Does adjuvant radiation therapy improve disease-free survival in completely resected Masaoka stage II thymoma?

OBJECTIVE: To determine whether or not patients with completely resected Masaoka stage II thymoma benefit from postoperative radiotherapy (RT). METHODS: We retrospectively review the case records and compared the long-term outcomes of patients affected by Masaoka stage II thymoma treated by resection alone with same stage thymoma patients submitted to resection and RT. Surgical specimens were reviewed to confirm pathological stage, negative resection margins and histological subtype. RESULTS: Between 1988 and 2000, we performed 197 resections for thymoma; 58 patients resulted to be affected by completely resected tumours with microscopic transcapsular invasion (stage IIA, n=25) or macroscopic invasion into the surrounding fatty tissue with or without adhesion to the mediastinal pleura (stage IIB, n=33). Thirty-two patients underwent only complete surgical resection (14 stage IIA and 18 stage IIB); 26 patients underwent complete resection and subsequent mediastinal RT (11 stage IIA and 15 stage IIB). RT dosages were 45-54grays (Gy), in 25-30 fractions. Histological subtypes were similarly represented in both groups. Median follow-up was 91 months (range 9-170). Five intrathoracic recurrences occurred: three radiated patients (2 stage IIB - 1 AB and 1 B2 thymoma; 1 stage IIA B1 thymoma) and two not-radiated patients (1 stage IIA AB thymoma and 1 stage IIB B1 thymoma). Disease-free survival rate at 5- and 10-year were 94% and 87%, respectively. Log-rank test showed no difference in Kaplan-Meier survival curves (p=0.432) between radiated and not-radiated patients. CONCLUSIONS: These data support the concept that radical surgical resection alone should be considered a sufficient treatment for stage II thymoma.

Pulmonary metastases from epithelial tumours: late results of surgical treatment.

OBJECTIVE: Development of distant metastases is one of the primary characteristics of malignant tumours. During the last decades, lung metastasectomy has been progressively accepted as a therapeutic option in oncology patients. The present paper aims to evaluate the long-term results and factors influencing prognosis in patients submitted to lung resection for metastases from extrapulmonary epithelial tumours. METHODS: We retrospectively analysed data of 202 patients undergoing 207 procedures of lung metastasectomy between January 1980 and December 2003. Factors that may influence long-term prognosis such as completeness of resection, histology of the tumour, disease-free interval, number of resected lesions, involvement of hilar or mediastinal lymph nodes, systemic treatments were investigated. RESULTS: Complete resection was carried out in 169 patients (83.7%). The more frequent lung resection was sublobar in 67.6% of cases, but rarely in selected patients bilobectomy or pneumonectomy has been carried out too. Perioperative morbidity and mortality were 7.7% and 0.9%. Mean disease-free interval was 49+/-48 months. Mean follow-up was 33+/-31 months, 5-year and 10-year survival rates for completely resected patients were 43% and 17%, respectively. By univariate and multivariate analyses, completeness of resection, disease-free interval of 36 months or more, and single resected metastasis were found to be significant prognostic factors. CONCLUSIONS: Resection of epithelial lung metastases allows an acceptable prognostic result in appropriately selected patients with very low perioperative morbidity and mortality. Factors such as high disease-free interval, single metastasis and completeness of resection are demonstrated and confirmed to be significantly associated with long-term survival.

Large-cell neuroendocrine carcinoma of the lung: a clinicopathologic study of eighteen cases and the efficacy of adjuvant treatment with octreotide.

OBJECTIVE: This study was undertaken to evaluate the efficacy of a new adjuvant protocol with octreotide, alone or in combination with radiotherapy, in radically resected large cell neuroendocrine carcinomas of the lung. METHODS: Between 1990 and 2001, a total of 18 consecutive patients affected by large cell neuroendocrine carcinomas of the lung were operated on. Lobectomy and systemic lymphadenectomy were performed in all cases. Postoperative radiotherapy was performed when stage was higher than Ib. Ten patients with positive results of preoperative indium In-111 pentetreotide scintigraphy received octreotide after the operation. RESULTS: Nine patients (50%) had local recurrences or distant metastases (mean recurrence time 14 months); palliative chemotherapy was given, but all patients died. In 10 cases (55.5%) octreotide alone or in combination with radiotherapy was administered as adjuvant treatment; 9 of these patients (90%) are alive and free of disease ( P = .0007), and the other had liver and brain metastases 21 months after surgery. CONCLUSIONS: Our preliminary results seem to demonstrate the efficacy of octreotide as adjuvant therapy in large cell neuroendocrine carcinomas of the lung when results of preoperative indium In-111 pentetreotide scintigraphy were positive. Further study are required to assess the utility of octreotide in patients with negative results of indium In-111 pentetreotide scintigraphy.

World Health Organization histologic classification: an independent prognostic factor in resected thymomas.

The histologic classification of thymoma remained controversial since 1999, when the World Health Organization (WHO) Consensus Committee published a histologic typing system for tumours of thymus. Clinical features, postoperative relapsing rates, and survival of patients with thymoma were evaluated with reference to the WHO histologic classification, based on a series of 178 patients, submitted to surgery between 1988 and 2000. There were 21 type A, 49 type AB, 45 type B1, 50 type B2 and 13 type B3 tumours. The invasiveness of tumours was 23.8%, 51%, 73.3%, 82% and 100% for types A, AB, B1, B2 and B3 tumours, respectively. The frequency of invasion of the great vessels increased according to the tumour type in the order A (0%), AB (4%), B1 (6.6%), B2 (22%), and B3 (23%). The 10-year disease-free survival was 95%, 90%, 85%, 71% and 40% for types A, AB, B1, B2 and B3, respectively. According to the Masaoka staging system, the disease-free survival rates were 94%, 88% and 66% for stages I, II and III, respectively, at 10 years. No stage IVA thymomas reached 10 years follow-up. Overall survival at 10 years were 88% and 25% when complete and incomplete resection were considered. By multivariate analysis, Masaoka staging system, WHO histologic classification and complete resection were significant independent prognostic factors, whereas age- and sex-associated myasthenia gravis were not. The present study demonstrated the World Health Organization histologic classification a good prognostic factor, such as completeness of surgical resection and Masaoka staging system.

Response variability to analgesics: a role for non-specific activation of endogenous opioids.

Individual differences in pharmacokinetics and pharmacodynamics, the type of pain and the method of drug administration can account for the response variability to analgesics. By integrating a clinical and an experimental approach, we report here that another important source of variability is represented by individual differences in non-specific (placebo) activation of endogenous opioid systems. In the first part of this study, we analyzed the effectiveness of buprenorphine, tramadol, ketorolac and metamizol in the clinical setting, where the placebo effect was completely eliminated by means of hidden infusions. We found that the hidden injections were significantly less effective and less variable compared with open injections (in full view of the subject), suggesting that part of the response variability was due to non-specific factors (placebo). Since we could not administer the opioid antagonist, naloxone, to these patients, in the second part of this study, we induced experimental ischemic arm pain in healthy volunteers and found that, as occurred in clinical pain, the analgesic response to a hidden injection of the non-opioid ketorolac was less effective and less variable than an open injection. Most importantly, we obtained the same effects by adding naloxone to an open injection of ketorolac, thus blocking the opioid-mediated placebo component of analgesia. These findings indicate that both the psychological (hidden injection) and pharmacological (naloxone) blockade of the placebo response reduce the effectiveness of, and the response variability to, analgesic drugs. Therefore, an important source of response variability to analgesics appears to be due to differences in non-specific activation of endogenous opioid systems.

Response expectancies in placebo analgesia and their clinical relevance.

Response expectancies have been proposed as the major determinant of placebo effects. Here we report that different expectations produce different analgesic effects which in turn can be harnessed in clinical practice. Thoracotomized patients were treated with buprenorphine on request for 3 consecutive days, together with a basal intravenous infusion of saline solution. However, the symbolic meaning of this basal infusion was changed in three different groups of patients. The first group was told nothing about any analgesic effect (natural history). The second group was told that the basal infusion was either a powerful painkiller or a placebo (classic double-blind administration). The third group was told that the basal infusion was a potent painkiller (deceptive administration). Therefore, whereas the analgesic treatment was exactly the same in the three groups, the verbal instructions about the basal infusion differed. The placebo effect of the saline basal infusion was measured by recording the doses of buprenorphine requested over the three-days treatment. We found that the double-blind group showed a reduction of buprenorphine requests compared to the natural history group. However, this reduction was even larger in the deceptive administration group. Overall, after 3 days of placebo infusion, the first group received 11.55 mg of buprenorphine, the second group 9.15 mg, and the third group 7.65 mg. Despite these dose differences, analgesia was the same in the three groups. These results indicate that different verbal instructions about certain and uncertain expectations of analgesia produce different placebo analgesic effects, which in turn trigger a dramatic change of behaviour leading to a significant reduction of opioid intake.

Bronchial carcinoid tumors: surgical management and long-term outcome.

OBJECTIVE: We sought to determine the variables influencing long-term survival of patients treated for bronchial carcinoid tumors. METHODS: A retrospective, mono-institutional review of patients subjected to surgical treatment since 1977 was conducted. RESULTS: Over 22 years, 126 patients with a final histologic diagnosis of bronchial carcinoid tumors were assessed for surgery. The group comprised 72 men (57%) and 54 women (43%) with a mean age at presentation of 47 +/- 16 years (range 11-77 years). Symptoms were present in 65 (53%) patients. Operations included lobectomy or bilobectomy in 88 (with 4 bronchoplastic procedures), pneumonectomy in 15, segmentectomy in 3, wedge resection in 16, and bronchial sleeve resection in 3 patients. One patient (0.7%) died in the perioperative period. Eighty-two patients (65%) had typical and 44 (35%) had atypical carcinoid tumors. Postoperative staging was complete for 113 of 126 patients (13 patients did not undergo lymphadenectomy): 90 patients had stage I disease, 6 had stage II, 15 had stage III, and 2 had stage IV disease. A typical subtype was stage I in 70 and more advanced (II-IV) in 5, whereas an atypical subtype was stage I in 20 and more advanced in 18 (P <.05). Mean follow-up was 99 +/- 73 months (range 6-282 months) during which 19 (15%) patients died (12 of recurrent disease). Recurrent tumor developed in 4 (5.5%) of 72 patients affected by typical subtypes and 8 (19.5%) of 41 by atypical subtypes with complete follow-up. Overall survival at 15 years was 74%; survival related to histologic type and nodal status at 15 years was significant (P <.05). CONCLUSIONS: Biologic behavior and prognosis for bronchial carcinoid tumors are better than for other lung cancers. Surgical treatment requires radical excision and lymph node sampling. Survival and long-term outcome are significantly related to the histologic type, nodal status, and pathologic stage.

Stage I pure bronchioloalveolar carcinoma: recurrences, survival and comparison with adenocarcinoma of the lung.

OBJECTIVE: Bronchioloalveolar carcinoma (BAC) is considered a subtype of adenocarcinoma of the lung, without pleural, stromal or vascular invasion (World Health Organization (WHO) classification). Previous reports had demonstrated a better prognosis following surgery for patients affected by early stage BAC than those affected by other type of non-small cell lung cancer (NSCLC). We aim to analyse differences between stage I peripheral nodular BAC and stage I peripheral adenocarcinoma of the lung, METHODS: From January 1, 1993 to December 31, 1999, 1158 patients were submitted to surgical resection for NSCLC. Out of them, 28 patients (2.4%) resulted affected by stage I peripheral pure BAC and 80 (6.9%) by stage I peripheral adenocarcinoma. We made a comparison between these two groups. RESULTS: The percentage of females in BAC patients was similar to that registered in adenocarcinoma patients (21.4 vs. 17.5%). No differences were detected between smokers in BAC and adenocarcinoma patients (P=0.331). The upper lobes were the most common sites of the primary tumour in both tumour subtypes (71.4 vs. 67.5%). Relapse of disease was less frequent in BAC than in adenocarcinoma patients (14.2 vs. 33.7%); recurrent disease developed intrathoracic with higher frequency in BAC patients (75 vs. 33.3%). Both 5-year disease-free and long-term survival were significantly higher in patients affected by BAC (81 vs. 51% and 86 vs. 71%, respectively) (P<0.05); when analysis is performed by dividing stage IA from IB tumours, BAC patients resulted to have higher DFS (stage IA, 93 vs. 58% - P=0.044; stage IB, 61 vs. 32.5%) and higher long-term survival (stage IA, 92 vs. 79%; stage IB, 75 vs. 56%). CONCLUSION: Patients with stage I pure BAC have significantly longer disease-free and overall survival than those with similar stage adenocarcinoma. Even if classified as subtype of adenocarcinoma, BAC is characterised by clinical behaviour less aggressive than similar stage adenocarcinoma.

Pulmonary resection for metastases from colorectal cancer: factors influencing prognosis. Twenty-year experience.

OBJECTIVE: We reviewed our experience in the surgical management of 80 patients with colorectal pulmonary metastases and investigated factors affecting survival. MATERIAL AND METHODS: From January 1980 to December 2000, 80 patients, 43 women and 37 men with median age 63 years (range 38-79 years) underwent 98 open surgical procedure (96 muscle-sparing thoracotomy, one clamshell and one median sternotomy) for pulmonary metastases from colorectal cancer (three pneumonectomy, 17 lobectomy, seven lobectomy plus wedge resection, six segmentectomy, three segmentectomy plus wedge resection and 62 wedge resection). Pulmonary metastases were identified at a median interval of 37.5 months (range 0-167) from primary colorectal resection. Second and third resections for recurrent metastases were done in seven and in four patients, respectively. RESULTS: Operative mortality rate was 2%. Overall, 5-year survival was 41.1%. Five-year survival was 43.6% for patients submitted to single metastasectomy and 34% for those submitted to multiple ones. Five-year survival was 55% for patients with disease-free interval (DFI) of 36 months or more, 38% for those with DFI of 0-11 months and 22.6% for those with DFI of 12-35 months (P=0.04). Five-year survival was 58.2% for patients with normal preoperative carcino-embryonic antigen (CEA) levels and 0% for those with pathologic ones (P=0.0001). Patients submitted to second-stage operation for recurrent local disease had 5-year survival rate of 50 vs. 41.1% of those submitted to single resection (P=0.326). CONCLUSIONS: Pulmonary resection for metastases from colorectal cancer may help survival in selected patients. Single metastasis, DFI>36 months, normal preoperative CEA levels are important prognostic factors. When feasible, re-operation is a safe procedure with satisfactory long-term results.

Lung tumors with mixed histologic pattern. Clinico-pathologic characteristics and prognostic significance.

OBJECTIVE: To analyze and compare clinico-pathologic characteristics and survival between lung tumors with mixed histologic pattern and our population of resected lung tumors with single histology in the same period. METHODS: From January 1993 to December 1999, 1158 patients received resection for lung tumors. Of these, 59 (5.1%) presented a mixed histologic pattern on the surgical specimen. There were 48 men and 11 women (mean age 64 years, range 43-79). Three groups of tumors were identified: adenosquamous carcinoma, combined neuroendocrine + non-neuroendocrine carcinoma (NNEC) and biphasic tumors (epithelial + mesenchymal malignant components) represented by carcinosarcoma and blastoma. The combined neuroendocrine tumors were further divided in small cell lung carcinoma (SCLC) + large cell neuroendocrine carcinoma (LCNEC)/NNEC and other neuroendocrine tumors/NNEC. Clinico-pathologic characteristics, pTNM and survival were analyzed and compared to our population of resected lung tumors with single histology. RESULTS: There were 33 adenosquamous carcinomas, 19 combined SCLC+LCNEC/NNEC, two other neuroendocrine tumors/NNEC and five biphasic tumors (three carcinosarcomas and two blastomas). Among adenosquamous carcinomas, high cell grading (G2 or G3), advanced stage (IIIa or higher) and intratumoral perineural invasion were significantly more evident than in the single histology population. Among combined neuroendocrine/NNEC, high cell grading (G3) and intratumoral vascular invasion were significantly more evident than in the single histology population. Among biphasic tumors, all were at early stages and showed high cell grading (G3). Three-year survival rates were 46% in the single histology group, 28% in the adenosquamous group and 21% in the combined SCLC + LCNEC/NNEC. The difference among the three groups was significant (P = 0.013). Median survival of biphasic tumors was 19 months (range 8-37). CONCLUSIONS: Lung tumors with mixed histologic pattern are rare tumors. Adenosquamous carcinoma and combined SCLC + LCNEC/NNEC present a more aggressive clinico-pathologic behaviour and reduced survival as compared to the single histology population of resected lung tumors.

The significance of intraoperative pleural effusion during surgery for bronchogenic carcinoma.

OBJECTIVES: To analyze patients submitted to thoracotomy for lung carcinoma presenting with an intraoperative pleural effusion (PE). METHODS: From 1993 to 1999, 1279 patients received thoracotomy with curative intent for primary lung carcinoma. Intraoperatively, 52 patients (4%) presented a PE >100ml which was not diagnosed preoperatively. Of these, seven patients had received preoperative transthoracic fine-needle biopsy FNB and were excluded from the analysis. In the remaining 45 patients pleural fluid cytology was undertaken. In patients with cytology-negative PE, clinico-pathologic characteristics including intratumoral vascular invasion, intratumoral perineural invasion, peritumoral lymphocytic infiltrate, visceral, parietal and mediastinal pleural involvement, pTNM and survival were analyzed and compared with our total population of lung cancer patients operated on during the same period. RESULTS: The mean amount of collected fluid was 210ml (100-450ml). Of the 45 patients with intraoperative PE, 16 (35%) received exploratory thoracotomy because of pleural carcinosis or major involvement of mediastinal structures; eight (18%) received resection of the tumor, although the cytologic examination of the pleural fluid eventually resulted positive for neoplastic cells. Median survival for the two groups was 6 and 9 months, respectively. Twenty-one patients (47%) received resection of the tumor with a cytology-negative pleural fluid. In this group, analysis of clinico-pathologic characteristics revealed that squamous cell type and mediastinal pleural involvement were significantly associated with the presence of intraoperative PE (P=0.01 and P=0.05, respectively); 3- and 5-year survivals of this group were similar to those observed in our total population of resected lung cancer patients (68 and 56% vs. 54 and 42%, P=0.27). CONCLUSIONS: The presence of a PE at thoracotomy during surgery for lung carcinoma is an infrequent occurrence. In more than 50% of the cases cytology is positive and prognosis is poor. In the remaining cases, however, cytology is negative and the PE should be considered as reactive; in these patients a curative resection can be accomplished with an anticipated chance of long-term survival.

Stage I non-small cell lung carcinoma: really an early stage?

OBJECTIVE: We review our results on surgical treatment of patients with stage I non-small cell lung carcinoma and we attempted to clarify the prognostic significance of some surgical--pathologic variables. METHODS: From 1993 to 1999, 667 patients received curative lung resection and complete hilar and mediastinal lymphadenectomy for non-small cell lung cancer. Of these, there were 436 Stage I disease (65%), of whom 144 T1N0 and 292 T2N0. No patients had pre- or postoperative radio- or chemotherapy. Prognostic significance of the following independent variables was tested using univariate (log-rank) and multivariate (Cox proportional-hazards) analysis: type of resection (sublobar vs lobectomy vs pneumonectomy), histology (squamous cell vs adenocarcinoma), tumour size (3cm), histologic vascular invasion, visceral pleura involvement, positive bronchial resection margin, general T status. RESULTS: Overall 5-year survival was 63%. In both univariate and multivariate survival analysis, significant prognostic factors were histology (adenocarcinoma 65% vs squamous cell carcinoma 51%), tumour size (3cm 46%), and the presence of negative resection margin. Five-year survival by general T status was 66% in T1N0 vs 55% in T2N0 disease (P=0.19). CONCLUSIONS: Despite advances in early diagnosis and surgical technique, 5-year survival of stage I non-small cell lung carcinoma remains low as compared to survival of other solid organ neoplasm. Tumour size