 to June 2015; from July 2015 to December 2018, data were collected prospectively. Number of new MRONJ cases per year, underlying disorder, drug(s) administered, treatment duration, site and onset timing of MRONJ were detailed. RESULTS: 459 MRONJ cases were identified. Primary diseases were breast cancer (46%), prostate cancer (21%), myeloma (19%), and other types of carcinoma (14%). Patients received antiresorptive treatment either alone (399; 88.47%) or in combination with biological agents (52; 11.53%); 8 patients (1.7%) received only antiangiogenic drugs. Zoledronic acid [388] and denosumab [59] were the most frequently administered drugs. Mandible was involved in 296 (64,5%) cases. Number of new MRONJ cases was stable from 2009 to 2015, with a mean of 51.3 cases per year (raw incidence: 11.6/million/year), declining in the 2016-2018 years to 33.3 cases per year (raw incidence: 7.5/million/year). CONCLUSIONS: With such discrepancy of cases overtime being partially explicable, number of new MRONJ cases per year are consistent with those observed in a previous study [2003-2008] in the same region, being instead higher than those reported in other populations.

Time to onset of bisphosphonate-related osteonecrosis of the jaws: a multicentre retrospective cohort study.

OBJECTIVES: Osteonecrosis of the jaw (ONJ) is a potentially severe adverse effect of bisphosphonates (BP). Although the risk of ONJ increases with increasing duration of BP treatment, there are currently no reliable estimates of the ONJ time to onset (TTO). The objective of this study was to estimate the TTO and associated risk factors in BP-treated patients. SUBJECTS AND METHODS: Retrospective analysis of data from 22 secondary care centres in seven countries relevant to 349 patients who developed BP-related ONJ between 2004 and 2012. RESULTS: The median (95%CI) TTO was 6.0 years in patients treated with alendronate (n = 88) and 2.2 years in those treated with zoledronate (n = 218). Multivariable Cox regression showed that dentoalveolar surgery was inversely associated, and the use of antiangiogenics directly associated, with the TTO in patients with cancer treated with zoledronate. CONCLUSIONS: The incidence of ONJ increases with the duration of BP therapy, with notable differences observed with respect to BP type and potency, route of administration and underlying disease. When data are stratified by BP type, a time of 6.0 and 2.2 years of oral alendronate and intravenous zoledronate therapy, respectively, is required for 50% of patients to develop ONJ. After stratification by disease, a time of 5.3 and 2.2 years of BP therapy is required for 50% of patients with osteoporosis and cancer, respectively, to develop ONJ. These findings have significant implications for the design of future clinical studies and the development of risk-reduction strategies aimed at either assessing or modulating the risk of ONJ associated with BP.

Clinically relevant quality assurance for intensity modulated radiotherapy plans: gamma maps and DVH-based evaluation.

PURPOSE: To explore a novel patient-dose DVH-based method for pretreatment dose quality assurance tests. METHODS: 20 IMRT plans for head-and-neck cancer patients were used. A comparison was performed between the planned dose distributions, the computed, and the reconstructed ones using the gamma-index (GI) method. The GI analysis was performed using both the 3%/3 mm and the 2%/2 mm criteria. RESULTS: No significant DVH-deviation was observed. Considering the 3%/3 mm criteria the mean GI% < 1 for the body and structures was significantly higher compared to 2%/2 mm criteria. CONCLUSIONS: Our results underline the importance of QA-methods based on DVH-metrics to predict the impact of delivered dose.

Assessing the risk of osteonecrosis of the jaw due to bisphosphonate therapy in the secondary prevention of osteoporotic fractures.

SUMMARY: There is evidence that the use oral bisphosphonates can lead to osteronecrosis of the jaws (ONJ). Although the occurrence of ONJ appears rare among oral bisphosphonates (BPs) users, it is important to know that it exists and can be opportunely minimized. INTRODUCTION: The purpose of this study is to evaluate the association between BPs prescribed for the secondary prevention of osteoporotic fractures and the occurrence of ONJ. METHODS: An Italian record linkage claims database with a target population of around 18 million individuals (6 million over 55 years of age) constituted the data source. We conducted a nested case-control study within a cohort of individuals aged 55+ years old, who were discharged from hospitals with a primary diagnosis of incident osteoporotic fracture. The date related to the discharge diagnosis of ONJ was the index date. Conditional logistic regression for matched data was fitted to estimate the odds ratio (OR) along with 95 % confidence intervals (95 % CI) for the likely association between use of BPs and the risk of ONJ. RESULTS: Any one of the 61 ascertained cases of ONJ (incidence rate, 36.6 per 100,000 person-years) was matched to 20 controls for a total of 1120 controls. When the exposure to BPs was modeled according to recency (i.e., exposure time window prior to the index date) of use, the adjusted OR (95 % CI) for current users was 2.8 (1.3-5.9) against never users. The cumulative use of BPs has shown to increase the incidence of ONJ among patients with primary osteoporotic fractures, although not statistically significant risk has been observed. CONCLUSIONS: Although the risk of BP-related ONJ appears low in non-oncological indications, it is important to be aware that it exists and to know how it may be predicted and possibly minimized.

Low-dose rate brachytherapy of the prostate in elderly patients.

PURPOSE: This study evaluated the biochemical diseasefree survival (bDFS) rate, overall survival rate (OS) and toxicity after low-dose rate I(125) permanent-implant prostate brachytherapy (LDR-BRT) in elderly patients affected by prostate cancer. METHODS AND MATERIALS: Patients aged ≥65 years with a diagnosis of prostate cancer and treated at our institution were retrospectively evaluated. All patients received LDR-BRT as monotherapy; the prescribed dose was 145 Gy to the prostate. Patients were stratified according to the National Comprehensive Cancer Network (NCCN) recurrence risk groups. Biochemical failure was defined according to the American Society of Therapeutic Radiology and Oncology (ASTRO) criteria. The Radiation Therapy Oncology Group (RTOG) scale was used for toxicity. The bDFS was calculated from implant date to biochemical recurrence. RESULTS: Between June 2003 and December 2008, 80 elderly patients with a median age of 75 (range, 65-86) years were treated with LDR-BRT: 51 low risk (64%), and 29 intermediate risk (36%). Over a median follow-up period of 53 (range, 28-94) months, the global actuarial 5-year bDFS rate was 91.3% and the 5-year OS was 95%. Toxicity was mild: late grade-3 genitourinary toxicity was observed in only four patients (5%). CONCLUSIONS: Our data suggest that LDR-BRT is effective and safe as monotherapy in elderly patients.

[Adjuvant radiochemotherapy in the elderly affected by glioblastoma: single-institution experience and literature review]. / Radiochemioterapia adiuvante nei pazienti anziani affetti da glioblastoma: esperienza di un singolo istituto e revisione della letteratura.

PURPOSE: Radiochemotherapy (RCT) is the standard adjuvant treatment for patients affected by glioblastoma (GBM). As there is no evidence in elderly patients with GBM, combined, single modality or best supportive care is used. The aim of this retrospective study was to evaluate acute toxicity and outcome of elderly patients with GBM treated with RCT with temozolomide (TMZ). MATERIALS AND METHODS: Patients >65 years with newly diagnosed GBM who underwent surgery or biopsy and RCT were evaluated. Recursive Partitioning Analysis (RPA) class and National Cancer Institute--Common Toxicity Criteria (NCI-CTC) version 3 were used to classify patients and evaluate acute toxicity, respectively. RESULTS: From April 2005 to January 2011, 35 patients (18 women and 17 men) with GBM were treated at our institution. Only 31.43% of cases underwent complete resection. Median progression-free survival (PFS) was 8 months and median overall survival (OS) 13 months. At univariate and multivariate analysis, only RPA class correlated with OS (p=0.01, p=0.03, respectively). During RCT, toxicity was mild (thrombocytopaenia G3-4, 11.43%; neurological toxicity, G3-4, 8.57%). CONCLUSIONS: Our data suggest that RCT with TMZ seems to produce a better outcome with a mild toxicity profile in elderly patients affected by GBM.

Experimental demonstration of emittance compensation with velocity bunching.

In this Letter we report the first experiments aimed at the simultaneous demonstration of the emittance compensation process and velocity bunching in a high brightness electron source, the SPARC photoinjector in INFN-LNF. While a maximum compression ratio up to a factor 14 has been observed, in a particular case of interest a compression factor of 3, yielding a slice current of 120 A with less than 2 microm slice emittance, has been measured. This technique may be crucial in achieving high brightness beams in photoinjectors aiming at optimized performance of short wavelength single-pass free electron lasers or other advanced applications in laser-plasma accelerators.

The clinical impact of a cardiologic follow-up in breast cancer survivors: an observational study.

Anthracycline-containing chemotherapy (A-CHT) can induce late cardiotoxicity adding a considerable burden to cardiovascular risk. Irradiation of left breast cancer has also been associated to an increased risk of cardiovascular disease. The aim of this observational study is to prove the usefulness of an accurate cardiovascular evaluation in left breast cancer survivors treated with radiotherapy (RT) and A-CHT. Patients with left breast cancer, on follow-up after treatment with A-CHT plus RT in an adjuvant setting, were eligible for this observational study. Patients underwent cardiovascular assessment with myocardial perfusion imaging. Thirty patients were enrolled in the study: mean age at diagnosis 55.8 years; stage: I/III; Er and/or pgR status: positive in 24/30 pts; 3 patients in pre-menopausal status. Twenty-two patients (73.3 percent) had normal perfusion imaging, 1 patient (3.3 percent) had a fixed myocardial perfusion defect, 7 patients (23.3 percent) had reversible myocardial perfusion defects; 1 patient (3 percent) with normal perfusion scan showed depressed rest and stress LVEF. Only 1 patient had a large defect and underwent coronary angiography and percutaneous coronary intervention. Five patients with small defect showed normal coronary arteries at Multislice Computed Tomography. Cardiovascular followup may reveal signs of A-CHT or RT-induced cardiotoxicity. A stress test combined with MPI- and GATED-derived data of ventricular systolic performance after stress can give information on the coronary reserve and the contractile reserve and allow early appropriate treatment.

Frequency-diverse multimode millimetre-wave constant-ϵr lens-loaded cavity.

This paper presents a physical frequency-diverse multimode lens-loaded cavity, designed and used for the purpose of the direction of arrival (DoA) estimation in millimetre-wave frequency bands for 5G and beyond. The multi-mode mechanism is realized using an electrically-large cavity, generating spatio-temporally incoherent radiation masks leveraging the frequency-diversity principle. It has been shown for the first time that by placing a spherical constant dielectric lens (constant-ϵr) in front of the radiating aperture of the cavity, the spatial incoherence of the radiation modes can be enhanced. The lens-loaded cavity requires only a single lens and output port, making the hardware development much simpler and cost-effective compared to conventional DoA estimators where multiple antennas and receivers are classically required. Using the lens-loaded architecture, an increase of up to 6 dB is achieved in the peak gain of the synthesized quasi-random sampling bases from the frequency-diverse cavity. Despite the fact that the practical frequency-diverse cavity uses a limited subset of quasi-orthogonal modes below the upper bound limit of the number of theoretical modes, it is shown that the proposed lens-loaded cavity is capable of accurate DoA estimation. This is achieved thanks to the sufficient orthogonality of the leveraged modes and to the presence of the spherical constant-ϵr lens which increases the signal-to-noise ratio (SNR) of the received signal. Experimental results are shown to verify the proposed approach.

The role of interventional radiotherapy (brachytherapy) in stage I esophageal cancer: an AIRO (Italian Association of Radiotherapy and Clinical Oncology) systematic review.

OBJECTIVE: This review aimed at examining efficacy of interventional radiotherapy (brachytherapy-IRT) alone or combined with external beam radiotherapy (EBRT) in stage I esophageal cancer as exclusive treatment. MATERIALS AND METHODS: A systematic research using PubMed, Scopus, and Cochrane library was performed. ClinicalTrials.gov was searched for ongoing or recently completed trials, and PROSPERO was searched for ongoing or recently completed systematic reviews. We analyzed only clinical study as full-text publication, reporting on patients with stage I esophageal cancer treated with IRT alone or in combination with other treatments (e.g., EBRT). Conference paper, survey, letter, editorial, book chapter, and review were excluded. Patients who underwent previous surgery were excluded. Time restriction (1990-2018) was applied for years of the publication. RESULTS: Twelve studies have been selected. The number of evaluated patients was 514; the median age was 69 years. In the IRT group, the median: local control (LC) was 77% (range 63%-100%), disease-free survival (DFS) was 68.4% (range 49%-86.3%), the overall survival (OS) was 60% (range 31%-84%), the cancer specific survival (CSS) was 80% (range 55-100%), and grade 3-4 toxicity range was 0%-26%. CONCLUSIONS: IRT alone or combined to EBRT is an effective and safe treatment option for patients with stage I esophageal cancer. Definitive radiation therapy could be an alternative to surgery in patients with superficial cancer.

Response of Escherichia coli O157:H7, Listeria monocytogenes, Salmonella typhimurium, and Staphylococcus aureus to the thermal stress occurring in model manufactures of Grana Padano cheese.

The purpose of this research was to investigate the effect of temperature in the technology of production of Grana cheese against Escherichia coli O157:H7, Listeria monocytogenes, Salmonella Typhimurium, and Staphylococcus aureus. According to the technology of production, the cheese curds are cooked at 55 degrees C and then cooled at room temperature (25 degrees C). A curd-cooling model was developed to estimate the temperature variation across the curd during cooling, and the thermal stress was applied to the pathogens according to the model in model-scale productions of Grana cheese artificially contaminated with approximately 10(4) cfu/mL of the selected pathogens. According to the numerical results, the initial temperature inside the cheese is kept at almost the initial value (above 50 degrees C) for at least 4 h during cooling, whereas the crust of the curd cools rapidly to 30 degrees C in the first hour. The best case was that of the core of the cheese where the high temperature was able to efficiently eliminate the contaminating pathogens. Moreover, the worst case was where the external ring of the curd in which a more rapid cooling allowed bacterial survival. Therefore, the thermal stress in the technology of production of Grana cheese can be only partially effective in the control of the selected pathogens. However, the whole technology of production includes other hurdles that can affect the survival of the pathogens and that need to be taken into account as a whole to evaluate the safety of Grana Padano cheese.

Etoposide v etoposide and cisplatin in the treatment of advanced non-small cell lung cancer: a FONICAP randomized study.

A multicenter Italian Cooperative Study Group (FONICAP) conducted a prospective, randomized trial comparing cisplatin and etoposide (VP-16) with single-agent etoposide. The national study accrued 216 patients with measurable or evaluable non-small cell lung cancer (NSCLC) with either unresectable stage III, or distant metastasis (stage IV). One hundred patients were evaluable for response in the single-agent arm, and 93 in the two-drug combination arm. The overall response rates for the etoposide group and cisplatin/etoposide (VP-16) group were 7% and 26%, respectively (P less than 0.005). Five patients (5.6%) in the combination arm and 1 (1%) in the single agent arm had a complete response. The overall median survival was 236 days for the two-drug arm and 178 days on the single-drug arm (P = 0.2). Treatment-related toxicity (nausea and vomiting, leukopenia, anemia, hearing-loss, peripheral neuropathy, serum creatinine elevation) was significantly more pronounced in the combined arm. The addition of cisplatin to etoposide gave a small non-statistically significant improvement in terms of performance status and thoracic symptoms.

Prostate-specific antigen (protein and mRNA) analysis in the differential diagnosis and staging of prostate cancer.

We analyzed complexed and free prostate-specific antigen (PSA), the free/total PSA and complexed/free PSA ratios, acid phosphatase, and prostatic phosphatase in serum from 36 patients with prostatic carcinoma and from 48 non-neoplastic control patients (20 with prostatitis and 28 with benign prostatic hyperplasia). Receiver-operating characteristic plots showed that serum PSA was the most efficient variable, singly used, in discriminating neoplastic from non-neoplastic patients. At a cut-off value of 10.0 ng/ml, serum PSA had a diagnostic sensitivity of 87% and a diagnostic specificity of 83%. In particular, three patients with prostatic carcinoma and twenty non-neoplastic controls had serum PSA levels of between 4 and 10 ng/ml. The subsequent analysis of the serum free/total PSA ratio, in this subgroup, using a cut-off level of 15%, allowed us to classify correctly all prostatic cancer cases and 18/20 non-neoplastic diseases. We next analyzed PSA mRNA in circulating cells using an improved reverse-transcriptase polymerase chain reaction dot blot procedure, from six patients with prostatic carcinoma with distant metastases, and in seventeen with localized cancer. The analysis had a high sensitivity (up to dilutions 1:10(6) of total RNA from prostatic cancer cells vs total RNA from normal blood cells). The analysis revealed circulating micrometastatic cells in 3/6 (50%) cases of metastatic cancer and in 4/17 cases of localized cancer. To conclude, serum total PSA combined with the free/total PSA ratio is a very efficient algorithm in discriminating neoplastic from non-neoplastic prostatic diseases, while other mRNA species must be analyzed, in addition to PSA mRNA, in circulating cells to increase the efficiency in detecting metastatic prostatic cancer.

Malignant pleural mesothelioma. Multivariate analysis of prognostic factors on 113 patients.

We report on clinical features of 113 cases of pathologically confirmed Malignant Pleural Mesothelioma, observed in Genoa (Italy) between 1979 and 1985. Overall median survival was 10 months. Among the pretreatment variables studied (age, sex, asbestos exposure, pathological type, chest pain and dyspnea at the time of diagnosis), the only one of prognostic value in the univariate analysis was the histological subtype: median survivals were 12, 7 and 4 months for the patients in the epithelial, mixed, and fibrosarcomatous groups, respectively (p = 0.0012). A multivariate analysis confirmed the independent predictive power of the histotype (p = 0.0022). A review of literature data concerning prognostic factors in Malignant Pleural Mesothelioma is presented.

Oral chemotherapy for poor risk small-cell lung cancer patients with combined idarubicin and etoposide.

Sixteen patients with previously untreated small-cell lung cancer, unsuitable for standard aggressive intravenous chemotherapy due to advanced age or poor performance status or very advanced disease including brain metastases or either extensive liver or marrow involvement with impaired organ function, were treated with combined oral chemotherapy including 4-demethoxydaunorubicin (IMI30, idarubicin) 30 mg/sm on day 1 and etoposide (VP16) 150 mg/sm on days 2,3,4 every 4 weeks. Out of 13 evaluable patients 1 had a complete response and 2 had a partial response with an overall objective response rate of 23% (95% confidence-limits 5-53.8%). Toxicity was generally very mild. Although the compliance of this regimen is excellent, its antitumor activity seems unsatisfactory even in this category of poor-risk small-cell lung cancer patients.

Alternating chemotherapy with cyclophosphamide, doxorubicin, vincristine and cisplatin, etoposide followed by prophylactic cranial and thoracic irradiation for small cell lung cancer (SCLC): long-term results.

Both CAV (Cyclophosphamide, Doxorubicin, Vincristine) and PE (Cisplatin, Etoposide) are effective and non cross-resistant regimens in the treatment of SCLC. We designed a chemotherapeutic scheme including CAV and PE given in an alternating fashion with the following schedule: Cyclophosphamide 1000 mg/sm, Doxorubicin 50 mg/sm, Vincristine 2 mg/sm I.V. on day 1, alternated every 21 days with Cisplatin 20 mg/sm and Etoposide 80 mg/sm I.V. days 1-5 for 6 cycles. Following chemotherapy (CT) chest radiotherapy in patients (pts) with limited disease (LD) in complete response (CR) or partial response (PR) and prophylactic cranial irradiation (PCI) in CRs were given, 32 pts entered the study and 27 were evaluable: 9/27 (33.3%) had CR (8/15 with LD had CR) and 15/27 (55.5%) PR. The overall median survival was 53.71 weeks: 79.85 weeks for LD pts and 32.86 for ED.4 pts with LD were alive after 2 years and 2 of them are still alive without disease at 44 and 46 months. Toxicity was acceptable in all patients. Alternating chemotherapy with CAV and PE followed by chest and brain RT in responding LD pts is an effective induction treatment for SCLC although long-term survival still remains disappointing.

The wall correction factor for a spherical ionization chamber used in brachytherapy source calibration.

The effect of wall chamber attenuation and scattering is one of the most important corrections that must be determined when the linear interpolation method between two calibration factors of an ionization chamber is used. For spherical ionization chambers the corresponding correction factors A(w) have to be determined by a non-linear trend of the response as a function of the wall thickness. The Monte Carlo and experimental data here reported show that the A(w) factors obtained for an Exradin A4 chamber, used in the brachytherapy source calibration, in terms of reference air kerma rate, are up to 1.2% greater than the values obtained by the linear extrapolation method for the studied beam qualities. Using the Aw factors derived from Monte Carlo calculations, the accuracy of the calibration factor N(K,Ir) for the Exradin A4, obtained by the interpolation between two calibration factors, improves about 0.6%. The discrepancy between the new calculated factor and that obtained using the complete calibration curve of the ion-chamber and the 192Ir spectrum is only 0.1%.

Bone formation markers and pain palliation in bone metastases treated with strontium-89.

In several bone disorders, including those with metastatic involvement, changes in procollagen type I C-terminal and type III N-terminal peptides are detected, as indications of altered bone metabolism. Assessment of bone turnover could play a role in the evaluation of response to Strontium-89 used as palliative treatment in symptomatic bone metastases from various primary tumors. A correlation between bone formation rate markers procollagen I and III and efficacy of ionic Strontium-89 was shown in a group of 13 patients who underwent treatment with 4 mCi of Strontium-89 for painful bone metastases: 5 from breast, 7 from prostate, and 1 from lung carcinoid cancer. Assessed as a modification of analgesic intake, pain, and ambulation, there were 6 complete remissions, 3 partial remissions, and 4 nonresponders. The duration of the response was from 2 to 11 months. Procollagen I and III levels were found to be highly abnormal in those with no benefit from Strontium-89 administration but were in the normal range or only slightly elevated in those achieving complete or partial pain control, thus correlating with the clinical response.

Sequential administration of cyclophosphamide, methotrexate, 5-fluorouracil, and folinic acid as salvage treatment in metastatic breast cancer.

Experimental data show that sequencing methotrexate (MTX) and 5-fluorouracil (5-FU) may result in synergistic antitumor activity. Moreover, the effect of 5-FU is increased by folinic acid (FA), and finally, cyclophosphamide (CPA) produces an expansion of tumor growth fraction, suggesting an increased cytotoxic effect of cycle-specific drugs subsequently administered. Based on these premises, we have performed a Phase II study with CPA (600 mg/m2 i.v., day 1), MTX (200 mg/m2 1-h i.v. infusion, day 7), 5-FU (600 mg/m2 i.v., day 8), and FA (500 mg/m2 2-h i.v. infusion, day 8 plus 15 mg p.o. every 6 h on days 8 and 9) administered every 3 weeks. Thirty-six patients with metastatic breast cancer were admitted into the study. Median age was 52 years, and all but two patients were postmenopausal. Dominant sites of metastases were soft tissues in 10 patients, bones in 7 patients, and viscera in 19 patients. All patients were pretreated with chemo- and/or hormone therapy. Sixteen patients achieved an objective response (44.5%: 1 complete response and 15 partial responses), 8 had stable disease (SD) (22.2%), and 12 progressed (33.3%). Twenty-one patients had previously received conventional CMF in an adjuvant setting (15 patients) or for metastases (6 patients): 1 complete response (CR) and 7 partial responses (PR) were obtained in the first group and 1 in the second. Major toxic effects were hair loss (56.4%), nausea and vomiting (72%), mucositis (52.5%), and leukopenia (61%). A randomized study could be useful to assess the role of sequential CMF versus conventional CMF in metastatic breast cancer patients.