Mitomycin C and etoposide in advanced colorectal carcinoma. A clinical and in vitro experience that focuses the problem of schedule dependence in combination therapy.

BACKGROUND: Aim of this study was to evaluate the activity of a combination regimen of chemotherapy containing mitomycin C (MMC) and etoposide (ETO) in advanced colorectal carcinoma. METHODS: Fourteen pretreated patients received MMC 2 mg/m2 and ETO 60 mg/m2, days 1-5 every 28 days. The clinical study was interrupted since no clinical response was observed in 14 patients following four courses of chemotherapy. An in vitro study was then performed on HTC-8 cell line. The cytotoxic activity of the MMC/ETO combination was tested by sulforhodamine B assay and the type of drug interaction was assessed using the method of Chou and Talalay. Cell cycle perturbations and apoptosis were evaluated by flow cytometry. RESULTS: While MMC and ETO were singularly active, the simultaneous exposure of cells to both drugs and the sequence MMC-->ETO ensued in antagonistic interaction at all levels of killed cell fraction. Conversely, the sequence ETO-->MMC produced a synergistic interaction. CONCLUSIONS: These results suggest that the activity of the MMC/ETO combination is highly schedule-dependent and that the experimental drug associations should be based on a preclinical rationale before clinical trials are designed.

[Surgical treatment of breast cancer in the elderly]. / Trattamento chirurgico del carcinoma della mammella in età avanzata.

AIM: The aim of this study is to evaluate the prognosis and survival of patients aged over 70 years and affected by breast cancer. METHODS: From January 1994 through December 2000, 56 patients with breast cancer aged 70 years or older were submitted to surgical treatment. Associated diseases were present in 24 patients, while no patient showed distant metastases at the time of hospital admission. All patients underwent breast preserving surgery regardless the tumour size and in 31 subjects out of 56, the surgical procedure was performed under local anesthesia. An axillary lymphectomy was associated in 46 patients. According to the TNM staging system, tumours were classified as follows: 10 T1Nx, 18 T1N0, 9 T1N1, 7 T2N0, 10 T2N1 and 2 T3N1. RESULTS: There was no postoperative mortality and in 6 cases an axillary seroma was observed. Radiotherapy and tamoxifen treatment followed surgery in all cases. The median follow-up was 44 months. Nineteen patients (34%) died during the follow-up: 6 patients of cancer progression with a specific cancer-death of 10.7% while 13 patients (23.2%) died because of concurrent diseases. A local relapse (1.8%) was observed in a single patient 2 years after the primary surgical treatment and, at 3 years, 37 patients (66%) are alive and disease-free. Long-term survival was significantly related to the stage of disease at the time of surgery, while our data do not allow any conclusions concerning the impact of axillary dissection on long-term outcome. CONCLUSIONS: In conclusion, results for breast cancer therapy are comparable in old and young patients and therefore strategies and treatment protocols should be similar, breast preserving surgery followed by radiotherapy and ormonal treatment being ''the gold standard''.

The surgeon's decision as a prognostic factor in a pool of patients with colorectal cancer coming from different institutions.

Different pathological and predictive factors are used to stratify patients submitted to radical surgery for colorectal carcinoma. In addition to stage and histotype, the surgeon's technique and decisions also appeared to affect the prognosis. The aim of the present study was to evaluate if the extent of lymphadenectomy was associated with a different long-term outcome in a pool of 117 patients. In particular, in patients classified as Dukes' B, some evidences seem to suggest that the staging procedure depends on a correct surgical lymphadenectomy with a higher risk of understaging colorectal carcinomas when the number of removed nodes is limited. Moreover, the promptness in forwarding patients to the chemotherapist seems to influence the disease-free survival.

[The role of endoscopic surgery in respiratory tract neoplasia]. / Il ruolo della chirurgia endoscopica nelle neoplasie dell'apparato respiratorio.

Laser therapy--either by contact or non-contact method--can be considered the best palliative option for patients affected by airway obstruction due to malignant tumors considered inoperable and/or in emergency because of inadequate ventilation. The Nd-YAG laser is widely used in endoscopy. From 1988 to September 2002 at the Department of Surgery "P Valdoni" of the University of Rome "La Sapienza" 251 clinical cases affected by airway obstruction caused by primary or metastatic malignant tumors are treated; moreover 76 stents were used. The symptomatological improvement and beneficial changes in functional breathing tests, haemogasanalysis and X-ray findings were registered 48-72 hours after each treatment. The results showed an improvement in functional breathing values especially after treatment of the main airways such as trachea and main bronchi. The therapy offered an acceptable quality of life. A fairly good number of patients may also return to radio and/or chemotherapy (if previously interrupted) and sometimes to radical surgery. In terms of costs-effectiveness, the endoscopic treatment is widely competitive.

Activity of ruboxyl, a nitroxyl derivative of daunorubicin, on experimental models of colorectal cancer metastases.

We evaluated the activity of ruboxyl (Rbx), a nitroxyl analogue of daunorubicin (Dauno), in experimental models of hepatic metastases from colorectal carcinoma (CRC) and compared it with its parent compound and with 5-fluorouracil (5FU). In mice treated by intraperitoneal injections Rbx and 5FU proved more effective than Dauno: the Index of Inhibition of Metastases in comparison with controls was 43% for Dauno, 70% for 5FU and 84% for Rbx. In BDIX rats implanted with the syngeneic cell line DHD K12/TRb, both Rbx and 5FU, administered as a continuous intravenous infusion for 7 days, reduced the development of liver metastases from a median of 23.8 +/- 2.16 for controls to 3.2 +/- 1.3 for 5FU and 1.0 +/- 1.4 for Rbx (p < 0.0001 versus controls for both treatments): the comparison of Rbx and 5FU showed a trend in favour of this new anthracycline. Median survival was prolonged from 40.6 +/- 3.4 days in controls to 56.0 +/- 5.8 days with Rbx and 58.0 +/- 4.69 days with 5FU. Considering that in a phase I study Rbx showed only minor and manageable toxic side effect, its activity in the clinical treatment of CRC metastases may deserve further attention.

[Use of endoprosthesis in the treatment of airway pathology]. / L'impiego di endoprotesi nel trattamento delle patologie delle vie aeree.

In patients affected by benign or malignant inoperable airway obstructions, therapeutical options include endoscopic treatment by Nd-YAG laser therapy, tracheobronchial dilatations with rigid or flexible bronchoscope, and inflating balloon dilators. Metal self-expanding or silicone stents allow to obtain stable results. Our experience is based on the use of 14 stents (10 Dumon and 4 Wallstent) in 13 cases of stenosis either due to vegetating malignant tumours not amenable to surgery or benign stenosis. In the following 24-48 hours both subjective and objective changes of the pulmonary function, blood gas analysis and radiologic aspects were observed. The results showed an improvement in the respiratory parameters and a sensible improvement in the quality of life.

[The use of laser through thoracoscopy in the treatment of spontaneous pneumothorax. Presentation of a clinical case]. / L'impiego del laser per via toracoscopica nel trattamento del pneumatorace spontaneo. Presentazione di un caso clinico.

The authors present the case of a patient with right plurirecidive pneumothorax. During the 12 months before the operation the patient suffered from 3 episodes of pneumothorax, treated with the insertion of an intrapleural drainage. Preoperative exams showed the presence of multiple emphysematous blebs with diameter ranging from 0.5 cm to 3 cm. The patient was treated with Nd:YAG laser photocoagulation of the blebs and mechanical abrasion of the parietal pleura through thoracoscopy. The laser photocoagulation of the blebs was performed using the contact technique and a 25 Watt power. After operation a TX of the thorax, using the high resolution technique, showed the presence of residual blebs involving the apex and the mediastinal surface of the inferior lobe of the right lung. After a 12 month follow-up no recidive pneumothorax occurred and the general conditions of the patient were good. The authors state that the laser treatment of spontaneous pneumothorax secondary to bullous emphysema is effective and safe and it is also successful in patients with multiple blebs. As it is often difficult to find and treat all the blebs, it may be useful to perform thoracography during thoracoscopy.

Increased number of cancer cells in bronchial washing fluid detected by combining conventional cytology and high-resolution flow cytometry.

The present study was performed to improve early lung cancer diagnosis in bronchial washing fluid, thereby increasing the diagnostic sensitivity of bronchoscopy by means of high-resolution flow cytometry (FC). We combined dual-parameter DNA/protein FC and conventional cytology in bronchial washing fluid samples from 112 patients with neoplastic and non-neoplastic lung diseases and found 43% of histologically confirmed tumor cases to be cytologically positive; 63% of the tumor samples were aneuploid, 52% of the aneuploid cases were cytologically positive and 48% were negative. In the negative cases, FC was an independent diagnostic factor. In 32% of the cases, FC also failed to detect abnormalities. However, the combination of both techniques increased the sensitivity in detecting neoplastic cells to 73%. Furthermore, simultaneous DNA/protein analysis allowed the recognition of aneuploid cell lines not detectable by single DNA measurement. Identification of aneuploid subpopulations by dual-parameter analysis in cytologically negative one-parameter FC "diploid" samples assumes an important diagnostic value. Dual-parameter DNA/protein FC is a valuable technique that increases the diagnostic yield of bronchoscopy with no risk for the patient and a low additional cost.

[Retroperitoneal sarcomas: recent advances in nosographic framework, diagnosis and integrated surgical treatment]. / I sarcomi retroperitoneali: recenti acquisizioni in tema di inquadramento nosografico, diagnosi e terapia chirurgica integrata.

In this paper the Authors reviewed the recent literature for a more comprehensive and clear vision of the epidemiological and pathological aspects of retroperitoneal sarcomas. The most effective procedures for a an early and accurate diagnosis were identified. Moreover, the different therapeutic choices were taken into account focusing on those provided of the major potential in terms of oncologically valid treatment.

[Treatment via laser of airway obstructions]. / Il trattamento mediante laser delle ostruzioni delle vie aeree.

The Nd-YAG laser is widely used in endoscopy. Laser therapy either by contact or non-contact method, can be considered the best palliative option for patients affected by airway obstruction due to endoluminal malignant tumours. It aims at the improvement of breathing conditions and symptomatology. In patients affected by benign obstructions, it often allows to obtain curative results avoiding the use of traditional surgery. From 1988 to 1993 at the First Department of Surgery of the University of Rome "La Sapienza", 163 treatments out of 111 clinical cases affected by airway obstruction, caused by malignant tumours considered inoperable or relapsed after operation, or by vegetating benign tumours, or granulomas or fibrous diaphragms were performed. The symptomatological improvement and beneficial changes in functional breathing tests, haemogasanalysis, and X-ray findings were registered 24-48 hours after each treatment. The results showed an improvement in functional breathing values especially after treatment of the main airways such as trachea and main bronchi. The therapy offered an acceptable quality of life. A fairly good number of patients may also return to radio and chemotherapy, if previously interrupted.

[Lung transplantation. Progress and perspectives]. / Il trapianto di polmone. Progressi e prospettive.

Techniques and indications for lung transplantation evolved significantly in the past few decades, at present there is a resurgence of interest in single- and double-lung transplantation for end-stage disease. The surgical procedure has been recently simplified and complications at the tracheal anastomosis have been significantly decreased. Many problems, common to organ transplantation, remain to be solved including availability of suitable donor organs, the ability to effectively treat organ rejection and improve the immunosuppressive regimens. The authors report a review of the international literature of the last three years, carrying on a critical analysis with the aim of identifying the problems related to this organ transplantation, progress in the research filed, complications and results.

The importance of heterogeneity and of multiple site sampling in the prospective determination of deoxyribonucleic acid flow cytometry.

Multiple fresh specimens from 59 nonsmall cell carcinomas of the lung, 38 carcinomas of the gastric tract and 55 carcinomas of the colon and rectum were analyzed by deoxyribonucleic acid (DNA) flow cytometry (FC) after radical resection to evaluate tumor ploidy as an independent prognostic factor. The minimum follow-up period was five years (range of five to ten years). Aneuploidy was observed in 98.0 percent of carcinomas of the lung, in 70.9 percent of carcinomas of the colon and rectum and in 63.1 percent of carcinomas of the gastric tract. FC DNA heterogeneity, in terms of different number of DNA stem lines or different DNA indices between core and periphery, or both, was found in 50.0 percent of carcinomas of the lung, 47.0 percent of carcinomas of the colon and rectum and in 34.5 percent of carcinomas of the gastric tract. A diploid pattern was more frequently observed in less advanced stages of the gastrointestinal tract. By univariate analysis (Kaplan-Meier), patients with carcinoma of the lung with hypodiploid or hypertetraploid peaks, or both, and aneuploid gastric tumors had poorer prognosis. These differences were only marginally significant. Cox analysis demonstrated that the single most important prognostic variable for predicting the overall survival rate was the stage of disease. Tumor DNA content can be considered a marker of advanced stages, particularly in tumors of the gastrointestinal tract, but there is no evidence that it is an independent prognostic variable able to predict long term survival in patients who have been radically resected.

Closure of a tracheoesophageal fistula by bronchoscopic application of fibrin glue and decontamination of the oral cavity.

A tracheoesophageal fistula was successfully closed with a fibrin adhesive applied by means of a fiberoptic bronchoscope, instead of by esophagoscopy. To facilitate closure of the fistula, the technique was combined with decontamination of the oral cavity, to avoid bacterial contamination. The procedure is proposed as an alternative to surgery for critically ill patients.

Prognostic significance of flow cytometry in lung cancer. A 5-year study.

Flow cytometrically determined cellular DNA content has been measured on specimens from 101 patients affected by lung cancer (40 epidermoid cell carcinoma, 22 adenocarcinoma, 21 large cell carcinoma, 11 small cell carcinoma, and seven undifferentiated carcinoma), and one by mesothelioma. Ninety-eight of 102 (96%) patients with neoplastic disease evidenced the occurrence of at least one cytometrically aneuploid cell subpopulation. Fifty-five of 102 (54%) cases evidenced the occurrence of multiclonality, that is, the presence of more than one aneuploid stem cell line. However, the incidence of multiclonality in lung carcinoma was statistically different in surgical cases (where multiple site sampling from the primary and lymph nodes was possible) in comparison to the nonsurgical ones (e.g., bronchial washing): 48/77 (62%) and six of 24 (25%), respectively. Therefore, only the 77 surgical patients were used for further analysis. The cases were classified according to the DNA index (DI) in the following way: Group A (tumors with one or more stem lines with DI ranging from 1 to 2) and Group B (tumors with at least one stem line with DI less than 1 or greater than 2). A significant correlation has been found between the cytometric ploidy condition so defined (Groups A and B) and the tumor mass doubling time (DT), Group B being associated with fast growing tumors (DT lower than 90 days). A statistically better 12-month survival rate (5-year maximum follow-up) was observed in Group A (88%) in respect to Group B (47%) and is evident in the patient survival time course. A better prognostic indication can be achieved by stratifying the patients according to both the cytometric ploidy condition and the tumor DT. Flow cytometric data can usefully contribute to the prognostic assessment of lung carcinoma provided that representative cellular material is collected by multiple site sampling.

Role of delayed cutaneous hypersensitivity reaction in classifying patients with bronchial carcinoma.

Cell-mediated immune response was evaluated in 150 patients with histologically confirmed bronchopulmonary carcinoma using bacterial and fungal recall antigens injected intradermally (PPD, candida, trichophyton). In the study group negative skin test reaction was found in 51 of 150 patients (34.0%), whereas in the control population it was found in 5 of 33 cases (15.1%) (p less than 0.05). Histologic cell type and stage of disease were defined for each patient. It was possible to calculate the growth rate of the primary tumor only in 68 of 150 patients, and it was recorded as doubling time. Evaluation of the skin test reaction in each prognostic subgroup showed no statistically significant differences. The only statistically significant differences were found when each prognostic subgroup was compared with the control population according to the frequency of a negative response to the skin test, particularly in stage III M1 (p less than 0.05) and stage III M0 (p less than 0.02). The delayed cutaneous hypersensitivity studied with recall antigen stimulation was mainly correlated with the stage of disease, and it should not be considered as an independent prognostic factor.