Lorenzo Spaggiari

Alterations of the Notch pathway in lung cancer

Notch signaling regulates cell specification and homeostasis of stem cell compartments, and it is counteracted by the cell fate determinant Numb. Both Numb and Notch have been implicated in human tumors. Here, we show that Notch signaling is altered in approximately one third of non–small-cell lung carcinomas (NSCLCs), which are the leading cause of cancer-related deaths: in ≈30% of NSCLCs, loss of Numb expression leads to increased Notch activity, while in a smaller fraction of cases (around 10%), gain-of-function mutations of the NOTCH-1 gene are present. Activation of Notch correlates with poor clinical outcomes in NSCLC patients without TP53 mutations. Finally, primary epithelial cell cultures, derived from NSCLC harboring constitutive activation of the Notch pathway, are selectively killed by inhibitors of Notch (γ-secretase inhibitors), showing that the proliferative advantage of these tumors is dependent upon Notch signaling. Our results show that the deregulation of the Notch pathway is a relatively frequent event in NSCLCs and suggest that it might represent a possible target for molecular therapies in these tumors.

Transmanubrial Osteomuscular Sparing Approach for Apical Chest Tumors

The transclavicular approach improved the treatment of apical chest tumors. However, removing the internal half of the clavicle and sectioning its muscular insertions led to serious postoperative alterations. We propose a transmanubrial approach, through a manubrial L-shaped transection and first costal cartilage resection, which allows retraction of an osteomuscular flap including but sparing the clavicle and all its muscular insertions. The elevation of the osteomuscular flap affords excellent access to the subclavicular region with safe control and resection of neurovascular outlet structures during the resection of apical chest tumors. Shoulder articulations and stability of the scapular girdle are respected, thus avoiding functional and cosmetic consequences of clavicle resection.

Surgical treatment of hepatic and pulmonary metastases from colorectal cancers

BACKGROUND Selected patients with double hepatic and pulmonary metastases from colorectal cancer may benefit from operation. METHODS From 1970 to 1995, 239 patients underwent operation for resection of pulmonary metastases from colorectal cancer at two French surgical centers. Among these patients, 43 (18%) had previously undergone complete resection of hepatic metastases and constitute the subject of this retrospective study. RESULTS The median interval time between hepatic and pulmonary resections was 18 months. Two pneumonectomies, 5 lobectomies, 3 segmentectomies, 6 wedge resections, and 27 metastasectomies were performed. No postoperative mortality was observed. Two patients had major postoperative complications. Seven patients (16%) underwent subsequent pulmonary resection for recurrences. Twenty-one patients were still alive, 14 free of disease. The median survival from pulmonary resection was 19 months and the 5-year probability of survival was 11%. Prethoracotomy carcinoembryonic antigen blood levels and the number of pulmonary resection were found to be significant prognostic factors; the interval time between hepatic and pulmonary resection (> 36 months) was borderline significant (p = 0.06). CONCLUSIONS Selected patients with combined hepatic and pulmonary metastases from colorectal cancer should be considered for surgical resection. Patients with normal prethoracotomy carcinoembryonic antigen levels and late metachronous pulmonary metastasis, appear to be the best surgical candidates.

Immediate and long-term results after surgical treatment of primary spontaneous pneumothorax by VATS

BACKGROUND Video-assisted thoracic surgery has recently evolved as a viable alternative to thoracotomy for spontaneous pneumothorax. METHODS A series of 163 patients with primary spontaneous pneumothorax were treated by video-assisted thoracic surgery. Seventy patients were treated for a recurrent episode, 64 patients for a persistent primary spontaneous pneumothorax, 24 patients for a contralateral episode, and 5 patients for a bilateral primary spontaneous pneumothorax. Stapling of bullae with an Endo-GIA stapler (Auto-Suture, Elencourt, France) was performed in 90% of the cases and parietal pleural abrasion was performed in each case. RESULTS One revisional lateral limited thoracotomy was required for bleeding. Six patients had a prolonged air leak; 2 of them were reoperated on by lateral limited thoracotomy. Two patients have had an incomplete reexpansion of the lung and required a reoperation. The duration of hospitalization was 6.9 +/- 3 days. With a mean follow-up of 24.5 months, three recurrences requiring a reoperation occurred; 3 other patients had a partial recurrence and healed by rest without drainage. The mean time to return to the occupational activity of the patients was 42 +/- 34 days. These results were compared with those of a previous series of 87 patients operated on by lateral limited thoracotomy. CONCLUSIONS With the development of surgical technique and video equipment, video-assisted thoracic surgery will probably become the treatment of choice of primary spontaneous pneumothorax.

Lung cancer screening with low-dose computed tomography: A non-invasive diagnostic protocol for baseline lung nodules

BACKGROUND Indeterminate non-calcified lung nodules are frequent when low-dose spiral computed tomography (LD-CT) is used for lung cancer screening. We assessed the diagnostic utility of a non-invasive work-up protocol for nodules detected at baseline in volunteers enrolled in our single-centre screening trial, and followed for at least 1 year. METHODS 5201 high-risk volunteers, recruited over 1 year from October 2004, underwent baseline LD-CT; 4821 (93%) returned for the first repeat LD-CT. Nodules <or=5mm underwent repeat LD-CT at 1 year; nodules 5.1-8mm underwent LD-CT 3 months later; lesions >8mm received combined CT-positron emission tomography (CT-PET). A subset of nodules >8mm was studied by CT with contrast. Protocol failures were delayed diagnosis with disease progression beyond stage I, and negative surgical biopsy. RESULTS 2754 (53%) volunteers presented one or more non-calcified nodules. Ninety-two lung cancers were diagnosed: 55 at baseline and 37 at annual screening (66% stage I). Among the 37 incident cancers, 17 had a baseline nodule that remained stage I, 7 had a baseline nodule that progressed beyond stage I, and 13 presented a new malignant nodule. Baseline and annual cancers were 79 (1.5%) and 13 (0.2%), respectively. In 15 of 104 (14%) invasive diagnostic procedures, the lesion was benign. Sensitivity, and specificity were 91 and 99.7%, respectively, for the entire protocol; 88 and 93% for CT-PET; and 100 and 59% for CT with contrast. CONCLUSIONS The protocol limits invasive diagnostic procedures while few patients have diagnosis delay, supporting the feasibility of lung cancer screening in high-risk subjects by LD-CT. Nevertheless further optimization of the clinical management of screening-detected nodules is necessary.

Four-arm robotic lobectomy for the treatment of early-stage lung cancer

OBJECTIVES We investigated the feasibility and safety of four-arm robotic lung lobectomy in patients with lung cancer and described the robotic lobectomy technique with mediastinal lymph node dissection. METHODS Over 21 months, 54 patients underwent robotic lobectomy for early-stage lung cancer at our institute. We used a da Vinci Robotic System (Intuitive Surgical, Inc, Mountain View, Calif) with three ports plus one utility incision to isolate hilum elements and perform vascular and bronchial resection using standard endoscopic staplers. Standard mediastinal lymph node dissection was performed subsequently. Surgical outcomes were compared with those in 54 patients who underwent open surgery over the same period and were matched to the robotic group using propensity scores for a series of preoperative variables. RESULTS Conversion to open surgery was necessary in 7 (13%) cases. Postoperative complications (11/54, 20%, in each group) and median number of lymph nodes removed (17.5 robotic vs 17 open) were similar in the 2 groups. Median robotic operating time decreased by 43 minutes (P = .02) from first tertile (18 patients) to the second-plus-third tertile (36 patients). Median postoperative hospitalization was significantly shorter after robotic (excluding first tertile) than after open operations (4.5 days vs 6 days; P = .002). CONCLUSIONS Robotic lobectomy with lymph node dissection is practicable, safe, and associated with shorter postoperative hospitalization than open surgery. From the number of lymph nodes removed it also appears oncologically acceptable for early lung cancer. Benefits in terms of postoperative pain, respiratory function, and quality of life still require evaluation. We expect that technologic developments will further simplify the robotic procedure.

Results of re-resection for recurrent thymomas.

BACKGROUND The treatment of recurrent thymomas remains controversial. PATIENTS The place for re-resection was retrospectively studied in 28 consecutive patients operated on during the last 40 years. The initial Masaoka staging of the thymoma was stage I, 4; stage II, 8; stage III, 11; and stage IVa, 3. Postoperatively, 14 have had radiation therapy, 1 chemotherapy, and 13 no adjuvant treatment. Seven patients had development of recurrences, 15 had pleuropulmonary metastases, 5 had both, and 1 had thoracotomy scar recurrence. Nineteen patients had a complete resection and 9 an incomplete one. RESULTS Most local recurrences appeared after resection of stage I or II thymomas. On the other hand, in patients with stage III or IV thymomas pleural or pulmonary metastases mainly developed. No local recurrence occurred in patients who initially received postoperative radiation therapy. Five-year and 10-year survival rates were 51% and 43%, respectively, for the overall population. Among the 19 patients with complete resection, only 3 patients had a subsequent recurrence; 1 of them could be reoperated on and is still alive and free of disease. CONCLUSIONS Thymoma recurrences often appear as a locoregional rather than a hematogenous spread. Reresection can be recommended in selected patients.

Randomized Phase III Study of Surgery Alone or Surgery Plus Preoperative Cisplatin and Gemcitabine in Stages IB to IIIA Non–Small-Cell Lung Cancer

PURPOSE This study aimed to determine whether three preoperative cycles of gemcitabine plus cisplatin followed by radical surgery provides a reduction in the risk of progression compared with surgery alone in patients with stages IB to IIIA non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Patients with chemotherapy-naive NSCLC (stages IB, II, or IIIA) were randomly assigned to receive either three cycles of gemcitabine 1,250 mg/m(2) days 1 and 8 every 3 weeks plus cisplatin 75 mg/m(2) day 1 every 3 weeks followed by surgery, or surgery alone. Randomization was stratified by center and disease stage (IB/IIA v IIB/IIIA). The primary end point was progression-free survival (PFS). Results The study was prematurely closed after the random assignment of 270 patients: 129 to chemotherapy plus surgery and 141 to surgery alone. Median age was 61.8 years and 83.3% were male. Slightly more patients in the surgery alone arm had disease stage IB/IIA (55.3% v 48.8%). The chemotherapy response rate was 35.4%. The hazard ratios for PFS and overall survival were 0.70 (95% CI, 0.50 to 0.97; P = .003) and 0.63 (95% CI, 0.43 to 0.92; P = .02), respectively, both in favor of chemotherapy plus surgery. A statistically significant impact of preoperative chemotherapy on outcomes was observed in the stage IIB/IIIA subgroup (3-year PFS rate: 36.1% v 55.4%; P = .002). The most common grade 3 or 4 chemotherapy-related adverse events were neutropenia and thrombocytopenia. No treatment-by-histology interaction effect was apparent. CONCLUSION Although the study was terminated early, preoperative gemcitabine plus cisplatin followed by radical surgery improved survival in patients with clinical stage IIB/IIIA NSCLC.

Estimating overdiagnosis in low-dose computed tomography screening for lung cancer: a cohort study.

BACKGROUND Lung cancer screening may detect cancer that will never become symptomatic (overdiagnosis), leading to overtreatment. Changes in size on sequential low-dose computed tomography (LDCT) screening, expressed as volume-doubling time (VDT), may help to distinguish aggressive cancer from cases that are unlikely to become symptomatic. OBJECTIVE To assess VDT for screening-detected lung cancer as an indicator of overdiagnosis. DESIGN Retrospective estimation of the VDT of cancer detected in a prospective LDCT screening cohort. SETTING Nonrandomized, single-center screening study involving persons at high risk for lung cancer enrolled between 2004 and 2005 who received LDCT annually for 5 years. PATIENTS 175 study patients diagnosed with primary lung cancer. MEASUREMENTS VDT was measured on LDCT and classified as fast-growing (<400 days), slow-growing (between 400 and 599 days), or indolent (≥600 days). RESULTS Fifty-five cases of cancer were diagnosed at baseline, and 120 were diagnosed subsequently. Of the latter group, 19 cases (15.8%) were new (not visible on previous scans) and fast-growing (median VDT, 52 days); 101 (84.2%) were progressive, including 70 (58.3%) fast-growing and 31 (25.8%) slow-growing (15.0%) or indolent (10.8%) cases. Lung cancer-specific mortality was significantly higher (9.2% per year) in patients with new compared with slow-growing or indolent (0.9% per year) cancer. Sixty percent of fast-growing progressive cancer and 45% of new cancer were stage I, for which survival was good. LIMITATIONS This is a retrospective study. Volume-doubling time can only indicate overdiagnosis and was estimated for new cancer from 1 measurement (a diameter of 2 mm assumed the previous year). CONCLUSION Slow-growing or indolent cancer comprised approximately 25% of incident cases, many of which may have been overdiagnosed. To limit overtreatment in these cases, minimally invasive limited resection and nonsurgical treatments should be investigated. PRIMARY FUNDING SOURCE Italian Association for Cancer Research.

Grading the neuroendocrine tumors of the lung: an evidence-based proposal.

Lung neuroendocrine tumors are catalogued in four categories by the World Health Organization (WHO 2004) classification. Its reproducibility and prognostic efficacy was disputed. The WHO 2010 classification of digestive neuroendocrine neoplasms is based on Ki67 proliferation assessment and proved prognostically effective. This study aims at comparing these two classifications and at defining a prognostic grading system for lung neuroendocrine tumors. The study included 399 patients who underwent surgery and with at least 1 year follow-up between 1989 and 2011. Data on 21 variables were collected, and performance of grading systems and their components was compared by Cox regression and multivariable analyses. All statistical tests were two-sided. At Cox analysis, WHO 2004 stratified patients into three major groups with statistically significant survival difference (typical carcinoid vs atypical carcinoid (AC), P=0.021; AC vs large-cell/small-cell lung neuroendocrine carcinomas, P<0.001). Optimal discrimination in three groups was observed by Ki67% (Ki67% cutoffs: G1 <4, G2 4-<25, G3 ≥25; G1 vs G2, P=0.021; and G2 vs G3, P≤0.001), mitotic count (G1 ≤2, G2 >2-47, G3 >47; G1 vs G2, P≤0.001; and G2 vs G3, P≤0.001), and presence of necrosis (G1 absent, G2 <10% of sample, G3 >10% of sample; G1 vs G2, P≤0.001; and G2 vs G3, P≤0.001) at uni and multivariable analyses. The combination of these three variables resulted in a simple and effective grading system. A three-tiers grading system based on Ki67 index, mitotic count, and necrosis with cutoffs specifically generated for lung neuroendocrine tumors is prognostically effective and accurate.