Filippo Lococo

EGFR-targeted therapy for non-small cell lung cancer: focus on EGFR oncogenic mutation.

The two essential requirements for pathologic specimens in the era of personalized therapies for non-small cell lung carcinoma (NSCLC) are accurate subtyping as adenocarcinoma (ADC) versus squamous cell carcinoma (SqCC) and suitability for EGFR molecular testing, as well as for testing of other oncogenes such as EML4-ALK and KRAS. Actually, the value of EGFR expressed in patients with NSCLC in predicting a benefit in terms of survival from treatment with an epidermal growth factor receptor targeted therapy is still in debate, while there is a convincing evidence on the predictive role of the EGFR mutational status with regard to the response to tyrosine kinase inhibitors (TKIs). This is a literature overview on the state-of-the-art of EGFR oncogenic mutation in NSCLC. It is designed to highlight the preclinical rationale driving the molecular footprint assessment, the progressive development of a specific pharmacological treatment and the best method to identify those NSCLC who would most likely benefit from treatment with EGFR-targeted therapy. This is supported by the belief that a rationale for the prioritization of specific regimens based on patient-tailored therapy could be closer than commonly expected.

Malignant solitary fibrous tumors of the pleura: retrospective review of a multicenter series.

Introduction: Available data on the malignant solitary fibrous tumor of the pleura (mSFTP), a very rare neoplasm with unpredictable prognosis, are scarce. The aim of this study is to collectively analyze the aggregated data from the largest series in the English literature to date, a multicenter, 10-year study of 50-cases. Methods: We retrospectively reviewed the clinical records of patients who underwent surgical resection for mSFTP in the period between January 2000 to July 2010. Long-term survival (LTS) and 5-year disease-free survival were analyzed in detail. Results: There were 24 men and 26 women (median age, 66 years; age range, 44–83 years). Thirty-two patients (64%) were symptomatic. A malignant pleural effusion was diagnosed in 12 cases. Surgical resection included isolated mass excision in 13 patients and extended resection in 35. In the remaining two cases only biopsies were undertaken. The resection was complete in 46 cases (92%). Adjuvant treatment was administered to 15 patients. Median follow-up was 116 months (range, 18–311 months). Overall LTS and disease-free survival were 81.1% and 72.1%, respectively. Fifteen patients (30%) experienced a relapse of the disease. Complete resection yielded much better LTS than partial resection (87.1% versus 0%; p < 0.001). At the Cox regression analysis, incomplete resection (hazards ratio [HR]: 39.02; 95% confidence interval [CI]:4.04–380.36; p = 0.002) and malignant pleural effusion (HR: 3.44; 95%CI: 0.98–12.05; p = 0.053) were demonstrated to be risk factors for earlier death. At multivariate analysis, chest-wall invasion and malignant pleural effusion increased the risk of recurrence (HR: 4.34; 95%CI: 1.5%–12.6%; p = 0.007 and HR: 3.48; 95%CI: 1.1%–11.0%; p = 0.038, respectively). Conclusions: Surgical resection remains the treatment of choice for mSFTP. Relapse is common (approximately 30%). Incomplete resection and malignant pleural effusion at diagnosis impact LTS negatively.

Solitary fibrous tumors of the pleura.

Purpose of review Solitary fibrous tumor of the pleura (SFTP) is a rare neoplasm of the pleura. Although an increasing number of case series have been reported in recent years, so far clinical behavior is still unpredictable. The following article presents a detailed review of the recent larger series of SFTP with particular attention to the clinical presentation, pathologic characteristics and surgical features in order to define more precisely the long-term outcome after treatment of this rare entity. Recent findings Usually, after a complete surgical resection a very long survival could be expected in almost all cases. However, the preoperative detection and management of malignant SFTPs are still challenging issues. Summary SFTP remains an enigmatic tumor. Clinical and radiological assessment is often unsatisfactory to obtain a definitive diagnosis. Benign SFTPs are almost always cured with complete surgical resection, and in cases of recurrence the re-do resection of benign recurrences is usually curative. Long-term survivals are also possible for malignant SFTPs, although a higher recurrence rate and higher tumor-related mortality can be expected in these cases. Histologic characteristics distinguishing benign from malignant variants are crucial in estimating the risk of recurrence and planning adjuvant therapies.

Single-centre 40-year results of redo operation for recurrent thymomas

OBJECTIVE Modes of treatment for recurrent thymoma remain controversial. The aim of this study is to analyse the early and long-term results of surgical intervention for this condition. METHODS Between 1972 and 2008, 43 out of 315 patients, who underwent resection with radical intent for thymoma, subsequently relapsed. Of these, 30 cases were deemed suitable for resection and operation, and were surgically treated. The remaining 13 were treated with radio- and/or chemotherapy (RT/CT). Overall outcomes for long-term survival up to 5 years (LTS) and disease-free survival (DFS) were analysed using standard statistics. RESULTS The average age of the relapsed patients was 54.7±12.7 years. There were 21 males and 22 females. Forty out of the 43 had myasthenia gravis (MG). Fifteen cases concerned a single detected relapse lesion. Among the 43 patients, relapses were found in the following sites: pleura (25 cases), mediastinum (12), lung (five), liver and bone (one). The perioperative mortality was 0% and the morbidity was 27%. Twenty-two of the surgically treated patients had complete resection; their LTS was 77% and DFS was 71%. Those patients who underwent surgery had significantly better outcomes compared with patients treated with radio- and/or chemotherapy (LTS only 35%; hazard ratio (HR): 0.22; 95% confidence interval (CI): 0.08-0.59; p=0.001). Complete repeated resection yielded much better outcomes than partial resection (LTS 91% vs 31%, p<0.001), whereas incomplete resection was associated, as one might expect, with a poor prognosis (HR: 6.12; 95% CI: 1.18-31.55; p=0.031). No evidence for an association with other clinical, surgical and pathological characteristics was found with regard to LTS or DFS. CONCLUSIONS Surgical resection is recommended for the treatment of recurrent thymoma, provided that criteria for suitability for resection/operation are satisfactory at the time of diagnosis. Best survival outcomes are found to depend on the degree of completeness of the repeat resection.

Surgery for oligometastatic non-small cell lung cancer: long-term results from a single center experience.

OBJECTIVE The role of surgery in the multimodal therapy for selected stage IV oligometastatic non-small cell lung cancer (NSCLC) is still a forum of open discussion. METHODS We have retrospectively analyzed the records of 53 patients with oligometastatic NSCLC who had been treated with curative intent in the period January 1997 to May 2010. RESULTS The mean age and the male/female ratio were 61 years and 32:21, respectively. A single metastatic lesion was present in 45 (84.9%) subjects, in 2 patients there were 2 different anatomic sites involved, and in 8 patients there were 2 metastases in the same site. The most common involved sites were brain (39), followed by adrenal gland (7), bone (3), vertebrae (3), liver (1), and contralateral supraclavicular lymph node (1). Distant disease was completely resected in 42 patients; 10 patients were treated with exclusive chemotherapy and/or radiotherapy and 1 with local laser therapy. Twenty-nine patients had been administered concurrent chemoradiation in a neoadjuvant setting before the surgical treatment at the lung or both sites (primary/distant). The pulmonary resection was complete (R0) in 42 patients (79.2%). Overall, 1- and 5-year survivals were 73.1% and 24%, respectively (median follow-up, 28 months). Median overall survival, local disease-free survival, and distant disease-free survival, estimated using the Kaplan-Meier method, were respectively 19, 72, and 12 months. After stepwise multivariate analysis, the weight loss (P<.001), the completeness of pulmonary resection (P=.0019), and, interestingly, the performance of a positron emission tomography-computed tomography scan in preoperative staging (P=.05) maintained their independent prognostic value as overall survival determinants. CONCLUSIONS Surgical treatment for selected stage IV NSCLC is feasible and safe. Furthermore, good survival can be expected in those patients in whom a complete resection of the primary tumor and radical control of the distant diseases are accomplished.

Thymectomy in myasthenia gravis: proposal for a predictive score of postoperative myasthenic crisis

OBJECTIVES Thymectomy plays an important role in patients with myasthenia gravis (MG). This study aimed to explore predictors of postoperative myasthenic crisis (POMC) after thymectomy and to define a predictive score of respiratory failure. METHODS The clinical data of 177 patients with MG undergoing thymectomy from January 1995 to December 2011 were retrospectively reviewed. The following factors were analysed in relation to the occurrence of myasthenic crisis: gender, age, body mass index (BMI), anti-acetylcholine receptor-antibody level, bulbar symptoms, comorbidities, duration of symptoms, Osserman-stage, Myasthenia Gravis Foundation of America (MGFA) stage, history of myasthenic crisis, use of immoglobulins or plasmapheresis, kind of therapy, spirometric and blood gas parameters, histology, kind of surgery, non-myasthenic complications and duration of intubation. RESULTS Twenty-two patients experienced postoperative respiratory failure after thymectomy. Univariate analysis revealed a correlation with age >60 years (odds ratio (OR) = 1.79, 95% confidence interval (CI) = 1.04-6.78; P = 0.040); Osserman-stage (IIB- OR = 5.16, 95% CI = 1.10-24.18; P = 0.037, III-IV- OR = 8.75, 95% CI = 1.53-50.05; P = 0.015); bulbar symptoms (OR = 7.42, 95% CI = 1.67-32.84; P = 0.008); BMI >28 (OR = 3.99, 95% CI = 1.58-10.03; P = 0.003); preoperative plasmapheresis (OR = 2.97, 95% CI = 1.18-14.04; P = 0.021); duration of symptoms >2 years (OR = 4.00, 95% CI = 1.09-14.762; P = 0.036); extended surgery (OR = 2.52, 95% CI = 1.02-6.22; P = 0.045); lung (OR = 4.05, 95% CI = 1.44-11.42; P = 0.008), pericardial (OR = 3.78, 95% CI = 1.45-9.82; P = 0.006) or pleural resection (OR = 3.23, 95% CI = 1.30-8.03; P = 0.012); Vital Capacity % <80% (OR = 0.20, 95% CI = 0.05-0.82; P = 0.025) and PaCO2 >40 mmHg (OR = 3.76, 95% CI = 1.12-12.68; P = 0.032). Multivariate logistic regression analysis showed that Osserman-stage (IIB- OR = 5.69, 95% CI = 1.09-29.69; P = 0.039 (III-IV- OR = 11.33, 95% CI = 1.67-76.72; P = 0.013), BMI >28 (OR = 3.65, 95% CI = 1.10-12.15; P = 0.035), history of myasthenic crisis (OR = 24.10, 95% CI = 2.34-248.04; P = 0.007), duration of symptoms >2 years (OR = 5.94, 95% CI = 1.12-31.48; P = 0.036) and lung resection (OR = 8.48, 95% CI = 2.18-32.97; P = 0.002) independently predict POMC. Excluding history of preoperative myasthenic crisis (statistically associated with Osserman-stage), we built a scoring system according to the OR of Osserman-stage (I-IIA, IIB, III-IV), BMI (<28, ≥ 28), duration of symptoms (<1, 1-2, >2 years) and association with a pulmonary resection. This model helped in creating four classes with increasing risk of respiratory failure (Group I, 6%; Group II, 10%; Group III, 25%; Group IV, 50%). CONCLUSIONS Our model facilitates the stratification of patient risk and prediction of the occurrence of POMC. Moreover, it could help to guide the anaesthesiologists decision on the duration of intubation. Further studies based on larger series are needed to confirm these preliminary data.

PET/CT assessment of neuroendocrine tumors of the lung with special emphasis on bronchial carcinoids

Pulmonary neuroendocrine tumors (pNETs) arise from bronchial mucosal cells known as enterochromaffin cells which are part of the diffuse neuroendocrine system. The pathological spectrum of pNETs ranges from low-/intermediate-grade neoplasms such as bronchial carcinoids (BCs), also known as typical or atypical carcinoids, to high-grade neoplasms as large-cell neuroendocrine carcinoma and small-cell lung cancer. The tumor biology of pNETs still represents a matter of open debate. The distinct features among the different pNETs include not only their pathologic characteristics but also their clinical behavior, epidemiology, treatment, and prognosis. In this sense, a correct pathological identification in the preoperative setting is a key element for planning the best strategy of care in pNETs and especially in BCs. Controversial results have been reported on the diagnostic accuracy of fluorine-18-fluorodeoxyglucose positron emission tomography or positron emission tomography/computed tomography (F-18-FDG PET or PET/CT) in BCs. On the other hand, there is increasing evidence supporting the use of PET with somatostatin analogues (DOTA-TOC, DOTA-NOC, or DOTA-TATE) labeled with gallium-68 (Ga-68) in pNETs. Herein, we review the pertinent literature aiming to better define the current state of art of PET/CT in the detection and histological differentiation of pNETs with special emphasis on BCs.

Role of combined 18F-FDG-PET/CT for predicting the WHO malignancy grade of thymic epithelial tumors: A multicenter analysis

INTRODUCTION To investigate the performance of combined (18)F-FDG-PET/CT as a predictor of the WHO-classification based malignancy grade in thymic epithelial tumors. METHODS From 05/06 to 02/12, the data of 47 patients with thymic epithelial tumors assessed by (18)F-FDG-PET/CT before being surgically treated were collected in 3 centers and retrospectively reviewed for the purposes of this study. The SUVmax and the SUVmax/T index (the ratio tumor-SUVmax to tumor-size) have been matched with specific subgroups of the WHO-classification: low-risk thymomas (types A-AB-B1), high-risk thymomas (types B2-B3) and thymic carcinomas (type C). RESULTS There were 22 men and 25 women (age range: 31-84 yrs). Mean tumor size was 44.7 ± 19.0 mm. The WHO-classification was: type-A #2, type-AB #11, type-B1 #9, type-B2 #9, type-B3 #9 and type-C #7. The SUVmax and the SUVmax/T were found to be predictive factors useful to distinguish thymomas from thymic carcinomas (SUVmax: area under ROC-curve: 0.955, p = 0.0045; SUVmax/T-size: area under ROC-curve: 0.927, p = 0.0022). Moreover, both parameters were found to be correlated with the WHO malignancy grade (low-risk thymomas; high-risk thymomas; thymic carcinoma), Spearman correlation coefficients being 0.56 (p < 0.0001) and 0.76 (p < 0.0001), respectively for the SUVmax and for the SUVmax/T index. In addition, the SUVmax is also significantly correlated with Masaoka stage (Spearman correlation coefficient: 0.30, p = 0.0436) CONCLUSIONS: A significant relationship was observed between (18)F-FDG-PET/CT findings and histologic WHO-classification for this cohort of thymic epithelial tumors. Thus, on the basis of these evidences, we infer that (18)F-FDG-PET/CT may be useful to predict histology and the WHO classes of risk.

Surgery for patients with persistent pathological N2 IIIA stage in non-small-cell lung cancer after induction radio-chemotherapy: the microscopic seed of doubt §

OBJECTIVE The surgical treatment of residual N2 disease following induction radio-chemotherapy (IT) for locally advanced cIIIA-N2 non-small-cell lung cancer (NSCLC) is still debated. The long-term results after resection in a pN2 series are at the focus of this study. METHODS From January 1992 to December 2008, 161 consecutive pathologically proven Stage IIIA-N2 NSCLC patients underwent IT. Among these, 40 pN2s were included in this retrospective analysis. The associations between the mortality and the disease-free status with potential risk factors were explored by means of the Kaplan-Meier and Cox regression analysis. RESULTS Mean age and male/female ratio were 58.7 ± 9.7 years and 36/4, respectively. Twelve patients (30%) showed a clinical partial response and 28 (70%) showed stable disease. There was one (3%) perioperative death and four (10%) major complications. In the total group, the 3- and 5-year survival rates were 24.2% and 19.3%, respectively. The Cox regression analysis suggested that the macroscopic pN2 status proved to be a negative prognostic factor (hazard ratio (HR)=2.8, confidence interval (CI) 95%: 1.1-7.3; p=0.04). The recurrence rate flattened at 30.8% at the 3rd year. Furthermore, the bilobectomy-pneumonectomy group had a risk of relapse 6.9 times higher than the lobectomy group (CI 95%: 2.5-18.8; p < 0.001). CONCLUSIONS The persistence of disease at the N2 level after IT and surgery for cIIIa-N2 NSCLC does not exclude favorable outcome after resection, in particular in those patients with minor residual disease.

Multicenter comparison of 18F-FDG and 68Ga-DOTA-peptide PET/CT for pulmonary carcinoid

Purpose The aims of this study were to retrospectively evaluate and compare the detection rate (DR) of 68Ga-DOTA-peptide and 18F-FDG PET/CT in the preoperative workup of patients with pulmonary carcinoid (PC) and to assess the utility of various functional indices obtained with the 2 tracers in predicting the histological characterization of PC, that is, typical versus atypical. Methods Thirty-three consecutive patients with confirmed PC referred for 18F-FDG and 68Ga-DOTA-peptide PET/CT in 2 centers between January 2009 and April 2013 were included. The semiquantitative evaluation included the SUVmax, the SUV of the tumor relative to the maximal liver uptake for 18F-FDG (SUVT/L) or the maximal spleen uptake for 68Ga-DOTA-peptides (SUVT/S), the ratio between SUVmax of 68Ga-DOTA-peptides PET/CT, and the SUVmax of 18F-FDG PET/CT (SUVmax ratio). Histology was used as reference standard. Results Definitive diagnosis consisted of 23 typical carcinoids (TCs) and 10 atypical carcinoids. 18F-FDG PET/CT was positive in 18 cases and negative in 15 (55% DR). 68Ga-DOTA-peptide PET/CT was positive in 26 cases and negative in 7 (79% DR). In the subgroup analysis, 68Ga-DOTA-peptide PET/CT was superior in detecting TC (91% DR; P < 0.001), whereas 18F-FDG PET/CT was superior in detecting atypical carcinoid (100% DR; P = 0.04). The SUVmax ratio was the most accurate semiquantitative index in identifying TC. Conclusions Overall diagnostic performance of PET/CT in detecting PC is optimal when integrating 18F-FDG and 68Ga-DOTA-peptide PET/CT findings. In the subgroup analysis, the SUVmax ratio seems to be the most accurate index in predicting TC. Both methods should be performed when PC is suspected or when the histological subtype is undefined.