Do bone marrow isolated tumor cells influence long-term survival of non-small cell lung cancer?

INTRODUCTION: Inconsistent information on the prognostic significance of non-small cell lung cancer (NSCLC) isolated tumor cells (ITC) has been reported to date. We sought to evaluate the survival for NSCLC in a group of patients in which the presence of bone marrow isolated tumor cells and their DNA ploidy was assessed. MATERIALS AND METHODS: Seventy patients (58 males [83%]; median age 70 years, range 49-89) with T1-4, N0, M0 clinical staging entered the study; 68 who underwent complete resection, were included in the follow-up. Two patients with clinical stage T2 and T4, N0, M0 were excluded because of pleural carcinosis discovered at thoracotomy. Recruitment ended in 2002. None received neoadjuvant therapy. The rib bone marrow was extracted and assessed for ITC by hematoxylin and eosin (H&E) staining, immunohistochemistry and flow cytometry. The latter was regarded as positive when >10% of cells reacted to pan-cytokeratin antibody MNF116. DNA ploidy was studied by propidium iodide staining. Patient follow-up was with chest X-ray and abdominal US every 6 months, and CT-PET scan every 12 months for at least 5 years after surgery. Causes of death were assessed. RESULTS: Rib bone marrow ITC were documented in 17 patients (25%), 6 with DNA euploidy (p stage: I 4; III 2), and 11 with DNA aneuploidy (p stage: I 5; II 4; III 2) while 51 (75%) patients were free of ITC (p stage: I 32; II 8; III 9; IV 2). The median follow-up was 61 months, 21 patients died from causes unrelated to NSCLC and 12 patients died from causes related to tumor relapse. Significant survival differences were observed according to stage, presence of ITC and DNA aneuploidy. In particular free from recurrence survival was significantly reduced in stage IA and IB patients presenting aneuploid ITC (Wilcoxon (Gehan) test p=0.031). CONCLUSIONS: The prognostic role of bone marrow ITC seems to be corroborated by DNA ploidy studies. Patients with bone marrow ITC with abnormal DNA content showed a significantly reduced survival particularly in stage I NSCLC.

Long-term results after Heller-Dor operation for oesophageal achalasia.

OBJECTIVE: In the literature, reports on the definitive rate of cure of the surgical treatment of oesophageal achalasia are not numerous. The aim of this study is to assess the clinical-instrumental-based patient's outcome related to long-term follow-up. METHODS: One hundred and seventy-four patients (80 men, median age 57 years, range 7-83) consecutively submitted to first instance transabdominal Heller-Dor in the period 1978-2002 were considered. Follow-up consisted of clinical interview, endoscopy, barium-swallow and oesophageal manometry if required. Twenty-six cases (15%) were sigmoid achalasias. RESULTS: One patient died post-operatively (severe haemorrhage in a patient previously operated upon for a cardiovascular malformation and suffering for portal hypertension), 173 were followed-up (mean 109 months, range 12-288, median 93 months) of whom 68 for more than 15 years. On the whole 151 patients (87.3%) had satisfactory and 22 (12.7%) had poor long-term results. Seven out of 173 patients (4%), 6 of whom were pre-operatively classified as sigmoid achalasia, subsequently underwent oesophagectomy, 3 for epidermoid cancer, 1 for Barrett's adenocarcinoma, 2 for stasis oesophagitis and recurrent sepsis, 1 for severe dysphagia. Fifteen patients (8.7%) had an insufficient result due to reflux oesophagitis which appeared in 2 (one erosion) after 184 and 252 months. All 22 patients, whether surgically or medically retreated, achieved satisfactory control of dysphagia and reflux symptoms. CONCLUSIONS: In the long term, insufficient results strictly related to Heller-Dor failure, always due to reflux oesophagitis, were recorded in 15/173 patients (8.7%) although it is questionable whether reflux oesophagitis appearing after more than 15 years is due to the Dor incompetence or to ageing. In sigmoid achalasia, oesophagectomy rather than myotomy should be taken into consideration in the first instance. In the long-term, surgery is the best definitive treatment for oesophageal achalasia.

[Laparoscopic and left thoracoscopic Collis-Nissen procedure: technique and short term results]. / Intervento di Collis-Nissen per via laparoscopica e toracoscopica sinistra: tecnica e risultati a breve termine.

The aim of this paper is to illustrate a laparoscopic-thoracoscopic technique for the surgical management of foreshortened esophagus in patients affected by severe gastro-esophageal reflux disease. The patient is placed on the operating table with the left chest and arm lifted to perform a thoracostomy in theV-VI space, posterior to the axillary line. The hiatus is opened and the distal esophagus is mobilized. With intraoperative endoscopy the position of the gastroesophageal junction in relationship to the hiatus is determined in order to decide whether to perform a standard procedure for reflux or to lengthen the esophagus. In the second case, short gastric vessels are divided and the gastric fundus is mobilized. An endostapler is introduced into the left chest. The Collis gastroplasty is performed over a 42 Maloney bougie. A floppy Nissen and the hiatoplasty complete the procedure. Twenty-two procedures of laparoscopic-thoracoscopic Collis gastroplasty were performed. The postoperative course was regular in 17 patients and complicated in 5 cases. Two procedures were converted for split of the endosuture caused by an oversized Maloney bougie (52 Ch). Other complications included intrathoracic migration of the fundoplication with need for repeating laparoscopic surgery, an empyema without fistula and atrial fibrillation. In conclusion, this technique corresponds to all principles of anti-reflux surgery and makes it possible to properly treat any anatomical condition.

Transthoracic endosonography for the intraoperative localization of lung nodules.

BACKGROUND: Transthoracic ultrasonography has been advocated for the localization of lung nodules during video-assisted thoracoscopic surgery (VATS) for nonperipheral nodules. METHODS: Video-assisted thoracoscopic surgery for lung nodules was performed in 54 consecutive patients. Preoperative computed tomography (CT) diagnosed 65 lesions. Positron emission tomography (PET) identified 2 lesions not revealed by CT. All nodules were judged whether visible and/or palpable. Diameter and distance of the nodule from the anterior, lateral, and posterior chest wall were measured on CT scan and served in a discriminant analysis to predict which nodule would be neither visible nor palpable. The deflectable multifrequency (7.5 to 10 MHz) endosonography probe was used to identify the nonvisible and nonpalpable nodules. RESULTS: Resected nodules were 69; 67 diagnosed preoperatively, and 2 intraoperatively by ultrasonography. At VATS exploration 16 of 65 (25%) of the CT diagnosed nodules were nonvisible and nonpalpable. The discriminant analysis failed to predict correctly whether nodules would be visible and/or palpable in 33% because of surrounding severe emphysema, proximity to a fissure, or to the hylum. The endosonography identified 15 out of 16 of the nonvisible and nonpalpable nodules, thus conversion to thoracotomy was necessary for one nodule. The combination of video, palpatory, and endosonographic inspections had 98% sensitivity and 100% specificity in localizing the nodules. CONCLUSIONS: Intraoperative transthoracic ultrasonography is useful to guide VATS resection of lung nodules. It is a bedside tool, not requiring planning and coordination with the interventional radiology suite, thus you use it if you need it. It has no related morbidity, and may also have a role in revealing lesions occult at preoperative work-up.

The surgical treatment of the intrathoracic migration of the gastro-oesophageal junction and of short oesophagus in gastro-oesophageal reflux disease.

OBJECTIVES: In the rush to implement laparoscopic surgery for gastro-oesophageal reflux disease (GORD), the necessity to treat a short oesophagus with dedicated techniques was not always adequately considered. The aim of this study was to define the frequency, patterns and surgical treatment of the intrathoracic migration of the g-o junction and short oesophagus in GORD. METHODS: Between 1980 and 2003 our group indicated surgery only for severe and complicated GORD and for drawbacks of medical therapy. Preoperatively patients underwent clinical-instrumental work up. The various degrees of the intrathoracic migration of the g-o junction were classified according to the barium swallow. A total of 319 patients operated upon were grouped according to the periods 1980-1991 and 1992-2003 with 149 and 170 patients, respectively. In the first period only 'open' procedures were performed; the Collis gastroplasty in addition to the antireflux procedure was performed when reduction of the g-o junction in the abdomen required excessive tension. In the second period mini-invasive techniques were progressively introduced. During laparoscopy, the relationship between the g-o junction and the hiatus, and the need to elongate the oesophagus, was assessed by intraoperative oesophagoscopy. RESULTS: The Collis gastroplasty was performed in 29% in the first period and in 23% in the second period. Radiology was a strong predictor of the necessity to elongate the oesophagus. In the second period, global long-term results improved with respect to the first period; P = 0.047 (first period satisfactory 82%, poor 18%, median FU 84, 12-252 months; second period satisfactory 93%, poor 7%, median FU 34, 6-126 months). In the second period, Collis-Nissen and Collis-Belsey procedures had satisfactory results in 80% and poor in 20%. CONCLUSIONS: In surgery for severe GORD, the Collis procedure is required in 23% of operations; radiology helps to plan surgery; intraoperative endoscopy avoids unnecessary oesophageal lengthening.

Recipient intramuscular administration of naked plasmid TGF-beta1 attenuates lung graft reperfusion injury.

BACKGROUND: Gene therapy may be an effective strategy for modulating lung graft ischemia-reperfusion injury. We investigated whether recipient intramuscular (IM) naked plasmid gene transfer of transforming growth factor beta1-active (TGF-beta1-active) ameliorates lung graft ischemia-reperfusion injury. METHODS: Preliminary studies in F344 rats demonstrated that gastrocnemius muscle transfection of TGF-beta1-active produced muscle and plasma protein expression at 24 and 48 hours after transfection. Recipients (n = 8) received IM injection of naked plasmid-encoding chloramphenicol acetyl transferase (CAT), TGF-beta1-latent or TGF-beta1-active, respectively, at 24 or at 48 hours before left lung transplantation. We did not treat the control group before transplantation (18-hour cold ischemia). Donor lungs were flushed with low-potassium dextran-1% glucose and stored for 18 hours at 4 degrees C. All groups were killed at 24 hours after transplantation. Immediately before killing the animals, we clamped the contralateral right hilum and assessed graft function. We measured wet-to-dry ratio (W/D), myeloperoxidase, pro-inflammatory cytokines (interleukin 1 [IL-1], tumor necrosis factor alpha [TNF-alpha], interferon-gamma [INF-gamma], and IL-2) and performed immunohistochemistry. RESULTS: Arterial oxygenation was greatest in the recipient group transfected with TGF-beta1-active at 24 hours before transplantation compared with CAT, TGF-beta1-latent, and 18-hour cold ischemia groups (p < 0.01). The W/D ratio and myeloperoxidase decreased in both 24- and 48-hour groups, with TGF-beta1-active compared with CAT, and 18-hour cold ischemia groups (W/D, p < 0.02 and p < 0.004, respectively; myeloperoxidase, p < 0.05 and p < 0.01, respectively). All pro-inflammatory cytokines decreased in the 24-hour TGF-beta1-active group compared with CAT, TGF-beta1-latent, 18-hour and 1-hour cold ischemia, and non-treated lung groups (IL-1beta, p < 0.03; TNF-alpha, p < 0.02; IFN-gamma, p < 0.001; IL-2, p < 0.0001). In 24- and 48-hour groups with TGF-beta1-active, immunohistochemistry showed marked staining of Type I and Type II alveolar cells and of macrophages from the apical to the caudal sections of the lung grafts. CONCLUSIONS: Recipient IM administration of naked plasmid encoding TGF-beta1-active before transplantation ameliorates lung isograft reperfusion injury after prolonged ischemia.

Hiatus hernia and intrathoracic migration of esophagogastric junction in gastroesophageal reflux disease.

The prevalence and clinical presentation of reducible and irreducible hiatus hernia were investigated within a gastro-esophageal reflux disease patient population. Reflux symptoms and esophagitis data were collected on 791 patients. The barium swallow was used to assess the esophagogastric junction. Clinical and endoscopic findings were tested to predict radiographic findings. The esophagogastric junction was normal in 17% of patients, 53% had a sliding hiatus hernia with a reducible esophagogastric junction; in 23% it was irreducible although axial, and 8% had massive incarcerated hiatus hernia. The presence of reducible sliding hiatus hernia did not influence clinical presentation. Axial irreducibility presented with long-standing severe symptoms and esophagitis in 80% of cases. Clinical and endoscopic findings predicted axial irreducibility in 52% of cases. In conclusion, sliding hiatus hernia with an reducible esophagogastric junction does not influence the severity of gastroesophageal reflux disease. An irreducible esophagogastric junction is associated with long-standing severe gastroesophageal reflux disease. Clinical and endoscopic findings may only be indicative of axial esophagogastric junction irreducibility; thus barium swallow should be part of the work-up.

Pharyngoesophageal manometry with an original balloon sensor probe for the study of oropharyngeal dysphagia.

The goal of our study was to verify the clinical applicability of an original balloon sensor probe for the manofluorographic study of oropharyngeal dysphagia. A prototype apparatus for manofluorography was developed and a standard perfused probe for esophageal manometry was modified by applying fluid-filled floppy balloons 0.5-, 1-, and 2.5-cm long. A group of healthy volunteers and a group of patients affected by oropharyngeal dysphagia underwent manofluorography. Statistically significant differences were calculated between the groups with regard to the upper esophageal sphincter (UES) basal and postrelaxation contraction pressures (p<0.05, Student's t test, 2.5- vs. 1-cm-long balloon sensors). In the group of patients versus the group of healthy volunteers, statistically significant differences were calculated with regard to pharyngeal intrabolus pressure, UES residual and UES postrelaxation contraction pressures, and mean diameter of the UES during maximal opening (p<0.05, Student's t test). A strong negative correlation (r=-0.92, p=0.001; r=-0.93, p=0.006 linear regression analysis) was observed between intrabolus pressure and UES diameter during maximum opening in the group of patients. The balloon probe demonstrated its reliability and clinical adequacy for the study of swallowing disorders.

Balloon sensors for the manometric recording of the pharyngoesophageal tract: an experimental study.

The goal of our study was to investigate manometric balloon sensors of original conception in order to overcome the limitations of perfused and solid-state sensors in the assessment of the pharyngoesophageal motility abnormalities. A standard perfused probe for esophageal manometry was modified by applying fluid-filled floppy balloons 0.5-, 1-, and 2.5-cm long. The balloon sensor probe was tested at the bench with regard to the response to the applied pressures, the frequency-response curve, and the behavior during propagation of the peristaltic waves in an esophageal model. The physical properties of the balloon sensors proved to be adequate for pharyngoesophageal motility studies. The static response of the balloon probe to the applied pressures was linear. For the frequency-response curve, the upper cutoff frequency (A=1/square root of 2) was 23 Hz, resonance frequency was 16 Hz, and resonance amplification was 1.6. No statistically significant differences were observed between balloon sensors of different length with regard to amplitude and duration of recorded peristaltic waves (p>0.05). In conclusion, the balloon probe has the physical and technical characteristics required for the study of swallowing disorders.

Recipient intramuscular cotransfection of naked plasmid transforming growth factor beta1 and interleukin 10 ameliorates lung graft ischemia-reperfusion injury.

OBJECTIVE: Multiple gene transfer might permit modulation of concurrent biochemical pathways involved in lung graft ischemia-reperfusion injury. In this study we analyzed whether recipient intramuscular naked plasmid cotransfection of transforming growth factor beta(1) and interleukin 10 would result in amelioration of lung graft ischemia-reperfusion injury. METHODS: Forty-eight hours before transplantation, 6 groups (n = 6) of F344 rats received intramuscular injection of naked plasmid encoding chloramphenicol acetyltransferase, chloramphenicol acetyltransferase plus beta-galactosidase, transforming growth factor beta(1), interleukin 10, or transforming growth factor beta(1) plus interleukin 10 or were not treated. Donor lungs were flushed and stored for 18 hours at 4 degrees C before transplantation. Twenty-four hours later, grafts were assessed immediately before the animals were killed. Arterial oxygenation, wet/dry ratio, myeloperoxidase, and proinflammatory cytokines (interleukin 1, tumor necrosis factor alpha, interferon gamma, and interleukin 2) were measured, and immunohistochemistry was performed. RESULTS: For lung graft function, the arterial oxygenation was considerably higher in the cotransfected group receiving transforming growth factor beta(1) plus interleukin 10 compared with that in all other groups (P < or =.03). The wet/dry ratio, reflecting lung edema, was reduced in the cotransfected group compared with that in control animals (nontreated, P <.02; chloramphenicol acetyltransferase, P <.03; chloramphenicol acetyltransferase plus beta-galactosidase, P <.01). Myeloperoxidase, which measures neutrophil sequestration, was also reduced with cotransfection compared with that seen in control animals (P < or =.03). All proinflammatory cytokines were decreased in the cotransfected group compared with those in all other groups (interleukin 1beta, P <.04; tumor necrosis factor alpha, P <.002; interferon gamma, P <.0001; interleukin 2, P <.03). These results indicate that cotransfection provides a synergistic benefit in graft function versus either cytokine alone, neutrophil sequestration, or inflammatory cytokine expression. Immunohistochemistry showed positive staining of transforming growth factor beta(1) plus interleukin 10 in type I and II pneumocytes and localized edema fluid. CONCLUSIONS: Recipient intramuscular naked plasmid cotransfection of transforming growth factor beta(1) and interleukin 10 provides a synergistic effect in ameliorating lung reperfusion injury after prolonged ischemia.

Radiological examinations in the morpho-functional evaluation of the esophago-gastric junction in gastro-esophageal reflux disease.

PURPOSE: The aim of our paper is to define, on the basis of a long experience, the anatomical and radiological classification of the progressive phases of the axial intrathoracic migration of the esophago-gastric junction (EGJ), through a standardised radiological method that allows precise identification of the anatomical structures involved. MATERIALS AND METHODS: From 1981 to 2001, 1388 patients with gastro-esophageal reflux disease (GERD) were examined by traditional contrast techniques that consisted in taking single contrast radiograms of the patients in different positions after administering a small high-density bolus of barium: with the patient standing up in frontal position, at rest, during forced inspiration, and during straining; standing up in a right front 30 degrees oblique position; and in prone position, in a right posterior 30 degrees oblique projection. On the basis of previous radiological and manometric studies aimed at verifying the diagnostic reliability of the radiological examination [8], the distance of the esophago-gastric junction from the esophageal hiatus was indirectly evaluated in an anterior-posterior projection, according to the criteria introduced by Monges [3]. The sling fibers, which form a radiologically detectable cut at the apex of the angle of His, are the lowest portion of the EGJ. RESULTS: On the basis of the radiological findings, and in agreement with the radiological classifications reported in the literature, we evidenced five groups, with pathologically characteristic signs: - 1(st) group (63%) patients who in orthostatic position have an EGJ regularly placed within the abdomen (16%), and patients with the EGJ regularly placed within the abdomen, but with a small sliding intermittent hiatus hernia (47%); - 2(nd) group (13%) cardial tuberosity malposition; - 3(rd) group (7%) concentric hiatus hernia; - 4(th) group (8%) acquired short esophagus; - 5(th) group (9%) massive incarcerated gastric hiatus hernia. CONCLUSIONS: Traditional radiography, performed with an adequate technique and with the necessary expedients, allows for the correct interpretation of the anatomical disoder called GERD, and is therefore the first diagnostic approach in defining correct patient management.