Postresectional pulmonary oxidative stress in lung cancer patients. The role of one-lung ventilation

Objective: The authors conducted a prospective analysis in order to investigate through lipid peroxidation metabolites the generation of oxygen free radicals after one-lung ventilation (OLV). Methods: From 2001 to 2003, 212 patients were prospectively studied for lung reexpansion/reperfusion injury. They were classified in six groups. Group A, non-OLV lobectomy group; B, OLV pneumonectonny group; C-E, OLV lobectomy of 60, 90, and 120 min duration, respectively; F, normal subjects as baseline group. Preoperative, intraoperative and postoperative strict blood sampling protocol was followed. Malondialdehyde (MDA) plasma levels were measured. The recorded values were analyzed and statistically compared between groups and within each one. Results: Comparison of groups C-E (OLV) to A other documented significant (P < 0.001) increase of MDA levels during lung reexpansion and for the following 12 h. The magnitude of oxidative stress was related to OLV duration (group E > D > C, all P < 0.001). The removal of cancer-associated parenchyma led to MDA level decrease postoperatively (P < 0.001) especially after pneumonectomy (A vs. B, P < 0.001). Conclusions: (1) Lung reexpansion provoked severe oxidative stress. (2) The degree of the amount of generated oxygen free radicals was associated to the duration of OLV. (3) Patients with lung cancer had a higher production of oxygen free radicals than normal population. (4)Tumor resection removes a large oxidative burden from the organism. (5) Mechanical ventilation and surgical trauma are weak free radical generators. (6) Manipulated lung tissue is also a source of oxygen free radicals, not only intraoperatively but also for several hours later. (c) 2005 Elsevier B.V. All rights reserved

A Phase II study of paclitaxel-ifosfamide-cisplatin combination in advanced nonsmall cell lung carcinoma

BACKGROUND. The necessity to develop more effective chemotherapy regimens in advanced nonsmall cell lung carcinoma (NSCLC) prompted the authors to evaluate the paclitaxel-ifosfamide-cisplatin (PIC) combination, developed on the basis of high individual single-agent activity, in vitro synergism, and tolerance as determined in a previous Phase I study by the authors. PATIENTS. Eligibility criteria included advanced NSCLC (American Joint Committee on Cancer [AJCC]/International Union Against Cancer [UICC] Stage III/IV), Eastern Cooperative Oncology Group performance status (PS) less than or equal to 2, no prior chemotherapy, and unimpaired hematopoietic and organ function. Chemotherapy included, paclitaxel 175 (in the first 10 patients) or 200 mg/m(2) on Day 1, ifosfamide: 5 g/m(2) divided over Days 1 and 2, and cisplatin 100 mg/m2 divided over Days 1 and 2, recycled every 21 days. Granulocyte-colony stimulating factor was administered from Day 4 to 13 or until leukocyte count reached greater than or equal to 10,000/mu L. RESULTS, Fifty patients were entered, and all were evaluable for response and toxicity: median age, 58 years (range, 40-72), PS, 1 (range, 0-2), Gender: 44 males and 6 females, Stages ILIA, 6 patients; IIIB, 17; IV, 27; histologies: adenocarcinoma, 27 patients; squamous, 17; large cells, 5; unspecified, 1. Metastatic sites at diagnosis included lymph nodes, 33 patients; bone, 6; liver, 5; brain, 10; lung nodules, 7; adrenals, 6; other, 2. Thirty-two of 50 (64%; confidence interval, 50.7-77.3%) evaluable patients responded: 4 complete remissions, 28 partial remissions, 13 stable disease, and 5 progressive disease. The quality-of-life score improved in 37 of 50 (74%) patients. The median response duration was 7 months (range 2-34+); median time-to-progression, 8 months (range, 1-36+), median overall survival, 12 months (range, 2-36+). One-par survival was 53%. Grade 3 and 4 toxicities included neutropenia 38 of 50 patients with 21 developing Grade 4 neutropenia (less than or equal to 5 days) and 7 of these febrile neutropenia (144b); thrombocytopenia, 4 of 50 patients with 1 Grade 4 requiring platelet transfusions, 1 Grade 3 neuropathy; Grade 1-2 central nervous system toxicity due to ifosfamide was seen in 22 patients, no renal toxicity, 15 Grade 2 myalgias, 17 Grade 2 diarrhea, and 10 Grade 3 vomiting. CONCLUSIONS. The PIC combination appears highly active and tolerable in advanced NSCLC administered in the outpatient setting, Future randomized comparisons to other current standard regimens in NSCLC will be warranted. (C) 2000 American Cancer Society

A phase I-II study of docetaxel-ifosfamide-cisplatin (DIP) combination chemotherapy regimen in advanced nonsmall cell lung cancer

In an attempt to develop more effective chemotherapy regimens in advanced nonsmall cell lung cancer (NSCLC), we evaluated docetaxel-ifosfamide-cisplatin (DIP) based on our previous experience with paclitaxel-ifosfamide-cisplatin. Patients with advanced NSCLC (stages III-IV), WHO-PSless than or equal to2, no prior chemotherapy and unimpaired hematopoietic and organ function were eligible. Chemotherapy was administered in successive dose levels (DLs) and included docetaxel (80100 rng/m(2) day 1), ifosfamide (4-5 g/m(2)) and cisplatin (80100 mg/m(2)), both divided over days I and 2 every 21 days. G-CSF (lenograstin) was administered from days 4-13. Fifty-five patients were accrued (phase 1: IS; phase II: 40) and all are evaluable for response and toxicity: median age = 58 (40-72); PS = 1 (0-2); gender = 48 males, 7 females; stages IIIA = 8, 11113 = 19, IV = 28; and histologies were adenocarcinoma (29), squamous (20), large cell (6). Metastatic sites at diagnosis included lymph nodes (33), bone (8), liver (6) brain (6), lung nodules (9), adrenals (7) and soft tissue (1). The dose-limiting toxicity (DLT) was reached at DL4 (Docetaxel: 100 mg/m(2)-Ifosfamide: 5 g/m(2)-Cisplatin: 100 mg/m(2)) consisting of 2 cases of febrile neutropenia (FN), and DL3 (Docetaxel: 100 mg/m(2)-Ifosfamide: S g/m(2)-Cisplatin: 80 mg/m2) was considered as the maximum tolerated dose (MTD) and recommended for further phase 11 testing. Among evaluable patients in phase 11, 31146 (67%; Cl = 54-81%) responded; 4 were complete responses, 27 partial responses, 12 with stable disease and 3 with progressive disease. The median response duration was 7 months (2-21 +), median time to progression (TTP) 8 months (1-23 +) and median overall survival (OS) 13 months (2-23 +). The 1-year survival was 57%. Grade (Gr) 314 toxicities included neutropenia 39146 with 27 developing Gr4 ( less than or equal to7 days) and 20% FN managed successfully with broad-spectrum antibiotics, thrombacytopenia Gr3 3/46-Gr4 1/46, no Gr3 neuropathy, Gr1-2 CNS toxicity in 12, no renal toxicity, IS Gr2 myalgias, 17 Gr2 diarrhea and 10 Gr3 vomiting. In the present phase I-II study, DIP appears highly active and tolerable in advanced NSCLC in the outpatient setting. Randomized comparisons to current standard 2-drug regimens will be warranted. (C) 2002 Wiley-Liss, Inc

Lung tumor MHCII immunity depends on in situ antigen presentation by fibroblasts

A key unknown of the functional space in tumor immunity is whether CD4 T cells depend on intratumoral MHCII cancer antigen recognition. MHCII-expressing, antigen-presenting cancer-associated fibroblasts (apCAFs) have been found in breast and pancreatic tumors and are considered to be immunosuppressive. This analysis shows that antigen-presenting fibroblasts are frequent in human lung non-small cell carcinomas, where they seem to actively promote rather than suppress MHCII immunity. Lung apCAFs directly activated the TCRs of effector CD4 T cells and at the same time produced C1q, which acted on T cell C1qbp to rescue them from apoptosis. Fibroblast-specific MHCII or C1q deletion impaired CD4 T cell immunity and accelerated tumor growth, while inducing C1qbp in adoptively transferred CD4 T cells expanded their numbers and reduced tumors. Collectively, we have characterized in the lungs a subset of antigen-presenting fibroblasts with tumor-suppressive properties and propose that cancer immunotherapies might be strongly dependent on in situ MHCII antigen presentation. © 2022 Kerdidani et al