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Iron is tightly connected to oxygen homeostasis and erythropoiesis. Our aim was to better understand how hypoxia regulates iron acquisition for erythropoiesis in humans, a topic relevant to common hypoxia-related disorders. Forty-seven healthy volunteers participated in the HIGHCARE project. Blood samples were collected at sea level and after acute and chronic exposure to high altitude (3400-5400 m above sea level). We investigated the modifications in hematocrit, serum iron indices, erythropoietin, markers of erythropoietic activity, interleukin-6, and serum hepcidin. Hepcidin decreased within 40 hours after acute hypoxia exposure (P < .05) at 3400 m, reaching the lowest level at 5400 m (80% reduction). Erythropoietin significantly increased (P < .001) within 16 hours after hypoxia exposure followed by a marked erythropoietic response supported by the increased iron supply. Growth differentiation factor-15 progressively increased during the study period. Serum ferritin showed a very rapid decrease, suggesting the existence of hypoxia-dependent mechanism(s) regulating storage iron mobilization. The strong correlation between serum ferritin and hepcidin at each point during the study indicates that iron itself or the kinetics of iron use in response to hypoxia may signal hepcidin down-regulation. The combined and significant changes in other variables probably contribute to the suppression of hepcidin in this setting.

Background: The patient population derived from lung cancer screening programs with low-dose spiral computed tomography (LDCT) is different from the general population accessing thoracic surgical services., Methods: Retrospective review of all surgical cases in the DANTE trial, a randomized study of lung cancer screening with LDCT. Patient characteristics, workup, procedures, resections for benign disease, complications, tumor features, and final outcomes have been analyzed in the LDCT and in the control arm., Results: In the LDCT arm, 77 suspicious lesions were surgically managed in 72 patients. A benign lesion was diagnosed in 17 cases (22%). Major video-assisted thoracoscopic surgery resection was carried out in five lung cancer cases (7%) and segmentectomy in 11 (19%). Complete resection was achieved in 93%, and stage I rate was 73%. Two patients had a local recurrence after open lobectomy, and three had a resectable new primary. In the control group, 28 patients underwent 31 surgical procedures, in five cases (16%) for benign lesions. No major video-assisted thoracoscopic surgery resections were carried out. Resectability rate was 88%, and stage I rate was 52%. Five patients had a local recurrence and two had a second primary., Conclusions: Surgery for benign lesions is a relevant issue in screening-derived patients. Local control may be achieved by minimally invasive techniques or segmentectomy; however, developing the necessary skills requires an effort by the surgical team. Long-term survivors have a noticeable chance of developing second primary cancers or resectable recurrences and may benefit from a second resection.

The rise in didanosine concentrations in plasma when given with tenofovir raises concern for a high risk of toxic effects. Recommendations to reduce didanosine dose have been issued, but only for adults weighing more than 60 kg. We reviewed cases of pancreatitis in patients receiving didanosine plus tenofovir, didanosine alone, and tenofovir alone to assess the incidence of and risk factors for pancreatitis. Between Aug 1, 2001, and Nov 30, 2003, five of 185 (2.7%) patients receiving didanosine plus tenofovir, one of 182 (0.5%) on didanosine without tenofovir, and none of 208 on tenofovir without didanosine developed pancreatitis (p=0.016). Co-administration of both drugs versus each of them individually was an independent risk factor for pancreatitis (crude hazard ratio 10.666, 95% CI 1.246-91.294, p=0.031). These results suggest that the risk of pancreatitis is heightened when didanosine and tenofovir are given together.

Background: Gefitinib (Iressa(TM), ZD1839) is an orally active, selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor. Phase I studies showed that it is well tolerated, with evidence of tumor regression in patients with advanced non-small-cell lung cancer (NSCLC). Therefore, we aimed to assess the antitumor activity and tolerability of gefitinib in a series of patients with previously treated, advanced NSCLC, as a part of a compassionate use program., Patients and Methods: To be eligible, all patients were required to have histologically or cytologically proven advanced or metastatic NSCLC, prior chemotherapy with at least one cisplatin-containing chemotherapy regimen or contraindication to cytotoxic drugs, Eastern Cooperative Oncology Group performance status < or =2, and adequate hematological, renal and hepatic parameters. All patients provided signed informed consent. Patient re-evaluation was performed every 4-6 weeks., Results: Seventy-three consecutive patients were enrolled. Response rate, including complete and partial response, was 9.6%; an additional 43.8% of patients achieved stable disease, for an overall disease control of 53.4%. EGFR1 status was evaluated by immunocytochemistry in 25 patients. According to EGFR1 immunoreactivity all responses were observed with medium/strong imunoreactivity while three out of four responses were observed in high expressive patients. Median survival for all patients was 4 months while it reached 6 months for patients with disease control. The 1-year survival rate was 13.1% for the entire series and 23.2% for patients with disease control. Non-hematological toxicity was generally mild., Conclusion: Gefitinib has promising activity with a good toxicity profile in patients with progressive NSCLC who have received one or two prior chemotherapy regimens. A possible relationship within response and EGFR1 expression is suggested.

A pedicled flap obtained by mobilizing the right lobe of the thymus was used to protect bronchial sutures in 29 consecutive patients undergoing a right pneumonectomy and in 4 additional patients. Fourteen patients had received preoperative chemotherapy with or without radiotherapy. The flap procedure was, in general, easy to do, required an average time of 20.4 minutes, and did not cause added operative morbidity. Postoperative magnetic resonance imaging, performed in 21 of the 29 patients who had pneumonectomy, showed a viable flap in every instance. One bronchopleural fistula occurred in a pneumonectomy patient after induction chemotherapy plus radiotherapy in a patient in the pneumonectomy group in whom adult respiratory distress syndrome developed postoperatively and who required prolonged mechanical ventilation.

Background: The cisplatin and gemcitabine (GC) regimen is usually administered as a 4- or 3-week schedule; however, the best schedule to use is still unclear. We therefore started a randomized phase II trial to compare toxicity and dose intensity (DI) between these two GC schedules., Patients and Methods: Ninety-six patients with non-small-cell lung cancer (NSCLC) and an additional 11 patients with an advanced epithelial neoplasm [bladder (n = 5), head and neck (n = 3), cervix (n = 1), esophageal (n = 1) or unknown primary carcinoma (n = 1)] were randomized to receive cisplatin 70 mg/m(2) intravenously on day 2 plus either gemcitabine 1000 mg/m(2) on days 1, 8 and 15 of a 28-day cycle or gemcitabine 1000 mg/m(2) on days 1 and 8 of a 21-day cycle. Planned DI (PDI) for the 4-week schedule was 750 mg/m(2)/week for gemcitabine and 17.5 mg/m(2)/week for cisplatin; for the 3-week regimen PDI was 666 mg/m(2)/week and 23 mg/m(2)/week for gemcitabine and cisplatin, respectively., Results: From July 1998 to March 2000, 107 patients were randomized. Grade 3/4 neutropenia was observed in 27.8% of patients in the 3-week versus 22.5% in the 4-week arm (P = 0.69), while grade 3/4 thrombocytopenia was higher in the 4-week arm (29.5% versus 5.5% of patients; P = 0.14). A total of 398 cycles of therapy were delivered. Overall, 51% of cycles were modified in dose, timing or both in the 4-week arm, and 19% in the 3-week arm. The 21-day schedule of GC leads to a similar received DI of gemcitabine and higher cisplatin DI. Both regimens had activity in NSCLC, with a response rate of 39% (38% for the 4-week arm, and 42% for the 3-week arm)., Conclusions: The 3-week schedule has similar DI to the 4-week schedule. However the 3-week regimen has a better compliance profile and a comparable response rate in NSCLC, supporting the use of such a schedule.

Background: One regimen consisting of a continuous infusion of cisplatin and fluorouracil was designed to be minimally toxic, and suitable for application with radiotherapy in non-small-cell lung carcinoma (NSCLC)., Patients and Methods: Forty-four NSCLC patients received daily 8 mg/m2 of cisplatin on days 1-2, 8-9, 15-16, 22-23, and 300 mg/m2 of fluorouracil on days 3-7, 10-14, 17-21, 24-28 (35-day courses)., Results: Two patients experienced grade 3-4 toxicities. Eleven achieved objective responses. The median progression-free and observed survival was 22 and 39.5 weeks., Conclusions: The schedule management was fully ambulatory. Toxicity was negligible. The activity was moderate, but the combination with radiotherapy is advisable due to the radioenhancing properties of both of the drugs.

The overall results of salvage surgery for lung metastases were evaluated on 174 consecutive patients with primary osteosarcoma below the age of 20, resected in Milan between 1970 and 1988. Seventy-two children treated in the years 1970-1981 were compared with 102 children treated in the years 1982-1988. In the latter period, adjuvant chemotherapy was replaced by neo-adjuvant programs and salvage surgery was applied systematically to all patients with resectable lung metastases through median sternotomy. During the last period, the overall 5 year survival improved significantly from 35% to 58% (P less than 0.001), while the disease free survival rose from 38% to 45% (median 15 vs. 33 months, P = 0.3). The proportion of patients with completely resected lung metastases rose from 17% (7/42) to 55% (27/49), without operative mortality, and the overall survival from detection of lung metastases (including unresected cases) improved from 0 to 28% at 5 years (P less than 0.001). The survival benefit was observed only in the group of children with resected metastases. These data indicate that systematic bilateral pulmonary resection, combined with neoadjuvant chemotherapy, has contributed to improve the final cure rate of childhood osteosarcoma.

Between 24 November 1977 and 16 September 1988, 18 consecutive chest wall resections for recurrent breast cancer after failure of radiotherapy, were evaluated as of 1 January 1990. Chest wall involvement was the only site of recurrence in 14 patients (Group I), and the most painful of the multiple recurrences in the remaining four (Group II). Of Group I, chest wall recurrence was local in eight patients (four with necrosis after radiotherapy), regional in four, and distant in two. Chest wall reconstruction was effected by contralateral breast flap in six, by random cutaneous flap in seven and by myocutaneous flap in the remaining five. Cosmetic results were better if both marlex mesh and myocutaneous flap were used. Of Group I, at surgical/pathological staging, one recurrence with sarcomatous findings, two multiple recurrences and residual cancer in all necrosed local recurrences were found: in three of these cases radionecrosis was prominent. Mortality was 0% and surgical morbidity 5%. For Group I, median disease-free interval from mastectomy was extended from 1611 days to 3220 by recurrence resection, and disease-free interval from chest wall resection was 28% cancer-free at 1657 days, without any difference between the local vs regional-distant recurrence. Correlation factor between first and second disease interval was 0.99 and R2 was 0.98. For Group II, survival was 0% at 635 days. Chest wall resection must be considered as an important part of palliative treatment in breast cancer, but the results reflects the biology of the disease more than the chest wall surgery.

Among lung tumors, well-differentiated neuroendocrine carcinomas are often misdiagnosed or may go unrecognized. Nineteen cases of well-differentiated neuroendocrine carcinoma (WDNC) were assessed at the National Cancer Institute of Milan over a ten-year period. There was only one woman and the age range was 50 to 77 years. Most of the patients were smokers (83 percent). All tumors were radically resected. There were 12 lobectomies, two sleeve-lobectomies, three bilobectomies, one pneumonectomy, and two segmentectomies (one patient had two synchronous WDNCs). There was neither operative mortality nor major complications. Sixteen tumors were stage 1, three were stage II, and one was stage IIIa. Five patients had adjuvant chemotherapy (cyclophosphamide, doxorubicin, and vincristine [CAV] regimen). One patient was given local or regional radiotherapy. In ten patients the tumors recurred, even though four had had adjuvant treatment. The brain was the first site of metastasis in seven cases. The pathologic stage seemed not to be closely related to the appearance of metastases (six patients with stage I disease had recurrences). Only two patients with recurrence were still alive 12 and 103 months after the procedure. The percentage of survival for patients with stage I disease after more than 100 months was 68 percent. WDNC is similar to small-cell lung carcinoma (SCLC) with regard to the neurotropism of metastases. Surgery is curative for more than one half of the patients with localized disease. Therefore, multimodal therapy, probably based on tumor behavior and investigations of tumor markers, is advisable.

We have reviewed our experience of limited resections for Stage I lung cancer for the years 1971-88. Sixty-one cases of sublobar resection (wedge or segmental) were compared with 411 lobar resections (lobectomies or bilobectomies), performed over the same period. Operative mortality was 0% in the limited resection group and 3% (12/411) in the control group. Cancer recurrence was detected respectively in 36% and 38% of patients, and actuarial survival at 5 years was 55% versus 49% overall. Sublobar resection had a slightly better outcome than lobar resection in pathological T1 (5-year survival of 73% vs 55%) but a worse outcome in pT2 (35% vs 46%); however, none of the differences was statistically significant. In 28 patients with pre-existing cardiac or pulmonary co-morbidity, limited resection yielded the same 5-year survival as lobectomy (53% vs 51%) with no peri-operative deaths (0 vs 5%). Although derived from a retrospective analysis, these data offer a further confirmation that limited resection combined with adequate nodal staging is a reliable and effective technique for early stage lung cancer management.

A retrospective evaluation of 199 consecutive patients undergoing resection for lung cancer revealed a significantly shorter long-term survival for those in whom empyema developed postoperatively. The overall five-year survival for the empyema group was 24% compared with 35% in the control group (patients without empyema), and the median survival was 15 months for the control group. These differences in survival were not found among patients with Stage I lung cancer. Pneumonectomy proved to be the main risk factor for the occurrence of empyema after operation, but a minor risk factor was the anatomical extent of disease. this correlation may be explained by major surgical contamination or manipulation as well as by lower immunological host reaction, all related to the extent of the tumor. A lower immunological defense could also explain the worse outcome for patients with Stage II or III lung cancer in whom empyema developed postoperatively.

The presence of cellular retinoic acid binding protein (cRABP) was analyzed in 13 consecutive patients with large bowel cancer (one right colon and 12 rectum-sigmoid, classified as three Duke B, eight C, and two D). Specimens of neoplastic tissue and of adjacent mucosa were obtained at surgery, and cRABP was determined by an assay based on incubation of partially purified cytosol with labeled retinoic acid and ultracentrifugation in sucrose density gradients. Sixty-one percent of tumors contained detectable levels of cRABP, whereas 58.3% of normal mucosal specimens were positive for cRABP. Among the positive tumors 62.5% contained cRABP also in the corresponding mucosa; in the group of cRABP-negative tumors, 40% showed cRABP in the adjacent mucosa. No correlation could be established with the grading or the stage of the tumors; however, interestingly, 100% (three cases) of gelatinous carcinomas were cRABP positive. Since cRABP seems to be a character of neoplastic cells contrary to normal ones, it would be interesting to investigate the conditions that influence the presence of this protein in normal appearing mucosa adjacent to carcinoma.