New approach for the step by step control of magnetic nanostructure functionalization.

This paper describes the synthesis, functionalization, and multitechnique analysis of magnetic nanoparticles. The synthetic method involves the covering of a magnetite nucleus by a silica layer and the further functionalization with different fluorophores via a cross-linker molecule. All synthetic intermediates were analyzed by fluorescence spectroscopy and AC magnetic susceptibility. For one of the considered molecules, a further investigation with STEM, EDXS, and DLS has been conducted in order to validate the proposed magnetic results. The comparison between the two techniques is used to ensure a complete characterization of the product confirming the success of the synthesis. By comparing the magnetic and the fluorescence measurements, we also demonstrate the effectiveness of AC susceptibility as a robust and versatile technique to follow the synthesis of complex magnetic nanostructures regardless of the nature of the functionalization.

Clinical management of patients with thymic epithelial tumors: the recommendations endorsed by the Italian Association of Medical Oncology (AIOM).

The Italian Association of Medical Oncology recommendations on thymic epithelial tumors, which have been drawn up for the first time in 2020 through an evidence-based approach, report indications on all the main aspects of clinical management of this group of rare diseases, from diagnosis and staging, to new available systemic treatments, such as targeted therapies and immunotherapies. A summary of key recommendations is presented here and complete recommendations are reported as Supplementary Materials, available at https://doi.org/10.1016/j.esmoop.2021.100188.

Sinusal localization of nodal micrometastases is a prognostic factor in breast cancer.

BACKGROUND: Breast cancer micrometastases are frequently found during pathological examination of sentinel lymph nodes and complete axillary lymph node dissection. Despite this, their clinical relevance is still debated. The aim of this study is to investigate features that affect disease-free survival (DFS) and overall survival (OS) in patients with nodal micrometastases from breast cancer. MATERIAL AND METHODS: We retrospectively investigated the outcome of 122 patients with nodal micrometastases from breast cancer followed up for 60 months. RESULTS: At univariate analysis, worse DFS was related to features of primary tumor (multifocality P = 0.002; size >2 cm, P = 0.022; grade P = 0.022; absence of estrogen P < 0.001 and progesterone P < 0.001 receptors; HER-2 overexpression P = 0.006; vascular invasion P = 0.039; proliferative fraction > or =20% P = 0.034) and micrometastases (sinusal localization P = 0.010). Among the above-mentioned features, two were strongly associated with worse DFS in the multivariate model, i.e. negative receptorial status [hazard ratio (HR) = 11.24, 95% confidence interval (CI) 4.06-31.09; P < 0.001] and sinusal localization of micrometastasis (HR = 3.66, 1.18-11.36; P = 0.025). The OS was influenced by multifocality (P < 0.001) and receptor status (P = 0.005). CONCLUSION: Our results indicate that in patients affected by breast cancer, in addition to the well-known pathological features of primary tumor, sinusal localization of micrometastasis strongly impacts on the prognosis.

Insulin-like growth factor receptor 1 (IGF1R) expression and survival in surgically resected non-small-cell lung cancer (NSCLC) patients.

BACKGROUND: The purpose of this study is to investigate the prognostic role of insulin-like growth factor receptor 1 (IGF1R) expression in surgically resected non-small-cell lung cancer (NSCLC). Patient characteristics and methods: This retrospective study was conducted in 369 stage I-II-IIIA, surgically resected, NSCLC patients. Patients exposed to anti-epidermal growth factor receptor (EGFR) agents were excluded. IGF1R expression was evaluated by immunohistochemistry in tissue microarray sections. RESULTS: A positive IGF1R expression (score > or = 100) was observed in 282 cases (76.4%) and was significantly associated with squamous cell histology (P = 0.04) and with grade III differentiation (P = 0.02). No difference in survival was observed between the positive and negative group when score 100 was used as cut-off for discriminating a positive versus a negative IGF1R result (52 versus 48 months, P = 0.99) or when median value of IGF1R expression was used (45 versus 55 months, P = 0.36). No difference in survival was observed between IGF1R-positive and -negative patients in a subgroup of stage I-II adenocarcinoma (n = 137) with known EGFR mutation and copy number status. CONCLUSIONS: IGF1R expression does not represent a prognostic factor in resected NSCLC patients. Patients with squamous cell carcinoma overexpress IGF1R more frequently than patients with nonsquamous histology, justifying the different sensitivity to anti-IGF1R agents observed in clinical trials.

MET increased gene copy number and primary resistance to gefitinib therapy in non-small-cell lung cancer patients.

BACKGROUND: MET amplification has been detected in approximately 20% of non-small-cell lung cancer patients (NSCLC) with epidermal growth factor receptor (EGFR) mutations progressing after an initial response to tyrosine kinase inhibitor (TKI) therapy. PATIENTS AND METHODS: We analyzed MET gene copy number using FISH in two related NSCLC cell lines, one sensitive (HCC827) and one resistant (HCC827 GR6) to gefitinib therapy and in two different NSCLC patient populations: 24 never smokers or EGFR FISH-positive patients treated with gefitinib (ONCOBELL cohort) and 182 surgically resected NSCLC not exposed to anti-EGFR agents. RESULTS: HCC827 GR6-resistant cell line displayed MET amplification, with a mean MET copy number >12, while sensitive HCC827 cell line had a mean MET copy number of 4. In the ONCOBELL cohort, no patient had gene amplification and MET gene copy number was not associated with outcome to gefitinib therapy. Among the surgically resected patients, MET was amplified in 12 cases (7.3%) and only four (2.4%) had a higher MET copy number than the resistant HCC827 GR6 cell line. CONCLUSIONS: MET gene amplification is a rare event in patients with advanced NSCLC. The development of anti-MET therapeutic strategies should be focused on patients with acquired EGFR-TKI resistance.

Differential diagnosis and management of focal ground-glass opacities.

Focal pulmonary ground-glass opacities (GGOs) can be associated with bronchioloalveolar carcinoma. The present retrospective study aimed to test the validity of a multistep approach to discriminate malignant from benign localised (focal) GGOs, identifies useful diagnostic features on computed tomography (CT), and suggests appropriate management guidelines. A stepwise approach, including oral antibiotics, follow-up high-resolution CT (HRCT) 40-60 days later and CT-guided core biopsy, was used. All cases with localised GGOs detected since 2001 were reviewed. CT features were described according to a structured scheme. In total, 40 patients were evaluated. Of these, 11 patients were diagnosed with benign GGOs, 19 patients had lung cancer and 10 were undetermined. Nonpolygonal shape, apparent radial growth and clear-cut margins were associated with a malignant histology. The specificity of CT findings was low. Diagnostic accuracy increased after oral antibiotics, follow-up HRCT and percutaneous core biopsy. Overall, 18 patients underwent surgery for lung cancer. In conclusion, malignant ground-glass opacities have a fairly typical appearance, but some benign lesions closely mimic their malignant counterparts. The stepwise approach adopted in the present study increased the diagnostic specificity and reduced time to definitive diagnosis. Segmentectomy might be the ideal resection volume for such tumours.

Effectiveness of stereotactic body radiotherapy in the treatment of inoperable early-stage lung cancer.

BACKGROUND: Non-small cell lung cancer (NSCLC) is the leading cause of cancer death worldwide. Stereotactic body irradiation offers a non-invasive treatment modality for patients with early stage NSCLC who are not amenable to surgery or other invasive approaches because of their poor medical condition. PATIENTS AND METHODS: Forty-three inoperable patients with NSCLC were treated with SBRT at our institution. A mean total dose of 30.5 Gy in 1-4 fractions was applied. The median follow-up duration was 14 months (range 6-36 months). RESULTS: The actuarial survival at two years was 53%: two patients died from cancer progression whereas a further 8 patients died from comorbidities. Acute toxicity was practically absent, with 7 (16.3%) patients suffering from grade 1 symptoms and two from (4.6%) grade II effects. At the time of this report, only 1 patient had grade II and 6 patients (13.9%) grade I chronic symptoms. CONCLUSION: Our results compare favourably with recently published studies and confirm that stereotactic radiotherapy has the potential to produce high local control rates with a low risk of lung toxicity in patients not amenable to curative resection. The low grade of side-effects is encouraging for shortening the treatment using a greater dose per fraction.

EGFR overexpression in malignant pleural mesothelioma. An immunohistochemical and molecular study with clinico-pathological correlations.

The epidermal growth factor receptor (EGFR) is overexpressed in many epithelial malignancies, against which some antitumoral drugs have been developed. There is a lack of information as to EGFR expression in malignant pleural mesothelioma (MPM), an aggressive and fatal cancer poorly responsive to current oncological treatments. Our aim was to: (a) compare EGFR immunohistochemical expression with mRNA levels measured by real time PCR; (b) assess the relationships between EGFR expression and clinico-pathological data including survival; (c) analyze the EGFR mutations. We developed an immunohistochemical method of EGFR evaluation based on the number of immunoreactive cells and staining intensity in 61 MPMs. EGFR immunoreactivity was documented in 34/61 (55.7%) cases. A significant correlation between EGFR protein and mRNA levels (p = 0.0077) was found, demonstrating the reliability of our quantification method of EGFR membrane expression. Radically resected patients (p = 0.005) and those with epithelial histotype (p = 0.048) showed an increased survival. No statistical correlation between EGFR immunoreactivity and patients survival was observed. No EGFR mutation was documented. This study documents EGFR overexpression in MPM at the protein and the transcriptional levels; it proposes a reliable method for EGFR expression evaluation in MPM. EGFR levels are not associated with clinico-pathological features of patients, including survival.

Extended bilateral mediastinal dissection via a limited thoracotomy for right-lung cancer.

In non small cell lung cancer (NSCLC) patients undergoing surgery after induction chemotherapy, all mediastinal lymphnodes potentially involved by tumor should be resected whenever possible. Paratracheal bilateral lymphadenectomy for left sided tumors can be disabling, i.e. median sternotomy plus a thoracotomy to reach the subcarinal region. From the right side, an extensive ipsilateral dissection is feasible through a standard thoracotomy, but contralateral lymphnodes, especially in the left hilum and aortopulmonary window are considered inaccessible. A technical tip is shown to reach and dissect the left paratracheal and aortopulmonary window nodes through a simple right thoracotomy in right-lung cancer. The procedure has been carried out in 3 cases and proved to be technically feasible. The value of such a procedure as to staging accuracy, local disease control and survival should be evaluated in a clinical trial setting.

Clinical Outcome of Stereotactic Ablative Body Radiotherapy for Lung Metastatic Lesions in Non-small Cell Lung Cancer Oligometastatic Patients.

AIMS: The aim of this observational study was the evaluation of toxicity, local control and overall survival in non-small cell lung cancer (NSCLC) oligometastatic patients who had undergone stereotactic ablative body radiotherapy (SABR) for lung metastatic lesions. MATERIALS AND METHODS: SABR was carried out in oligometastatic patients with controlled primary tumour (adequate pulmonary function). We adopted the following dose prescriptions according to the site and the maximum diameter of the lung lesions: 60 Gy in three fractions for peripheral lesions with diameter ≤ 2 cm, 48 Gy in four fractions for peripheral lesions between 2 and 5 cm and 60 Gy in eight fractions for central lesions. A radiological response was defined according to RECIST criteria. Toxicity was recorded according to the Common Toxicity Criteria version 4.0. RESULTS: Between October 2010 and December 2014, 60 NSCLC patients with 90 lung lesions in total were treated at our institution. A radiological response was obtained in most patients. No pulmonary toxicity grade 4, chest pain or rib fracture occurred. The median follow-up from diagnosis was 28 months (range 5.4-104.5 months). The local control at 2 years was 88.9%. Overall survival at 1 and 2 years was 94.5 and 74.6%, respectively. CONCLUSION: SABR is well tolerated with a good radiological response and toxicity profile. Discussion within a multidisciplinary team is crucial to identify the oligometastatic patients who would probably benefit from ablative local therapy.

[Chest wall and vertebral en-bloc resection for sarcoma: ten-year experience]. / Toracectomia e vertebrectomia per sarcoma: dieci anni di esperienza.

AIM: We reviewed our ten-year experience with surgical en-bloc chest wall and vertebral resection for sarcoma invading the spine, and verified five-year survival and feasibility of this aggressive surgery. METHODS: From 1994 to 1999, 13 patients underwent surgical en-bloc resection for primary sarcoma of the chest wall involving the spine. Concurrent pulmonary resection was performed in 12 cases. A single hemi-vertebrectomy was performed in 2 patients, a triple hemi-vertebrectomy in 2, a complete vertebrectomy in 4, a triple complete vertebrectomy in 5. RESULTS: Significative morbidity occurred in 1 patient who had lower limbs paralysis (9%). Perioperative mortality occurred in 2 patients (15.4%): 1 operative death for bleeding and 1 patients for a adult respiratory distress syndrome (ARDS). The overall five-year survival was 30.8%, excluding the 2 perioperative deaths the five-year survival resulted 36.4%. CONCLUSIONS: In spite of the limited number of patients, the morbidity and mortality outcome and the five-year survival leads us to think that surgery is the main therapy for primary chest wall sarcomas involving the spine. En-bloc chest wall and vertebral resection is a safe and effective treatment.

K-ras and p16(INK4A)alterations in sputum of NSCLC patients and in heavy asymptomatic chronic smokers.

NSCLC rates among the most frequent and lethal neoplasm world-wide and a significant decrease in morbidity and mortality relies only upon effective early diagnostic strategies. We investigated K-ras mutations and p16(INK4A) hypermethylation in tumor tissue and sputum of 50 patients with NSCLC and correlated them with sputum cytology and with tumor staging, grading and location, to ascertain, in sputum, their potential diagnostic impact. The same genetic/epigenetic abnormalities and cytological features were also evaluated in sputum from 100 chronic heavy smokers. Genetic analysis identified molecular abnormalities in 64% tumors (14/50 K-ras mutations and 24/50 p16(INK4A) hypermethylation) and in 48% sputum (11/50 K-ras mutations and 16/50 p16(INK4A) hypermethylation). In tumors K-ras mutations and p16(INK4A) hypermethylation were mostly mutually exclusive, being found in the same patients in 3 cases only. Genetic abnormalities in sputum were detected only in molecular abnormal tumors. Molecular changes in sputum had rates of detection similar to cytology (42%) but the cyto-molecular combination increased the diagnostic yield up to 60%. Interestingly, the rate of detection of genetic changes in sputum of tumors at early stage (T1) was not significantly different from that of tumors at more advanced stage (T2-T4). In fact K-ras point mutations were frequently recognised in tumors at early stage while p16(INK4A) inactivation prevailed in tumors at advanced stage ( P=0.0063). As expected, diagnostic cytological findings were more frequently found in tumors at advanced stage (P=0.004). No correlation was found between tumor grading and location (central versus peripheral) and molecular changes. p16(INK4A) hypermethylation, but not K-ras mutations, was documented in sporadic cases of asymptomatic heavy smokers (4%) where it was uncoupled from cytological abnormalities. In conclusion the cyto-molecular diagnostic strategy adopted in this study was able to detect the majority of tumors but in order to be proposed as effective and early diagnostic tool, this molecular panel needs to be tested in prospective studies with adequate follow-up.

Prognostic significance of lymphatic spread in head and neck carcinomas: therapeutic implications.

A series of 618 patients with neck dissections were performed in 455 consecutively admitted patients with head and neck carcinomas at the Istituto Nazionale Tumori, Milan, from 1976 to 1978. Clinical and pathologic node factors were considered in an effort to correlate lymph node involvement with prognosis. Actuarial survival decreased with the increase in the size of nodes, although no significant difference was found for all categories and the prognosis was poor when nodes were greater than 5 cm and/or hypomobile (33%, 5-year survival). The presence of histologically proven neck metastases significantly reduces the 5-year survival, and the presence of distant metastases correlates directly with the pathologic staging of neck nodes.

Synchronous triple carcinoma of the lung in one patient.

A case is reported of the simultaneous occurrence of a squamous cell carcinoma and a small cell carcinoma, both centrally located, in the right upper lobe and a peripheral adenocarcinoma in the right lower lobe. The simultaneous occurrence of three primary lung carcinomas is discussed in the light of a probable common cell origin.

A fifteen years' experience in the diagnosis and treatment of benign lung tumors.

Even the most sophisticated examinations, such as computerized tomography and percutaneous fine needle biopsy, often do not allow a certain preoperative diagnosis of benign lung cancer. The clinical history may also be deceiving: a smoker over 35 years of age need not necessarily have a primary lung cancer, but this event is frequent enough to justify a diagnostic thoracotomy. In our series, chest tomography proved to be useful and sometimes revealed unsuspected lesions. In contrast, bronchoscopy is useful only for centrally located lesions, and the same is true for bronchial washing and brushing. Finally, thoracotomy, possibly an axillary one with enucleation or possibly transegmentary resection, is the most frequent operation in benign lung tumors, because of the unfailing diagnosis and for the minimal functional damage to the patient. A diagnostic thoracotomy may also avoid the psychologic stress suffered by a patient with a simple but undiagnosed benign lung tumor.

Leiomyoma of the esophagus.

A review of the clinical records from 1947 to 1984 of the Istituto Nazionale Tumori of Milan provided 20 cases (14 males and 6 females) of esophageal leiomyoma. Eighteen of the tumors were in the thoracic esophagus and 2 were at the cardiac level. The most frequent symptoms were dysphagia, slight epigastralgia and odynophagia. Differential diagnosis should be made with mediastinic neoplasms and esophageal cancer. Barium swallow and esophagoscopy are the most sensitive procedures for a correct preoperative diagnosis. Surgery is mandatory because of the tendency to a continuous endoluminal growth (in 97% of the cases) and a possible malignant transformation. However, surgery is conservative: extramucosal enucleation of the leiomyoma is the procedure of choice. The long-term results are excellent, and morbidity is acceptable.

Surgical treatment for carcinoma of the gastric cardia: a modified proximal esophagogastrectomy.

Proximal esophagogastrectomy saving only the distal half of the greater curvature of the stomach was retrospectively evaluated in 91 consecutive patients with resectable carcinoma of the gastric cardia. Division of the right gastric artery at its beginning provided a free nodal margin if N1 diffusion was observed. Operative mortality was 6.5% and fatal leak rate 3.8%. Survival without dysphagia occurred in all but stage I tumors; for larger tumors recurrence and reflux esophagitis were not able to produce dysphagia because distant metastases were faster to kill the patients. Five-year survival was 0% for stage IV (i.e. incomplete macroscopic resection), 8% for stage III, 12% for stage II and 53% for stage I. Local recurrence occurred only at esophageal anastomosis and for every stage, whereas regional recurrence occurred only for tumors with nodal diffusion. The results of this study are not suitable for a comparison with total esophagogastrectomy by inductive logic, nevertheless deductive arguments are possible if patterns of recurrence are considered. The possibility of regional recurrence for N1 and not for N0 tumors means that the volume of nodal resection has diagnostic specificity for N0 but not for N1 tumors. If N2 nodal diffusion is really a sistemic disease, as indicated by current reports, than greater nodal resection by total esophagogastrectomy can only improve the diagnostic specificity of N1 assessment but not survival.

Lung resection as salvage treatment for metastatic osteosarcoma.

Resection of pulmonary metastases has achieved a central role in the overall management of osteosarcoma, since a number of studies have demonstrated that salvage surgery is able to cure 20 to 40% of all relapsing patients. This paper presents the results of surgical management of 27 consecutive cases of pulmonary metastases from osteosarcoma, who underwent complete resection at the Istituto Nazionale Tumori of Milan between 1975 and 1986. In the present series, overall actuarial survival at 3 years from the first thoracotomy was 47%, with a median survival of 28 months and no operative mortality. Better results were observed in patients with single lesions (68% survival) or when the interval to lung metastases exceeded 12 months (60% survival). These data support the concept of pulmonary metastasectomy as effective salvage therapy for metastatic osteosarcomas whose distant spread is confined in the lungs.

Current results of esophageal cancer surgery. Time trends in operative mortality and long term survival.

This paper represents a historical analysis of the results achieved by esophageal cancer surgery over the last three decades, as they appear in the literature of the years 1954-1985, and in our own experience between 1965 and 1985, with the aim of assessing the evolution of operative mortality and long-term survival. In a review of 4930 resections reported in western literature, mean values of perioperative mortality went down from 30% to 9%, while the five-year survival increased from 8% to 19%. Similar changes were evident in Japanese and Chinese literature where the survival rose from 9% to 23% in unscreened populations and up to 90% in early cancers. In our experience, dividing the series in two decades (1965-74 and 1975-85), the overall perioperative mortality changed from 28% to 13%. The actuarial survival for the two periods was 8% vs 18% at 5 years, with a median survival of 9 and 18 months. A greater difference was evident for N0 patients where the survival rose from 15% to 35% at 5 years, with a median survival of 15 vs 38 months.

Modified Schoemacher resection for distal gastric cancer.

Between October 1979 and February 1987, 30 consecutive patients with cancer of the lower stomach underwent B1-Schoemacher resection with a tubular gastric pouch. Operative mortality was 0% and operative morbidity 10% (leak 3%, anastomotic stricture 3% and abscess 3%). After a mean follow-up of 30 months, the expected 5-year survival was 32%. The causes of death were: 7 distant relapses, 2 noncancer diseases and 1 new primary cancer. The overall incidence of postgastrectomy symptoms was 23% for the whole series and 35% for the patients harboring small tumors. Mild dyspepsia occurred in 71%. The declining concept of total gastrectomy as an essential requirement for curative resection and the recent evidence that B2 for gastric lesions is a carcinogenic operation necessitate alternative procedures. The data show that modified Schoemacher resection can be consider a valid challenge to B2.