Biomedical subjects

G B Ratto

Publications and source records attributed to G B Ratto.

At least 19 recordsLinked to original sources

PubMed2000

Phase II study of combined immunotherapy, chemotherapy, and radiotherapy in the postoperative treatment of advanced non-small-cell lung cancer.

The association of adoptive immunotherapy (AI) and radiotherapy has been shown to be effective in the control of residual intrathoracic disease, while having no systemic advantages, in patients operated on for locally advanced non-small-cell lung cancer (NSCLC). The potential synergy of coupling immunotherapy and chemotherapy has been emphasized in several tumors including NSCLC. The aim of this work was to determine the feasibility and activity of a combined therapeutic program, including AI, chemotherapy, and radiotherapy in patients who had undergone incomplete resections for NSCLC. In a phase II trial, 13 patients received the combined treatment. AI was given from week 4 after surgery until week 8. Concurrent chemo-(cisplatin and etoposide)-radiotherapy (60 Gy) was given from week 9 to week 14. Twenty eligible patients received chemoradiotherapy only and were used as a non-randomized concomitant group for merely descriptive purposes. At 9-month follow-up, 10 of the 13 patients had progression of disease and the study was stopped. Progression-free survival and survival were similar to those of the chemoradiotherapy group. The present study showed that the sequence of immunotherapy followed by chemotherapy is not effective as adjuvant treatment in patients operated on for stage III NSCLC, at least when used according to the adopted schedule.

Adult↗

PubMed1999

Cytotoxic properties of CD4(+) T-cell clones which lyse HLA class II negative autologous non-small-cell lung cancer cells.

In this report, a subset of CD4(+) cells which kills autologous HLA class I positive and HLA class II negative non-small-cell lung cancer (NSCLC) cells is described. Killing was performed both by direct cytolytic mechanisms and by apoptosis. The peculiar characteristic of these effectors was their capability of lysing only interferon (IFN)-gamma-treated NSCLC target cells, expressing high numbers of HLA class I molecules. Analysis at the clonal level confirmed that cytolytic capability was distributed clonotypically. The addition of anti-HLA class I monoclonal IgM abrogated the susceptibility to lysis. Notably, the CD4-mediated cytolytic effect on IFN-gamma-treated targets was incomplete. Thus cytofluorimetric DNA and HLA class I expression analyses of target cells were performed: "resistant" targets consisted of large, aneuploid cells expressing a low number of HLA class I molecules. These findings suggested a direct role of HLA class I expression in the recognition of autologous cancer cells mediated by cytolytic CD4(+) cells.

Aged↗

PubMed1999

Pleural space perfusion with cisplatin in the multimodality treatment of malignant mesothelioma: a feasibility and pharmacokinetic study.

INTRODUCTION: Malignant pleural mesothelioma is an ideal model for testing new locoregional multimodality approaches because of its aggressive local behavior. METHODS: This study was planned to investigate the feasibility, safety, and pharmacokinetics of a multimodality therapy including an operation, pleural space perfusion (60 minutes) with cisplatin (100 mg/m2), hyperthermia (41. 5 degrees C), and postoperative radiotherapy (55 Gy to chest wall incisions). The effects of the extent of resection and perfusion temperature on cisplatin pharmacokinetics were evaluated. Ten patients with epithelial or mixed, stage I or II, malignant pleural mesothelioma underwent the following procedures: group A (3 patients), pleurectomy/decortication and normothermic pleural space antineoplastic perfusion; group B (3 patients), pleurectomy/decortication and hyperthermic perfusion; and group C (4 patients), pleuropneumonectomy and hyperthermic perfusion. Operations were selectively applied depending on tumor extent. Platinum levels were serially measured by atomic absorption in systemic blood, perfusate, lung, and endothoracic fascia. RESULTS: The overall procedure was completed in every case, without any death or toxicity. No lung damage was demonstrated after treatment. Major complications included 1 wound infection and 1 diaphragmatic prosthesis displacement. The mean peak platinum plasma levels were reached within 45 to 60 minutes after perfusion was started. Systemic drug concentrations were greater after pleurectomy/decortication than after pleuropneumonectomy (P =.006). The local tissue/perfusate ratio of platinum concentrations tended to be higher after hyperthermic perfusion rather than normothermic perfusion. CONCLUSION: This multimodality approach is feasible, pharmacokinetically advantageous, and safe enough to undergo further clinical investigations.

Adult↗

PubMed1999

Induction chemotherapy followed by concurrent standard radiotherapy and daily low-dose cisplatin in locally advanced non-small-cell lung cancer.

Both induction chemotherapy and concurrent low-dose cisplatin have been shown to improve results of thoracic irradiation in the treatment of locally advanced non-small-cell lung cancer (NSCLC). This phase II study was designed to investigate activity and feasibility of a novel chemoradiation regimen consisting of induction chemotherapy followed by standard radiotherapy and concurrent daily low-dose cisplatin. Previously untreated patients with histologically/cytologically proven unresectable stage IIIA/B NSCLC were eligible. Induction chemotherapy consisted of vinblastine 5 mg m(-2) intravenously (i.v.) on days 1, 8, 15, 22 and 29, and cisplatin 100 mg m(-2) i.v. on days 1 and 22 followed by continuous radiotherapy (60 Gy in 30 fractions) given concurrently with daily cisplatin at a dose of 5 mg m(-2) i.v. Thirty-two patients were enrolled. Major toxicity during induction chemotherapy was haematological: grade III-IV leukopenia was observed in 31% and grade II anaemia in 16% of the patients. The most common severe toxicity during concurrent chemoradiation consisted of grade III leukopenia (21% of the patients); grade III oesophagitis occurred in only two patients and pulmonary toxicity in one patient who died of this complication. Eighteen of 32 patients (56%, 95% CI 38-73%) had a major response (11 partial response, seven complete response). With a median follow-up of 38.4 months, the median survival was 12.5 months and the actuarial survival rates at 1, 2 and 3 years were 52%, 26% and 19% respectively. The median event-free survival was 8.3 months with a probability of 40%, 23% and 20% at 1, 2 and 3 years respectively. Induction chemotherapy followed by concurrent daily low-dose cisplatin and thoracic irradiation, in patients with locally advanced NSCLC, is active and feasible with minimal non-haematological toxicity. Long-term survival results are promising and appear to be similar to those of more toxic chemoradiation regimens, warranting further testing of this novel chemoradiation strategy.

Aged↗

PubMed1998

Limiting dilution analysis of peripheral blood lymphocytes reacting with non-small-cell lung cancer: functionally heterogeneous effectors efficiently lyse autologous cancer cells.

It has recently been shown that the infusion of tumor infiltrating lymphocytes (TIL) and recombinant interleukin-2 (rIL-2) in patients operated on for advanced non-small-cell lung cancer (NSCLC), has significant effects in terms of the survival time and control of local relapses. Despite the evident clinical effects, the treatment is unavailable for patients in which TIL have lost their proliferative potential. In an attempt to identify new sources of effector cells using mixed lymphocyte/tumor cultures (MLTC), populations of peripheral blood (PB) lymphoid cells, which have the capability of lysing autologous NSCLC, were studied at the clonal level. Specific cytolytic lymphocytes were detected at very low frequencies in two out of four patients, whereas non-MHC restricted cytolytic T cells were frequently detected. Cytolytic CD4+ belonged to the Th0 or Th2 subsets and were characterized by cytokine secretion patterns suggestive of a lymphokine cascade that could be involved in cancer control. The identification of different efficient effector mechanisms at the clonal level strongly supports the use of in vitro activated lymphocytes, derived from PB, in protocols of adoptive immunotherapy in patients with advanced NSCLC in which TIL are unavailable.

Aged↗

PubMed1996

A randomized trial of adoptive immunotherapy with tumor-infiltrating lymphocytes and interleukin-2 versus standard therapy in the postoperative treatment of resected nonsmall cell lung carcinoma.

BACKGROUND: A previous pilot study from our group suggested that: (1) adoptive immunotherapy (A1) with tumor-infiltrating lymphocytes (TIL) and recombinant interleukin-2 (rIL-2) may be applied with safety to more than 80% of the patients who had surgery for Stage III nonsmall cell lung carcinoma (NSCLC); and (2) AI could be useful in patients with locally advanced disease. The present randomized study was planned to assess the efficacy of AI in the postoperative treatment of Stage II, IIIa, or IIIb NSCLC: METHODS: TIL were expanded in vitro from tissue samples obtained from the surgically removed specimens of 131 patients. Eighteen cultures yielded no growth of TIL. The remaining 113 patients were stratified according to disease stage and randomized to receive AI or standard chemoradiotherapy. TIL were infused intravenously 6 to 8 weeks after surgery, rIL-2 was administered subcutaneously at escalating doses for 2 weeks, and then at reduced doses for 2 weeks and then for 2 to 3 months. RESULTS: Three-year survival was significantly better (P < 0.05) for patients who underwent AI than for controls. AI was of no benefit to patients with Stage II NSCLC, potentially useful to patients with Stage IIIa NSCLC (P = 0.06), and significantly advantageous to patients with Stage IIIb (T4) NSCLC (P < 0.01). For patients with Stage III NSCLC, local relapse (but not distant relapse) was significantly reduced following AI (P < 0.05). CONCLUSIONS: AI should be considered when designing future adjuvant therapy protocols for the treatment of NSCLC:

Antineoplastic Agents↗

PubMed1996

CT-guided needle localization of lung nodules for thoracoscopic resection.

We used CT to guide positioning of hookwires within 19 lung nodules in order to localize them prior to thoracoscopic surgery. Both Hawkins III and Kopans-type needles with internal hookwires were employed. Nodule diameter ranged between 0.7 and 4 cm (mean 1.7 cm), and depth from the site of entry of the needle into the pleural surface ranged from 0.5 to 8 cm. Needles were advanced using a technique identical to that for CT-guided biopsy, and localization proved successful in 18 of 19 cases. During surgery, dislodgement of the guidewire occurred in 5 cases, probably due to traction manoeuvers on it. In all these cases the hook of the wire had been opened within the nodule. No dislodgement occurred in patients in whom the needle had been advanced beyond the nodule and the hook allowed to open in the pulmonary parenchyma deep to it. Severe complications did not occur: there was moderate pleuritic pain in 16 cases and asymptomatic pneumothorax in 13 patients. Computer-tomography-guided needle localization of lung nodules is a safe and relatively easy procedure that allows thoracoscopic surgery of lesions which otherwise might be impossible to locate and resect.

Adult↗

PubMed1996

Isolated lung perfusion with platinum in the treatment of pulmonary metastases from soft tissue sarcomas.

A multimodality approach including operation and isolated lung perfusion with platinum was used in six patients with lung metastases from soft tissue sarcomas. Staged thoracotomies were used in two patients with bilateral lesions. The inclusion criteria generally applied for surgical excision were adopted in this study. The pulmonary artery and a portion of the left atrium were isolated from systemic circulation and cannulated. The cannulas were then connected to a perfusion circuit and normothermic isolated lung perfusion was done for 60 minutes. The lung was then flushed and metastasectomy was done. Serial blood (systemic and pulmonary), tissue (normal lung and tumor), and urine samples were obtained for platinum content measurement by flameless atomic absorption spectroscopy. Lung damage was assessed by light and electron microscopy examination and by serial respiratory tests. Isolated lung perfusion was accomplished in all patients without any death, operative complication, or systemic toxicity. After operation, interstitial and alveolar edema developed in two patients (48 hours after treatment), necessitating respiratory support in one case. Total platinum concentrations in pulmonary plasma were about 43 times greater than those in systemic plasma. No differences in platinum concentrations between normal lung and metastatic tissue were found. Thus the proposed isolated lung perfusion technique is feasible and safe enough to be offered as a valid model to study combined chemosurgical approaches in the treatment of lung metastases.

Adult↗

PubMed1996

Treatment of stage IIIB non-small-cell lung cancer with surgery followed by infusion of tumor infiltrating lymphocytes and recombinant interleukin-2: a pilot study.

Stage IIIb non-small-cell lung cancer (NSCLC) has a poor prognosis. The median survival is approximately 6 months, and only 30% of patients are alive 1 year after diagnosis. The need for effective treatment is evident. The aim of this study was to evaluate whether the infusion of tumor-infiltrating lymphocytes (TILs), isolated from resected tumor, expanded in vitro and injected together with recombinant Interleukin-2, is feasible and may at least partially modify the poor prognosis in these patients. The infusion of TILs, derived from surgically resected NSCLC and expanded in vitro, together with subcutaneous (s.c.) injections of recombinant interleukin-2 (rIL-2) was attempted in a group of 11 patients. Treated patients were infused i.v. with in vitro expanded TILs (from 4 to 70 x 10(9) cells), and rIL-2 was injected s.c. at doses varying from 61 to 378 x 10(6) IU. Toxic side effects (fever and, in some cases, hypotension) were observed and limited the dose of rIL-2 infused. Follow-up was continued for 40 months. The mean survival time was 13.8 months. Three of five TIL-treated patients with residual disease have no evident disease after 1 year, and two of them are still alive and have no evidence of disease after 40 months. This pilot study suggests that the infusion of in vitro expanded TILs, derived from surgical samples, is feasible and seems to prolong overall survival and to control the residual disease in patients with advanced NSCLC.

Aged↗

PubMed1995

Detection of oligoclonal T lymphocytes in lymph nodes draining from advanced non-small-cell lung cancer.

Despite the combined use of surgery and chemoradiotherapy, the poor prognosis of advanced non-small-cell lung cancer (NSCLC) requires the definition of new therapeutic approaches. The presence of T lymphocytes, with peculiar phenotypic, functional and molecular characteristics within the tumour, suggested the possible use of these cells, expanded in vitro, in protocols of adoptive immunotherapy. We have described how a population of oligoclonal T lymphocytes, derived from advanced NSCLC, can be expanded in vitro and has the capability of lysing autologous cancer cells. What is more important, we observed that patients with advanced NSCLC, treated with TIL expanded in vitro and recombinant interleukin-2, seemed to have a disease-free period longer than that of patients treated with conventional chemoradiotherapy. In an attempt to find new sources of specific lymphocytes for immunotherapy, we describe the analysis of the phenotypic, functional and molecular characteristics of T lymphocytes, derived from lymph nodes draining advanced NSCLC. In this paper we show that these cells, have restriction patterns of T cell receptor beta chain similar to those detectable in the population of infiltrating T lymphocytes. This finding suggests that T cells derived from draining lymph nodes of advanced NSCLC have peculiar characteristics and can be a suitable source of effector cells for protocols of adoptive immunotherapy in lung cancer treatment.

Aged↗

PubMed1995

Immunotherapy with the use of tumor-infiltrating lymphocytes and interleukin-2 as adjuvant treatment in stage III non-small-cell lung cancer. A pilot study.

This study assesses the feasibility and toxicity of adoptive immunotherapy with tumor infiltrating lymphocytes and recombinant interleukin-2 in 29 patients who underwent resection for stage III non-small-cell lung cancer. In five patients cultures yielded no growth of tumor infiltrating lymphocytes. In the remaining 24 patients (stage IIIa, 14 cases; stage IIIb, 10 cases) tumor infiltrating lymphocytes were in vitro expanded from surgically obtained tissue samples, including samples from both the tumor and surrounding lung. A number of tumor infiltrating lymphocytes, ranging from 4 to 70 billion cells, were reinfused intravenously 4 to 6 weeks after operation. Interleukin-2 was administered subcutaneously at escalating does for 2 weeks and then at reduced doses for 2 to 3 months. Median survival was 14 months, and the 2-year survival was 40%. Three patients remain alive and disease-free at more than 2 years after operation. Two of these patients did not have complete resection at thoracotomy. Multivariate analysis showed no correlation between the factor of incomplete resection and survival. Intrathoracic recurrence without concomitant distant failure was documented in two patients only and none of the patients with incomplete resection (12 cases) had relapse within the thorax. The present experience demonstrates that adoptive immunotherapy may be applied with safety in patients operated on for stage III non-small-cell lung cancer and suggests that it can be useful, notably in patients with locally advanced disease.

Carcinoma, Non-Small-Cell Lung↗

PubMed1994

Long-term antimicrobial prophylaxis in lung cancer surgery: correlation between microbiological findings and empyema development.

This study was planned in order to determine the value of antimicrobial prophylaxis in preventing post-operative empyema in patients undergoing lung cancer surgery. Two-hundred consecutive subjects operated upon for lung cancer received teicoplanin and aztreonam, starting at the induction of anesthesia and lasting until removal of the pleural drains. Cultures for aerobic and anaerobic bacteria were taken from: (1) the bronchus at the time of surgical division; (2) the pleural space before closure of the chest; (3) the pleural fluid during the post-operative period; and (4) the tips of chest drains at the time of their removal. In the 200 patients receiving antibiotic prophylaxis, the number of post-operative empyemas (1%) was lower than that (7.5%) found in 53 comparable patients who were previously treated with placebo. In the 'placebo group', empyema was due to gram-positive bacteria, while in the 'prophylaxis group', it was caused by Gram-negative bacteria (Pseudomonas aeruginosa). A significant (P < 0.05) correlation between infected bronchial secretions, pleural space contamination at surgery, contamination of chest fluid and drains during the post-operative period, and empyema development was demonstrated. In conclusion, antibiotic prophylaxis, while being effective in preventing post-operative empyema, may induce the colonization of the respiratory tract with highly resistant gram-negative bacteria.

Aged↗

PubMed1993

In situ lung perfusion with cisplatin. An experimental study.

BACKGROUND: This research work was planned to evaluate the soundness of in situ lung perfusion as a regional administration modality of chemotherapeutic agents. METHODS: Sixteen pigs were randomly divided into four groups and received cisplatin (2.5 mg/kg) through the pulmonary artery using one of the following techniques: stop-flow (Group 1); stop-flow/out-flow occlusion (Group 2); lung perfusion (Group 3); or lung perfusion with 5 mg/kg of infused drug (Group 4). Serial blood (carotid, pulmonary artery and vein) and tissue samples (lung and mediastinal node), were taken before, at completion of, and 5, 10, 15, 30, 60, 120, 180 and 240 minutes after cisplatin infusion for blood gas and platinum content measurement. Blood circulation was restored to the treated organ (for 60 minutes). The animals were killed, and specimens from lung, thyroid, esophagus, heart, liver, spleen, adrenal glands, kidney, bone marrow, stomach, ileum, colon, psoas muscle, and skin were obtained. Platinum concentrations in plasma, plasma ultrafiltrate (free platinum) urine, and tissues were determined by flameless atomic absorption spectroscopy. Lung damage was evaluated by light and electron microscopic examination. RESULTS: Greater systemic plasma, lower pulmonary plasma, and tissue platinum levels were detected when cisplatin was given using the stop-flow technique with respect to the other administration modalities. No significant difference in regional and systemic platinum exposure was found between Groups 2 and 3. However, lung perfusion resulted in higher mediastinal node and lower bone marrow platinum values. Morphologic alterations and impairment of gas exchanges in the treated lung were not dependent on the applied infusion technique. CONCLUSION: This study provides the pharmacokinetic rationale for the application of lung perfusion to patients with pulmonary metastases.

Animals↗

PubMed1993

Multiple tumour markers for diagnosis, management and follow-up of potentially resectable lung cancer.

The present prospective study has been carried out to evaluate the role of tumour markers in the preoperative assessment and follow-up of patients with potentially resectable lung cancer. The carcinoembryonic antigen (CEA), neuron specific enolase (NSE), and tissue polypeptide antigen (TPA) have been preoperatively measured in 133 lung cancer patients and in 75 healthy smokers. The same tumour markers have been serially determined during the 12 to 30 month-follow-up of 53 subjects who had a complete resection. In screening for localized lung cancer, TPA determination was the single most accurate diagnostic test. The combined measurement of several tumour markers did not result in a greater diagnostic accuracy of the assay. In predicting lung cancer unresectability, CEA, though being the most suitable test, allowed preoperative detection of only one third of patients with unremovable tumours. In monitoring the postresectional course of subjects who had a complete resection, the combined measurement of TPA and NSE proved to be a very reliable predictor of disease recurrence.

Adenocarcinoma↗

PubMed1991

Chest wall involvement by lung cancer: computed tomographic detection and results of operation.

The aim of this prospective study was to evaluate: (1) the role of computed tomographic scanning in predicting chest wall invasion by peripheral lung cancer and (2) the results of operation according to the depth of chest wall involvement and other potential indicators of long-term survival. One hundred twelve patients with non-small cell lung cancer adjacent to the pleural surface who underwent computed tomographic scanning and subsequent thoracotomy were entered into this study. Tumor invasion was confined to the visceral pleura in 53 patients, to the parietal pleura in 18 patients, and to intercostal muscles in 25 patients; invasion extended beyond this layer in 16 patients. The computed tomographic criteria for chest wall invasion were (1) obliteration of the extrapleural fat plane, (2) the length of the tumor-pleura contact, (3) the ratio between the tumor-pleura contact and the tumor diameter, (4) the angle of the tumor with the pleura, (5) a mass involving the chest wall, and (6) rib destruction. The computed tomographic criteria 1 and 3 were significantly related to pathologic findings. Sensitivity was 85% for criterion 1 and 83% for criterion 3, specificity being 87% and 80%, respectively. Long-term survival of patients with T3 disease critically depended on the lymph node state and completeness of resection. The adenocarcinoma cell type and the T4 category were unfavorable prognostic factors. The depth of chest wall invasion did not affect survival, except for extensive rib and soft tissue infiltration. En bloc resection yielded better results than discontinuous resection.

Adenocarcinoma↗

PubMed1991

Comparative evaluation of acid- and bile-induced damage to pedicled jejunal or colonic segments in the rat.

The choice of the esophageal substitute after surgical resection for peptic stricture lies between the colon and jejunum. The current study was designed to compare long-term resistance of the colonic and jejunal mucosa to gastric or mixed duodenogastric secretions. The following preparations were performed in Wistar rats: transposition of a colonic or jejunal patch (a) to the gastric body, with or without truncal vagotomy, or (b) to the gastric antrum and proximal duodenum, with or without truncal vagotomy. Jejunal and colonic patches were removed 4, 8, and 12 months after surgery. The only damage to the transposed mucosae was the alteration of microvilli. The alteration was more severe in colonic than in jejunal patches and was prevented by truncal vagotomy. Long-term resistance of the transposed mucosae to the environmental challenge may depend on their adaptation potentiality, involving both specific and nonspecific mechanisms. Nonspecific mechanisms include the increased production of mucus and the gastric-like transformation of the superficial epithelial layer. Specific mechanisms include the reduction of the mucosal surface size for jejunal segments and the shifting in mucin secretion patterns for colonic segments.

Animals↗

PubMed1991

Pyloric antrum gastrin cell hyperplasia after jejunum or colon transposition: effects of jejunal or colonic mucosa on G cells.

Jejunal or colonic segments are currently used as esophageal substitutes after resection of intractable peptic stenoses. The present study was carried out in order to investigate the effects of the jejunal or colonic mucosa on antral gastrin (G) cells. Colonic or jejunal patches with intact vascular supply were sutured to the pyloric antrum or the higher portion of the gastric body in 40 rats. Ten further animals were used as controls. Three to 4 months after surgery, the serum gastrin levels were weekly determined in fasted (24 h) and freely fed rats using radioimmunoassay. The pyloric antrum was then removed, and the G cell density was assessed with an immunoperoxidase method. Transposal of the colonic mucosa to the antrum increased G cell density and basal serum gastrin levels, while grafting of the jejunal mucosa did not. G cell proliferation proved to be dependent on the topographic location of the colonic patch with respect to the pyloric antrum. Serum gastrin values in freely fed rats tended to be greater in the colon-to-antrum transposition group than in the other experimental groups, but the difference was not significant. In conclusion, variations between the properties of the jejunal and colonic mucosa would include their uneven effects on antral G cells.

Animals↗

PubMed1991

Glutaraldehyde-tanned mandril-grown grafts as venous substitutes.

The present study was performed to evaluate the potential of glutaraldehyde-tanned mandril-grown grafts as caval substitutes. Short-term experiments consisted of 30 tubular grafts (35 x 8 mm), either of tanned collagen or polytetrafluoroethylene, that were sutured in the infrarenal inferior vena cava of pigs and removed 1 hour after implantation. There was no significant difference between the extent of the thrombus-lined graft surface in the biologic group and that in the polytetrafluoroethylene group. The amount of inner thrombus on tanned collagen grafts was significantly correlated to platelet activity. Long-term experiments involved 30 similar segments of both materials, which were sutured in the inferior vena cava and harvested 7, 14, 28, 56, and 112 days after operation. The 112-day patency rate of collagen grafts was 67%. The 56-day patency rate of polytetrafluoroethylene grafts was 16%. The difference was statistically significant (p less than 0.01). Collagen grafts were lined by a thin neointima (200 micron) in all but two cases. The neointima was completely endothelialized within 4 weeks from implantation. In conclusion, tanned collagen grafts may represent a suitable material for venous replacement.

Analysis of Variance↗