Prognostic value of the expression of p53, bcl-2, and bax oncoproteins, and neovascularization in patients with radically resected non-small-cell lung cancer.

PURPOSE: To assess the prognostic value of p53, bcl-2, bax, and neovascularization in radically resected non-small-cell lung cancer (NSCLC) patients. PATIENTS AND METHODS: Tumors from 116 patients were assessed by immunohistochemistry for expression of p53 (DO7 and PAb1081), bcl-2, and the quantification of microvessel density (CD-31). In addition, the expression of bax was assessed in 61 stage I tumors. The median levels of expression of each marker were used as cutoff points. RESULTS: p53 was not correlated to any patient or tumor characteristic, whereas bcl-2 showed higher expression in squamous cell carcinomas (P < .001). bax expression was significantly related with male sex (P = .006) and adenocarcinoma type (P = .0013). p53 status, assessed with one monoclonal antibody (MoAb), was not predictive for survival; however, the combination of staining results obtained with two MoAbs identified the DO7-/PAb1801+ tumors as those with the worst prognosis. bcl-2 expression was associated with longer survival in stage I patients (P = .0169). The combined group expressing p53+(PAb1801)/bcl-2- had the worst survival in stage I patients (P = .034) and in the whole series in comparison with the other combinations of the two oncoproteins. bax expression alone had no influence on survival of stage I patients, but patients with bax+/bcl-2- tumors had the worst prognosis (P = .02 in comparison with bax+/bcl-2+). Tumor neovascularization was not related with other factors, and patients with CD-31+ tumors had a shorter survival duration than those with CD-31- tumors only in stage II (P = .0283). By multivariate analysis including all patients, the presence of p53+/ bcl-2- tumor expression and large tumor diameter (> or = 4cm) were independent prognostic factors for shorter survival duration. For stage I, only the presence of bax+/ bcl-2- tumor expression had a significant negative influence on survival. CONCLUSION: The interaction and the regulation of new biologic markers, such as those involved in the apoptotic pathway, are complex. Combinations of the expression of several of them may give more valuable information than the study of just one. Prognostic influence of p53 staining varied depending on the choice of antibody and the combination of bcl-2- together with p53+ (PAb1801) or with bax+ had the worst influence on survival for patients with stage I NSCLC.

The influence of fixation delay on mitotic activity and flow cytometric cell cycle variables.

Proliferation variables such as mitotic activity and the percentage of S-phase cells have been shown to be of prognostic value in many tumors, especially in breast cancer. However, some studies reported a decrease in mitotic activity caused by delay in fixation of the tissue. In contrast, other studies showed that the identifiability of mitotic figures decreases after fixation delay, but the total number of mitotic figures and also the percentage of S-phase cells remain unchanged. Most studies have been done on small numbers of experimental tumors, thus introducing the risk of selection bias. The aim of this study was to reinvestigate the influence of fixation delay on mitotic activity and cell cycle variables assessed by flow cytometry in an adequate number of resected human tissues to reach firmer conclusions. Resection specimens of 19 and 21 cases, respectively, for the mitotic activity estimate and the flow cytometric percentage of S-phase calculation were collected directly from the operating theater using lung, breast, and intestinal cancers and normal intestinal mucosa. The tissues were cut in pieces, and from each specimen, pieces were fixed in 4% buffered formaldehyde (for mitosis counting) as well as snap frozen (for flow cytometry) immediately after excision, as well as after a fixation delay of 1, 2, 4, 6, 8, 18, and 24 hours. Moreover, during the fixation delay, one series from each specimen was kept in the refrigerator and the second at room temperature. Thus, a total of 304 (19 X 16) and 336 (21 X 16) specimens were investigated for the mitotic activity estimate and the percentage of S-phase cells calculation, respectively. With regard to the estimation of the mitotic activity, both clear and doubtful mitotic figures were registered separately, obtaining an "uncorrected" and "corrected" (for doubtful mitotic figures) mitotic activity estimate. The percentage of S-phase cells was obtained by cell cycle analysis of flow cytometric DNA-histograms. The results showed that the quality of the material decreased during the fixation delay, as reflected by poorer cellular morphology in the hematoxylin-and-eosin-stained slides, resulting in more difficult identification of mitotic figures and a more time-consuming procedure with regard to the mitosis counts, but not in a worse intraobserver and interobserver reproducibility, which was acceptable. The reduction in quality of the tissues also was shown by the flow cytometric measurements because the coefficient of variation and percentage of debris increased after 4 hours or more of fixation delay. However, the mean values of the "uncorrected" mitotic activity and the "corrected" mitotic activity showed no decreasing trend; neither did the average percentage of S-phase cells. In conclusion, within the time investigated, fixation delay has no clear influence on the proliferation features studied. Because of the decreasing quality of the histological sections, resulting in more difficult identification of mitoses and interpretation of DNA histograms, fixation delay should be kept as short as possible, keeping the tissue at 4 degrees C until fixation.

Bronchoscopic treatment of intraluminal typical carcinoid: a pilot study.

OBJECTIVE: The curative potential of various bronchoscopic treatments such as Nd:YAG laser, photodynamic therapy, and brachytherapy for the treatment of intraluminal tumor has been reported previously. Bronchoscopic treatment can be used to treat small intraluminal tumor with curative intent, such as in patients with roentgenologically occult squamous cell cancer. In a retrospective study, we showed that bronchoscopic treatment provided excellent local control with surgical proof of cure in 6 of 11 patients with intraluminal typical bronchial carcinoid. METHODS: In a prospective study, 19 patients (8 women and 11 men) with resectable intraluminal typical bronchial carcinoid have undergone bronchoscopic treatment under general anesthesia. Median age was 44 years (range, 20-74 years). If tumor persisted after 2 bronchoscopic treatment sessions, surgery was performed within 4 months after the treatment. RESULTS: Bronchoscopic treatment was able to completely eradicate tumor in 14 of the 19 patients (complete response rate 73%, 95% CI: 49%-91%). Median follow-up of these patients is 29 months (range, 8-62 months). One patient had severe cicatricial stenosis after bronchoscopic treatment, and sleeve lobectomy was necessary. No residual carcinoid was found in the resected specimen. In the remaining 5 patients, bronchoscopic treatment did not result in a complete response and radical surgical resection was performed afterward with confirmation of residual carcinoid in the resected specimen. Median follow-up of the surgical group is 34 months (range, 12-62 months). CONCLUSIONS: Current data suggest that bronchoscopic treatment may be an effective alternative to surgical resection in a subgroup of patients with resectable intraluminal typical bronchial carcinoid. It alleviated the necessity of surgical resection in 68% (95% CI: 43%-87%) of the patients.

Autofluorescence bronchoscopy improves staging of radiographically occult lung cancer and has an impact on therapeutic strategy.

BACKGROUND: The ability of conventional CT scans and fiberoptic bronchoscopy to localize and properly stage radiographically occult lung cancer (ROLC) in the major airways is limited. High-resolution CT (HRCT) scanning and autofluorescence bronchoscopy (AFB) may improve the assessment of ROLC before the most appropriate therapy can be considered. PATIENTS AND METHODS: We prospectively studied 23 patients with ROLC, who were referred for intraluminal bronchoscopic treatment (IBT) with curative intent. Additional staging with HRCT and AFB was performed prior to treatment. Twenty patients were men, 9 patients had first primary cancers, and 14 patients had second primary cancers or synchronous cancers. RESULTS: HRCT scanning showed that 19 patients (83%) had no visible tumor or enlarged lymph nodes. With AFB, only 6 of the 19 patients (32%) proved to have tumors < or = 1 cm(2) with visible distal margins. They were treated with IBT. In the remaining 13 patients, abnormal fluorescence indicated more extensive tumor infiltration than could be seen with conventional bronchoscopy alone. Six patients underwent radical surgery for stage T1-2N0 (n = 5) and stage T2N1 (n = 1) tumors. Specimens showed that tumors were indeed more invasive than initially expected. The remaining seven patients technically did not have operable conditions, so they were treated with external irradiation (n = 4) and IBT (n = 3). The range for the time of follow-up for all patients has been 4 to 58 months (median, 40 months). The follow-up data underscore the correlation between accurate tumor staging and survival. CONCLUSIONS: Our data showed that 70% of patients presenting with ROLC had a more advanced cancer than that initially diagnosed, which precludes IBT with curative intent. Additional staging with HRCT and AFB enabled better classification of true occult cancers. Our approach enabled the choice of the most appropriate therapy for each individual patient with ROLC.

Clonally related but phenotypically divergent human cancer cell lines derived from a single follicular thyroid cancer recurrence (TT2609).

Starting from different regional samples taken from a heterogeneous follicular thyroid cancer recurrence in a male patient, a series of cell cultures was initiated. Three stable cancer cell lines were successfully established (TT2609-A02, TT2609-B02, and TT2609-C02) and kept in continuous culture for more than 3 years. The lines are each characterized by a unique set of biological parameters such as morphology, ploidy state, cell proliferation rate, ultrastructure, thyroid marker expression, p53 expression, karyogram, agar clonogenic capacity and tumorigenicity as xenografts in nude mice. These characterization studies point to a marked heterogeneity at the level of the clinical tumor recurrence. Karyotype analysis of the cell lines showed a pattern of aberrations indicating that the lines are clonally related and that the A02 and C02 lines are subsequently derived from the more "original" tumor cell type B02 after a tetraploidization event. It is concluded that the obtained cell lines represent an in vitro/in vivo model for human follicular thyroid cancer. The availability of a series of cell lines for human follicular thyroid cancer, mimicking the biological heterogeneity observed in patient tumors, enables both detailed fundamental investigation of thyroid cancer cell biology and the experimental exploration of new treatment approaches.

Positron emission tomography for the detection of metastases of differentiated thyroid carcinoma.

OBJECTIVE: To show the value of positron emission tomography (PET) with 18-F-fluorodeoxyglucose (18-FDG) for the detection of metastases of differentiated thyroid carcinoma in selected patients. PATIENT HISTORIES: There were four patients, who had undergone total thyroidectomy for papillary (two) or follicular thyroid carcinoma (two). All patients had subsequent treatment with (131)iodine. Three patients had an increasing serum concentration of thyroglobulin, one patient had antibodies against thyroglobulin. A diagnostic (131)iodine scintigraphy was negative in two patients, and uncertain in two patients. Positron emission tomography was performed about 45 min after administration of 10 mCi 18-F-fluorodeoxyglucose. In three patients PET showed uptake in the cervical region, caused by lymph node metastases in two (confirmed by neck dissection) and recurrent tumor on the trachea in one patient (confirmed by surgery). In the fourth patient uptake of 18-FDG was seen in the neck and in both lungs. This led to discontinuation of treatment with (131)iodine because the lung metastases did not accumulate (131)iodine. DISCUSSION: In selected patients with differentiated thyroid carcinoma with an increasing serum concentration of thyroglobulin, PET is an important diagnostic option when scintigraphy with (131)iodine is negative or uncertain. In the four presented case histories, the results of PET led to a therapeutic decision: surgery in three patients and discontinuation of (131)iodine in one patient. The development of guidelines for the use of PET in the diagnosis of recurrent thyroid cancer is discussed.

Emergency resection of an extra-adrenal phaeochromocytoma: wrong or right? A case report and a review of literature.

Phaeochromocytomas are rare neuroendocrine tumours that produce symptoms through excess release of catecholamines. Treatment of choice is elective, complete surgical removal after pretreatment with alpha-adrenergic blocking drugs, to prevent dangerous haemodynamic fluctuations. In rare cases a 'catecholamine crisis' develops presenting with pulmonary oedema and circulatory shock. We report such a case of a patient with familial extra-adrenal phaeochromocytoma who successfully underwent emergency surgery. Pathophysiological mechanisms are discussed. Although pretreatment with alpha-adrenergic blocking drugs seems advisable in terms of morbidity and mortality, the concept is based on theory rather than clinical evidence. Surgical management of a catecholamine crisis is associated with high mortality rates. However, proof of better outcome by avoidance or discontinuation of emergency surgery is not available. Based on literature and on this case, we conclude that emergency surgery in phaeochromocytoma does not have to be structurally avoided and may be considered under life-threatening circumstances.

Failure patterns of combined modality treatment in lung cancer: the impact of staging.

BACKGROUND: Patients with locally advanced non-small cell lung cancer (NSCLC) may be treated with induction chemotherapy (IC) followed by surgery with curative intent. The impact of staging inaccuracies on the failure rate of this intensive combined modality treatment approach, i.e. non-curative chemotherapy and thoracotomy, requires further investigation. METHODS: The records of a cohort of 38 consecutive NSCLC IIIA-N2 patients treated with IC followed by surgery were reviewed. RESULTS: The clinical course strongly suggested that the standard diagnostic algorithm failed to demonstrate stage IV disease in 34% of the cases. Surgery instigated by CT-based response criteria at restaging after chemotherapy proved to be irradical in 70% of cases. CONCLUSION: Our data confirm the limitations of the current work-up of patients with apparently locally advanced NSCLC. This applies to the selection of patients to be assigned to combined modality treatment as well as to the post-chemotherapy assessment of resectability. Improved (re)staging of these patients will enhance the efficiency of intervention trials and prevent patients from being exposed to intensive and toxic therapy from which they derive no benefit.

[Satisfactory results of conservative treatment in traumatic esophageal perforation]. / Goede resultaten van conservatieve behandeling bij traumatische oesofagusperforatie.

OBJECTIVE: Evaluation of diagnosis and management of 18 patients with iatrogenic or traumatic oesophageal perforation. DESIGN: Descriptive retrospective. SETTING: University hospital Vrije Universiteit Amsterdam. PATIENTS AND METHODS: In the period 1981-1991 18 patients received conservative treatment for iatrogenic/traumatic oesophageal perforation. RESULTS: The perforation was located in the cervical part of the oesophagus in 13 cases and in the thoracic part in 5 cases. Various incidents had led to the perforation. For radiological examination X-rays of the thorax or lateral neck were made or an oesophagogram using iodine as the contrast medium. Treatment consisted of antibiotics, a stomach catheter, intravenous nutrition and if necessary suction drainage. Seventeen patients recovered completely, one patient died. CONCLUSION: Conservative treatment of iatrogenic oesophageal perforation consisting of antibiotics, stomach catheter, enteric or parenteral nutrition and if necessary suction drainage gives good results.

[Role of chemo(radio)theray prior to surgery for stage IIIa non-small cell lung carcinoma (localized non-resectable tumor)]. / De plaats van chemo(radio)therapie voorafgaand aan operatie bij niet-kleincellig longcarcinoom in stadium IIIA (lokaal niet-resectabele tumor).

Neoadjuvant chemotherapy with or without combined radiotherapy followed by surgery may yield a survival profit for selected patients with non-small cell lung carcinoma in stage IIIA. It has not yet been established which is the most efficacious neoadjuvant chemotherapy nor what is the best postneoadjuvant chemotherapy, especially resection or radiotherapy. Comparative clinical studies to find the answer to these two questions are in progress. New forms of treatment are required in order to achieve 5-year survival in more stage IIIA patients than is currently the case.

[Thoracoscopic clipping of thoracic duct in a woman with persisting chylothorax]. / Thoracoscopisch clippen van de ductus thoracicus bij een patiënte met persisterende chylothorax.

A 78-year-old female had chest pain, radiating to the back, caused by a thoracic aneurysm of the aorta. A vascular prosthesis was sutured into place through a left-sided thoracotomy. Six days after the operation she developed chylothorax on the right side. Following 14 days of conservative management, chyle leakage persisted at a rate of 1500 ml per 24 hours. By thoracoscopy the thoracic duct was dissected and clipped, which stopped the chyle leakage. The patient recovered moderately well. Conservative measures, such as adjusted nutrition, are successful in 50% of patients. Clipping of the thoracic duct by thoracoscopy is a definitive and minimally invasive procedure to treat persistent chyle leakage.

Fractures of the sternum.

The records of 71 patients treated for sternal fracture were reviewed: 52 patients sustained isolated sternal fracture, 19 patients had a sternal fracture in combination with multiple other injuries, with in 12 patients only rib fractures. Forty-one patients were involved in a car accident, 29 of them used safety belts. Three patients (3/71, 4%) died, two multitrauma patients, in whom artificial ventilation was necessary, died of multiple organ failure. One patient with a sternal fracture and bilateral multiple rib fractures died of cardiac contusion and myocardial infarction. Three patients (3/71, 4%) showed signs of myocardial contusion. The morbidity in the patients with an isolated sternal fracture was very low. The prognosis of an isolated sternal fracture is good. Cardiac contusion was an uncommon complication of sternal fracture. Clinical observation for only a short period is advised.

Refractures of the femoral shaft.

A retrospective analysis of refracture in 148 femoral shaft fractures is presented. Nineteen (13%) refractures occurred, mostly after plate fixation. Based on the outcome of this analysis and on the literature, recommendations are given to prevent refracture of the femoral shaft after primary therapy by a plate-osteosynthesis. If possible external compression should be used in the treatment of femoral fractures. Cancellous bone grafting should be carried out in all fractures with medial cortical bone defects, or if there is devascularization of bone fragments. Furthermore, a delayed cancellous bone graft (8-12 weeks after primary surgery) is advocated in some of these fractures.

Surgical treatment of pathological fractures caused by bone metastases.

A survey of the surgical treatment of 31 patients with metastases in the long bones is presented. Early diagnosis is essential to prevent pathological fractures in patients with a malignancy. Localized bone pain and an abnormal isotope bone scan or X-ray are the most reliable clues to diagnosis. Should a pathological fracture occur, reduction and internal fixation are indicated to keep the patient active and reduce pain. This was performed in 29 of the cases reported here. Fixation prior to fracture was carried out in six patients. The advantage of this strategy is that it reduces both operative risks and duration of hospitalization. Furthermore, it creates a more favourable situation with regard to preoperative diagnostic appraisal and choice of approach to improve the mechanical qualities of the bone involved, thus preserving function and activity.